Discovered by
Tillett and Francis in 1930,[9] it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including
cancer.[6] The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein.[10][11][12] Initially, CRP was measured using the
quellung reaction which gave a positive or a negative result. More precise methods nowadays use
dynamic light scattering after reaction with CRP-specific antibodies.[13]
CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the
cell wallpolysaccharide (C-polysaccharide) of
pneumococcus.[14]
Genetics and structure
It is a member of the small
pentraxins family (also known as short pentraxins).[15] The polypeptide encoded by this gene has 224 amino acids.[16] The full-length polypeptide is not present in the body in significant quantities due to
signal peptide, which is removed by
signal peptidase before
translation is completed. The complete protein, composed of five monomers, has a total mass of approximately 120,000 Da. In serum, it assembles into stable pentameric structure with a discoid shape.[17]
Function
CRP binds to the
phosphocholine expressed on the surface of bacterial cells such as pneumococcus
bacteria. This activates the
complement system, promoting
phagocytosis by macrophages, which clears
necrotic and
apoptotic cells and bacteria.[18][13] With this mechanism, CRP also binds to ischemic/hypoxic cells, which could regenerate with more time. However, the binding of CRP causes them to be disposed of prematurely.[19][20] CRP is a prehistoric antibody and binds to the Fc-gamma receptor IIa, to which antibodies also bind.[21] In addition, CRP activates the classical complement pathway via C1q binding.[22][23] CRP thus forms immune complexes in the same way as IgG antibodies.
CRP binds to phosphocholine on micro-organisms. 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 plays a role in
innate immunity as an early defense system against infections.[13]
Traditional CRP measurement only detected CRP in the range of 10 to 1,000 mg/L, whereas high sensitivity CRP (hs-CRP) detects CRP in the range of 0.5 to 10 mg/L.[25] hs-CRP can detect
cardiovascular disease risk when in excess of 3 mg/L, whereas below 1 mg/L would be low risk.[26] Traditional CRP measurement is faster and less costly than hs-CRP, and can be adequate for some applications, such as monitoring
hemodialysis patients.[27]
Normal
In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L and 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. CRP concentrations also increase with age, possibly due to
subclinical conditions. There are also no
seasonal variations of CRP concentrations.
Gene polymorphism of
interleukin-1 family,
interleukin 6, and polymorphic GT repeat of the CRP gene do affect the usual CRP concentrations when a person does not have any medical illnesses.[6]
Acute inflammation
When there is a stimulus, the CRP level can increase 10,000-fold from less than 50 μg/L to more than 500 mg/L. Its concentration can increase to 5 mg/L by 6 hours and peak at 48 hours. The plasma half-life of CRP is 19 hours, and is constant in all medical conditions.[28] Therefore, the only factor that affects the blood CRP concentration is its production rate, which increases with inflammation, infection, trauma, necrosis, malignancy, and
allergic reactions.[citation needed] Other inflammatory mediators that can increase CRP are
TGF beta 1, and
tumor necrosis factor alpha. In acute inflammation, CRP can increase as much as 50 to 100 mg/L within 4 to 6 hours in mild to moderate inflammation or an insult such as
skin infection,
cystitis, or
bronchitis[clarification needed]. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 and 500 mg/L is considered highly predictive of inflammation due to bacterial infection. Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.[13]
CRP is used mainly as an inflammation marker. Apart from
liver failure, there are few known factors that interfere with CRP production.[6]Interferon alpha inhibits CRP production from liver cells which may explain the relatively low levels of CRP found during viral infections compared to bacterial infections [31][32]
CRP cut-off levels indicating bacterial from non-bacterial illness can vary due to
co-morbidities such as
malaria,
HIV and
malnutrition and the stage of disease presentation.[36]
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR[37] (
erythrocyte sedimentation rate). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.[citation needed]
Cardiovascular disease
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of
diabetes,[38][39]hypertension 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.[40] Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease,[41] 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.[42] Others have shown that CRP can exacerbate
ischemicnecrosis in a
complement-dependent fashion and that CRP inhibition can be a safe and effective therapy for
myocardial and
cerebralinfarcts; this has been demonstrated in animal models and humans.[43][44][45]
It has been hypothesized that patients with high CRP levels might benefit from use of
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.[6][46] Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins.[47][48] A subsequent trial however failed to find that CRP was useful for determining statin benefit.[49]
In a
meta-analysis of 20 studies involving 1,466 patients with
coronary artery disease, CRP levels were found to be reduced after exercise interventions. Among those studies, higher CRP concentrations or poorer lipid profiles before beginning exercise were associated with greater reductions in CRP.[50]
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.[51] A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.[52]
Coronary heart disease risk
Arterial damage results from
white blood cell 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.[53][54] 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;[6] 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. Currently, C-reactive protein is not recommended as a cardiovascular disease screening test for average-risk adults without symptoms.[55]
But hs-CRP is not to be used alone and should be combined with elevated levels of
cholesterol,
LDL-C,
triglycerides, and glucose level.
Smoking, hypertension and diabetes also increase the risk level of cardiovascular disease.
High levels of CRP has been associated to point mutation Cys130Arg in the APOE gene, coding for
apolipoprotein E, establishing a link between
lipid values and inflammatory markers modulation.[59][unreliable medical source?][58]
Cancer
The role of inflammation in cancer is not well understood. Some organs of the body show greater risk of cancer when they are chronically inflamed.[60] While there is an association between increased levels of C-reactive protein and risk of developing cancer, there is no association between genetic polymorphisms influencing circulating levels of CRP and cancer risk.[61]
In a 2004
prospective cohort study on colon cancer risk associated with CRP levels, people with
colon cancer had higher average CRP concentrations than people without colon cancer.[62] It can be noted that the average CRP levels in both groups were well within the range of CRP levels usually found in healthy people. However, these findings may suggest that low inflammation level can be associated with a lower risk of colon cancer, concurring with previous studies that indicate
anti-inflammatory drugs could lower colon cancer risk.[63]
Obstructive sleep apnea
C-reactive protein (CRP), a marker of systemic inflammation, is also increased in
obstructive sleep apnea (OSA). CRP and interleukin-6 (IL-6) levels were significantly higher in patients with OSA compared to obese control subjects.[64] Patients with OSA have higher plasma CRP concentrations that increased corresponding to the severity of their
apnea-hypopnea index score. Treatment of OSA with CPAP (
continuous positive airway pressure) significantly alleviated the effect of OSA on CRP and IL-6 levels.[64]
Rheumatoid arthritis
In the context of
rheumatoid arthritis (RA), CRP is one of the acute phase reactants, whose assessment is defined as part of the joint 2010 ACR/
EULAR classification criteria for RA with abnormal levels accounting for a single point within the criteria [65] Higher levels of CRP are associated with more severe disease and a higher likelihood of radiographic progression. Rheumatoid arthritis associated antibodies together with 14-3-3η
YWHAH have been reported to complement CRP in predicting clinical and radiographic outcomes in patients with recent onset inflammatory polyarthritis.[66] Elevated levels of CRP appear to be associated with common comorbidities including cardiovascular disease,
metabolic syndrome, diabetes and interstitial lung (pulmonary) disease. Mechanistically, CRP also appears to influence
osteoclast activity leading to
bone resorption and also stimulates
RANKL expression in peripheral blood
monocytes.[67]
It has previously been speculated that
single-nucleotide polymorphisms in the CRP gene may affect clinical decision-making based on CRP in rheumatoid arthritis, e.g. DAS28 (Disease Activity Score 28 joints). A recent study showed that CRP
genotype and
haplotype were only marginally associated with serum CRP levels and without any association to the DAS28 score.[68] Thus, that DAS28, which is the core parameter for inflammatory activity in RA, can be used for clinical decision-making without adjustment for CRP gene variants.[citation needed]
Viral infections
Increased blood CRP levels were higher in people with
avian fluH7N9 compared to those with
H1N1 (more common) influenza,[69] with a review reporting that severe H1N1 influenza had elevated CRP.[70] In 2020, people infected with
COVID-19 in
Wuhan, China, had elevated CRP.[71][72][73]
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