C-reactive protein (
CRP) is a protein found in the blood, the levels of which rise in response to
inflammationInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
(an acute-phase protein).
CRP is synthesized by the
liverThe 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-peptideC-peptide is a peptide that is made when proinsulin is split into insulin and C-peptide. They split before proinsulin is released from endocytic vesicles within the pancreas—one C-peptide for each insulin molecule....
or
protein CProtein C is a major physiological anticoagulant. It is a vitamin K-dependent serine protease enzyme that is activated by thrombin into activated protein C . The activated form degrades Factor Va and Factor VIIIa...
.
History and nomenclature
C-reactive protein was originally discovered by Tillett and Francis in 1930 as a substance in the serum of patients with acute
inflammationInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
that reacted with the
C polysaccharide of
pneumococcus. Initially it was thought that CRP might be a pathogenic secretion, as it was elevated in people with a variety of illnesses, including cancer. Discovery of hepatic synthesis and secretion of CRP closed that debate. It is thought to bind to
phosphocholinePhosphocholine 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. Phosphocholine is a molecule found for example in lecithin.It is also used by...
, thus initiating recognition and
phagocytosisPhagocytosis is the cellular process of phagocytes and protists of engulfing solid particles by the cell membrane to form an internal phagosome...
of damaged cells.
Genetics and biochemistry
The
CRP gene is located on the first
chromosomeA chromosome is an organized structure of DNA and protein that is 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...
(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. Proteins with this type of configuration are known as
pentraxinsThe Pentraxins are a family of proteins characterised by calcium dependent ligand binding and a distinctive flattened β-jellyroll structure similar to that of the legume lectins...
. Native CRP is a bit different, as it has 10 subunits making two pentameric discs, with an overall molecular mass of 251060 Da.
CRP is usually quantified with laser
nephelometryNephelometry is a technique used in immunology to determine levels of IgM, IgG, and IgA.It is performed by shining light on a sample, and measuring the amount of light scattered....
. It can give results in 30 minutes with a sensitivity able to detect 0.04 mg/L. Its concentration in healthy human serum is usually lower than 10 mg/L, slightly increasing with
ageingAgeing or aging is the accumulation of changes in an organism or object over time. Ageing in humans refers to a multidimensional process of physical, psychological, and social change. Some dimensions of ageing grow and expand over time, while others decline...
. Higher levels are found in late
pregnantPregnancy is the carrying of one or more offspring, known as a fetus or embryo, inside the uterus of a female. In a pregnancy, there can be multiple gestations, as in the case of twins or triplets. Human pregnancy is the most studied of all mammalian pregnancies. Obstetrics is the surgical field...
women, mild
inflammationInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
and viral infections (10–40 mg/L), active inflammation, bacterial infection (40–200 mg/L), severe bacterial infections and
burnA burn is an injury to the skin caused by heat, cold, electricity, chemicals, or radiation.Burn may also refer to:*Concrete things and phenomena:**Combustion**Burn , type of watercourses so named in Scotland and north-eastern England...
s (>200 mg/L).
Function
CRP is a member of the class of acute-phase reactants as its levels rise dramatically during
inflammatoryInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
processes occurring in the body. This increment is due to a rise in the plasma concentration of IL-6, which is produced predominantly by macrophages as well as adipocytes. CRP binds to phosphocholine on microbes. It is thought to assist in
complementThe complement system is a biochemical cascade that helps clear pathogens from an organism. It is part of the larger immune system that is not adaptable and does not change over the course of an individual's lifetime; as such it belongs to the innate immune system...
binding to foreign and damaged cells and enhances phagocytosis by macrophages, 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 ASerum 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.
Diagnostic use
CRP is used mainly as a marker of inflammation. Apart from
liver failureAcute 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 C-reactive protein values can prove useful in determining disease progress or the effectiveness of treatments.
BloodBlood is a specialized bodily fluid that delivers necessary substances to the body's cells — such as nutrients and oxygen — and transports waste products away from those same cells....
, usually collected in a
serum-separating tubeSerum-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 "red top tubes", referring to the stoppers which are either gold or red-gray...
, is analysed in a
medical laboratoryA 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
ELISAEnzyme-linked immunosorbent assay, also called ELISA, enzyme immunoassay or EIA, is a biochemical technique used mainly in immunology to detect the presence of an antibody or an antigen in a sample. The ELISA has been used as a diagnostic tool in medicine and plant pathology, as well as a quality...
, immunoturbidimetry, rapid
immunodiffusionImmunodiffusion is a diagnostic test which involves diffusion through a substance such as agar.One commonly known form is Ouchterlony double immunodiffusion....
and visual
agglutinationAgglutination is the clumping of particles. The word agglutination comes from the Latin agglutinare, meaning "to glue to."This occurs in biology in three main examples:...
.
Viral infections tend to give a lower CRP level than bacterial infection.
Normal reference ranges for blood tests are less than 5-6 mg/l.
A
high-sensitivity CRP test measures low levels of CRP (see below).
Cardiology diagnostic test
Arterial damage results from
white blood cellMacrophages are white blood cells within tissues, produced by the division of monocytes. Human macrophages are about in diameter...
invasion and
inflammationInflammation is 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 as well as initiate the healing process for the tissue. Inflammation is not a...
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
specificSpecific can mean:* ParticularIn science, specific can denote that a measurement is expressed per unit mass :* Specific heat capacity* Specific energy* Specific impulseor is relative to a standard value:...
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.
Glycosylation
CRP may have sugars—
sialic acidSialic acid is a generic term for the N- or O-substituted derivatives of neuraminic acid, a monosaccharide with a nine-carbon backbone. It is also the name for the most common member of this group, N-acetylneuraminic acid...
,
glucoseGlucose , a monosaccharide also known as - grape sugar, blood sugar, or corn sugar, is a very important carbohydrate in biology. The living cell uses it as a source of energy and metabolic intermediate...
,
galactoseGalactose is a type of sugar which is less sweet than glucose. It is considered a nutritive sweetener because it has food energy. Its name comes from the Ancient Greek word for milk, γάλακτος ....
and
mannoseMannose is a sugar monomer of the aldohexose series of carbohydrates.-Metabolism:Mannose is not well metabolized in humans.Therefore, it does not significantly enter the carbohydrate metabolism when taken orally, and although traces of exogeneously introduced mannose have been detected in all body...
—attached to it (i.e., it gets
glycosylatedGlycosylation is the enzymatic process that links saccharides to produce glycans, attached to proteins, lipids, or other organic molecules. This enzymatic process produces one of the fundamental biopolymers found in cells . Glycosylation is a form of co-translational and post-translational...
.) 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. Different diseases (each of which raises CRP) will add sugars to it in different patterns. The patterns are different across diseases, but similar among patients that had the same disease. A 2003 study looked at patients with lupus, leukemia, tuberculosis, leishmaniasis, Cushing's syndrome, and bone cancer. (Healthy subjects did not have enough CRP to successfully characterize "normal" CRP.)
Previous work had shown that CRP increased the rate at which a
particular parasiteTrypanosomes are a group of kinetoplastid protozoa distinguished by having only a single flagellum. All members are exclusively parasitic, found primarily in insects. A few genera have life-cycles involving a secondary host, which may be a vertebrate or a plant...
could invade blood cells. The study showed that the different CRPs had very different potencies in this regard. The authors speculate that subtyping CRP may give us more insight into heart attack mechanisms. Although this did not demonstrate whether this glycation of CRP was a 'good thing' or a 'bad thing', it offered circumstantial evidence that the differing glycation is part of CRPs mode-of-action.
Role in cardiovascular disease
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes,
hypertensionHypertension is a chronic medical condition in which the blood pressure is elevated. It is also referred to as high blood pressure or shortened to HT, HTN or HPN. The word "hypertension", by itself, normally refers to systemic, arterial hypertension.Hypertension can be classified as either...
and
cardiovascular diseaseCardiovascular disease or cardiovascular diseases is the class of diseases that involve the heart or blood vessels ....
. A study of over 700 nurses showed that those in the highest
quartileIn descriptive statistics, a quartile is any of the three values which divide the sorted data set into four equal parts, so that each part represents one fourth of the sampled population....
of
trans fatTrans fat is the common name for unsaturated fat with trans-isomer fatty acid. Trans fats may be monounsaturated or polyunsaturated but never saturated.Unsaturated fat is a fat molecule, containing one or more double bonds between the carbon atoms...
consumption had blood levels of C-reactive protein that were 73% higher than those in the lowest quartile. Although one group of researchers indicated that CRP may only be 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
necrosisNecrosis is the premature death of cells and living tissue. Necrosis is caused by external factors, 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 and cerebral infarcts; so far, this has been demonstrated only in animal models.
The
JUPITER trialThe 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...
was conducted to determine if patients with elevated
high-sensitivity CRP levels but without hyperlipidemia might benefit from statin therapy. Statins were selected because they have been proven to reduce levels of CRP. The trial found that patients taking
rosuvastatinRosuvastatin is a member of the drug class of statins, used to treat high cholesterol and related conditions, and to prevent cardiovascular disease. Shionogi developed the product and the pharmaceutical company AstraZeneca markets it as Crestor...
with elevated high-sensitivity CRP levels experienced a decrease in the incidence of major cardiovascular events. The trial specifically found, "the number of patients who would need to be treated with rosuvastatin for 2 years to prevent the occurrence of one primary end point is 95, and the number needed to treat for 4 years is 31." In other words, after four years of treatment, out of every 31 patients, one cardiovascular event would be prevented.
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.
CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.
High-sensitivity CRP
To measure the CRP level, a "high-sensitivity" CRP or hs-CRP test needs to be performed and analyzed by a laboratory. This is an automated blood test designed for greater accuracy in measuring low levels of CRP, which allows the physician to assess cardiovascular risk. If a result in the low-risk range is found ( < 1 mg/L), it does not need repeating. Higher levels need repeating, and clinical evaluation as necessary.
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 drugsNon-steroidal anti-inflammatory drugs, usually abbreviated to NSAIDs or NAIDs, are drugs with analgesic, antipyretic and, in higher doses, with anti-inflammatory effects...
could lower colon cancer risk.
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