C-reactive protein: Difference between revisions

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{{Infobox gene}}
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'''C-reactive protein''' ('''CRP''') is an annular (ring-shaped), [[pentameric protein]] found in [[blood plasma]], whose levels rise in response to [[inflammation]]. It is an [[acute-phase protein]] of hepatic origin that increases following [[interleukin-6]] secretion by [[macrophage]]s and [[T cell]]s. Its physiological role is to bind to [[lysophosphatidylcholine]] expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the [[complement system]] via [[C1q]].<ref name="pmid10368284">{{cite journal | vauthors = Thompson D, Pepys MB, Wood SP | title = The physiological structure of human C-reactive protein and its complex with phosphocholine | journal = Structure | volume = 7 | issue = 2 | pages = 169–77 | date = February 1999 | pmid = 10368284 | doi = 10.1016/S0969-2126(99)80023-9 }}</ref>
| require_manual_inspection = no
| update_protein_box = yes
| update_summary = no
| update_citations = no
}}
{{GNF_Protein_box
| image = CRP_pretty.png
| image_source =
| Name = C-reactive protein, pentraxin-related
| HGNCid = 2367
| Symbol = CRP
| AltSymbols =; MGC149895; MGC88244; PTX1
| OMIM = 123260
| ECnumber = 
| Homologene = 476
| MGIid = 88512
| GeneAtlas_image1 = PBB_GE_CRP_37020_at_tn.png
| GeneAtlas_image2 = PBB_GE_CRP_205753_at_tn.png
| Function = {{GNF_GO|id=GO:0005488 |text = binding}} {{GNF_GO|id=GO:0005509 |text = calcium ion binding}}
| Component = {{GNF_GO|id=GO:0005576 |text = extracellular region}}
| Process = {{GNF_GO|id=GO:0006953 |text = acute-phase response}} {{GNF_GO|id=GO:0006954 |text = inflammatory response}}
| Orthologs = {{GNF_Ortholog_box
    | Hs_EntrezGene = 1401
    | Hs_Ensembl = ENSG00000132693
    | Hs_RefseqProtein = NP_000558
    | Hs_RefseqmRNA = NM_000567
    | Hs_GenLoc_db = 
    | Hs_GenLoc_chr = 1
    | Hs_GenLoc_start = 157948703
    | Hs_GenLoc_end = 157951003
    | Hs_Uniprot = P02741
    | Mm_EntrezGene = 12944
    | Mm_Ensembl = ENSMUSG00000037942
    | Mm_RefseqmRNA = NM_007768
    | Mm_RefseqProtein = NP_031794
    | Mm_GenLoc_db = 
    | Mm_GenLoc_chr = 1
    | Mm_GenLoc_start = 174534731
    | Mm_GenLoc_end = 174535702
    | Mm_Uniprot = Q542I3
  }}
}}
{{SI}}
{{CMG}}


== Overview ==
CRP is synthesized by the [[liver]]<ref name="Pepys">{{cite journal | vauthors = Pepys MB, Hirschfield GM | title = C-reactive protein: a critical update | journal = The Journal of Clinical Investigation | volume = 111 | issue = 12 | pages = 1805–12 | date = June 2003 | pmid = 12813013 | pmc = 161431 | doi = 10.1172/JCI18921 }}</ref> in response to factors released by [[macrophage]]s and fat cells ([[adipocytes]]).<ref name="Lau">{{cite journal | vauthors = Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S | title = Adipokines: molecular links between obesity and atheroslcerosis | journal = American Journal of Physiology. Heart and Circulatory Physiology | volume = 288 | issue = 5 | pages = H2031–41 | date = May 2005 | pmid = 15653761 | doi = 10.1152/ajpheart.01058.2004 }}</ref> It is a member of the [[pentraxin]] family of proteins.<ref name=Pepys/> It is not related to [[C-peptide]] (insulin) or [[protein C]] (blood coagulation). C-reactive protein was the first [[pattern recognition receptor]] (PRR) to be identified.<!-- The page for CD14 (http://en.wikipedia.org/wiki/CD14) says that CD14 was the first PRR to be described. Which is it? --><ref name="pmid17828584">{{cite journal | vauthors = Mantovani A, Garlanda C, Doni A, Bottazzi B | title = Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3 | journal = Journal of Clinical Immunology | volume = 28 | issue = 1 | pages = 1–13 | date = January 2008 | pmid = 17828584 | doi = 10.1007/s10875-007-9126-7 }}</ref>


'''C-reactive protein''' ('''CRP''') is a [[plasma protein]], an [[acute phase protein]] produced by the [[liver]]. It is a member of the [[pentraxin]] family of proteins. It should not be confused with [[C-peptide]] or [[Protein C]].
== History and nomenclature ==
Discovered by [[William S. Tillett|Tillett]] and Francis in 1930,<ref name="pmid19869788">{{cite journal | vauthors = Tillett WS, Francis T | title = Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus | journal = The Journal of Experimental Medicine | volume = 52 | issue = 4 | pages = 561–71 | date = September 1930 | pmid = 19869788 | pmc = 2131884 | doi = 10.1084/jem.52.4.561 }}</ref> it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer.<ref name="Pepys"/> The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein.<ref name="isbn0-07-162591-7">{{cite book |vauthors=Kennelly PJ, Murray RF, Rodwell VW, Botham KM | title = Harper's illustrated biochemistry | publisher = McGraw-Hill Medical | location = | year = 2009 | pages = | isbn = 0-07-162591-7 }}</ref><ref name="isbn1-4160-0287-1">{{cite book |vauthors=Pincus MR, McPherson RA, Henry JB | title = Henry's clinical diagnosis and management by laboratory methods | publisher = Saunders Elsevier | location = | year = 2007 | pages = | isbn = 1-4160-0287-1 }}</ref><ref name="isbn1-4160-3285-1">{{cite book |vauthors=Ratey JJ, Noskin GA, Braun R, ((Hanley EN Jr)), McInnes IB, Ruddy S | title = Kelley's Textbook of Rheumatology: 2-Volume Set, Expert Consult: Online and Print (Textbook of Rheumatology (Kelley's)(2 Vol)) | publisher = Saunders | location = Philadelphia | year = 2008 | pages = | isbn = 1-4160-3285-1 }}</ref> Initially, CRP was measured using [[Quellung reaction]] which gave a positive or a negative reaction. More precise methods nowadays is using [[dynamic light scattering]] on antibodies specific to CRP.<ref name="Bray 2016">{{cite journal | vauthors = Bray C, Bell LN, Liang H, Haykal R, Kaiksow F, Mazza JJ, Yale SH | title = Erythrocyte Sedimentation Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine | journal = Wisconsin Medical Journal (WMJ) | volume = 115 | issue = 6 | pages = 317–21 | date = December 2016 | pmid = 29094869 | url = http://www.wisconsinmedicalsociety.org/_WMS/publications/wmj/pdf/115/6/317.pdf }}</ref>
 
CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the antibody against the somatic [[bacterial capsule|capsular]] polysaccharide (C-polysaccharide) of [[pneumococcus]].<ref>{{cite book | vauthors = Ananthanarayan R, Paniker CJ | name-list-format = vanc | title = Ananthanarayan and Paniker's Textbook of Microbiology | date = 1978 | publisher = Orient Longman | location = Himayatnagar, Hyderabad | isbn = 9788125028086 | page = 218 | edition = 7th  | url = https://books.google.com/books?id=MXMazr0LRDsC&pg=PA218 }}</ref><ref>{{cite book | vauthors = Levine M | chapter = Chapter 13: Chronic Periodontitis |title=Topics in Dental Biochemistry |publisher=Springer | location = Berlin, Heidelberg | date = 2011 |isbn=978-3-540-88115-5 | quote = C-reactive protein (CRP) was originally identified as binding to the phosphocholine attachment site of capsular polysaccharide (C-polysaccharide) from Streptococcus pneumoniae. }}</ref>
 
== Genetics and structure ==
 
The ''CRP'' gene is located on [[chromosome]] 1 (1q23.2<ref>{{cite web | title = CRP C-reactive protein [Homo sapiens] | url = https://www.ncbi.nlm.nih.gov/gene/1401 | work = Entrez Gene | publisher = National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine }}</ref>). It is a member of the small [[pentraxins]] family. The monomer has 224 amino acids,<ref>{{cite web | url = https://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=30224 | work = NCBI Entrez Protein | title = #CAA39671 }}</ref> and molecular mass of 25,106 [[Dalton (unit)|Da]].  In serum, it assembles into stable pentameric structure with a discoid shape.
 
== Function ==
 
CRP binds to the [[phosphocholine]] expressed on the surface of dead or dying cells and some bacteria. This activates the [[complement system]], promoting [[phagocytosis]] by macrophages, which clears necrotic and apoptotic cells and bacteria.<ref name="Bray 2016"/>
 
This so-called [[acute phase response]] occurs as a result of a rise in the concentration of [[Interleukin-6|IL-6]], which is produced by [[macrophage]]s<ref name=Pepys/> as well as [[adipocyte]]s<ref name="Lau"/> in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of [[interleukin-6]] and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.
 
CRP binds to phosphocholine on micro-organisms. It is thought to assist in [[Complement system|complement]] binding to foreign and damaged cells and enhances phagocytosis by macrophages ([[opsonin|opsonin-mediated phagocytosis]]), which express a receptor for CRP. It plays a role in [[innate immunity]] as an early defense system against infections.<ref name="Bray 2016"/>
 
== Serum levels ==


C-reactive protein (CRP) is an inflammatory marker with a very large body of evidence demonstrating its prognostic utility in apparently healthy patients, as well as patients with acute coronary syndromes. Pre-angioplasty levels of CRP predict outcome, CRP levels rise after angioplasty, and it appears that the rise can be blunted by GP IIb/IIIa inhibitors.
In healthy adults, the normal concentrations of CRP varies between 0.8&nbsp;mg/L to 3.0&nbsp;mg/L. However, some healthy adults show elevated CRP at 10&nbsp;mg/L. When there is a stimulus, the CRP level can rise 10,000-fold from less than 50 μg/l to more than 500&nbsp;mg/L. Such levels can rise to 5&nbsp;mg/L by 6 hours and peaks at 48 hours. The plasma half-life of CRP is 19 hours. Such half-life is constant in all medical conditions. Therefore, the only factor that affects the level of CRP in blood is its rate of production. The rate of CRP production increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reaction. The CRP level also increases with age, possibly due to increasing subclinical condition. There is also no seasonal variations of CRP levels. [[Gene polymorphism]] of [[interleukin-1 family]], [[interleukin 6]], and polymorphic GT repeat of the CRP gene do affects the usual CRP levels when a person does not have any medical illnesses.<ref name=Pepys/> Other inflammatory mediators that can cause a rise in CRP are [[TGF beta 1]], and [[tumor necrosis factor alpha]]. In acute inflammation, CRP can raise as much as 50 to 100&nbsp;mg/dL within 4 to 6 hours in mild to moderate inflammation or insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 to 500&nbsp;mg/dL is considered as bacterial inflammation. CRP concentrations between 2 to 10&nbsp;mg/dL are considered as metabolic inflammation (metabolic pathways that causes [[arteriosclerosis]] and [[type II diabetes mellitus]]). Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.<ref name="Bray 2016"/>


== History and nomenclature ==
== Clinical significance ==


C-reactive protein was originally discovered by Tillett and Francis in 1930 as a substance in the serum of patients with acute [[inflammation]] that reacted with the ''C'' polysaccharide of ''[[pneumococcus]]''.<ref> {{cite journal|author=Tillett WS, Francis Jr T | title = Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus | journal = J Exp Med | volume = 52 | pages=561-585 | year = 1930}}</ref> Initially it was thought that CRP might be a pathogenic secretion, as it was elevated in people with a variety of illnesses, including carcinomas.  Discovery of hepatic synthesis and secretion of CRP closed that debate
===Diagnostic use===
CRP is used mainly as a marker of inflammation. Apart from [[liver failure]], there are few known factors that interfere with CRP production.<ref name=Pepys/> 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 <ref>{{cite journal | vauthors = Enocsson H, Sjöwall C, Skogh T, Eloranta ML, Rönnblom L, Wetterö J | title = Interferon-alpha mediates suppression of C-reactive protein: explanation for muted C-reactive protein response in lupus flares? | journal = Arthritis and Rheumatism | volume = 60 | issue = 12 | pages = 3755–60 | date = December 2009 | pmid = 19950271 | doi = 10.1002/art.25042 }}</ref>


==Genetics and biochemistry==
Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. [[ELISA]], [[immunoturbidimetry]], [[nephelometry]], rapid [[immunodiffusion]], and visual [[agglutination (biology)|agglutination]] are all methods used to measure CRP.


The ''CRP'' gene is located on the first [[chromosome]] (1q21-q23). CRP is a 224 residue protein<ref>NCBI Entrez Protein #CAA39671 [http://www.ncbi.nlm.nih.gov/entrez/viewer.fcgi?db=protein&val=30224]</ref> with a monomer molar mass of 25106 [[Dalton (unit)|Da]].  The protein is an annular pentameric disc in shape. Proteins with this type of configuration are known as ''[[pentraxins]]''.  Native CRP is a bit different as it has 10-subunits making two pentameric discs, with an overall molecular mass of 251060 Da.
<div class="noprint">
[[File:Blood values sorted by mass and molar concentration.png|thumb|450px|[[Reference ranges for blood tests]], showing C-reactive protein in brown-yellow in center.]]
</div>


==Pathophysiology==
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&nbsp;mg/L.


In the field of atherosclerosis, it is unclear if CRP plays a putative role in disease or is a marker of ongoing disease.
The risk of developing cardiovascular disease is quantified as follows:<ref>{{cite web|title=Normal results|url=https://www.nlm.nih.gov/medlineplus/ency/article/003356.htm|website=C-reactive protein|publisher=MedlinePlus|access-date=23 April 2015}}</ref>
* C-reactive protein (CRP) is an acute phase protein formed in the liver. The stimulus for CRP production is IL-6.
* CRP rises more than 6 hours after triggering stimulus
* Upon resolution of condition, CRP rapidly declines
* CRP is considered to be a better indicator for an inflammatory response because of its shorter half-life and rapid increase


==Function==
* low: hs-CRP level under 1.0&nbsp;mg/L
* average: between 1.0 and 3.0&nbsp;mg/L
* high: above 3.0&nbsp;mg/L


CRP is a member of the class of acute phase reactants as its levels rise dramatically during [[inflammation|inflammatory]] processes occurring in the body. This increment is due to a rise in the plasma concentration of [[Interleukin-6|IL-6]], which is produced by macrophages, endothelial cells and T-cells as well as adipocytes. CRP binds to phosphorylcholine on microbes. It is thought to assist in [[Complement system|complement]] binding to foreign and damaged cells and 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.
Normal levels increase with [[aging]].<ref>Thomas, Lothar, ''Labor und Diagnose''. TH-Books, Frankfurt, 2008, p. 1010</ref> Higher levels are found in late [[Pregnancy|pregnant]] women, mild [[inflammation]] and [[viral infection]]s (10–40&nbsp;mg/L), active inflammation, bacterial infection (40–200&nbsp;mg/L), severe [[bacterial infections]] and [[burn]]s (>200&nbsp;mg/L).<ref name="pmid22787338">{{cite journal | vauthors = Chew KS | title = What's new in Emergencies Trauma and Shock? C-reactive protein as a potential clinical biomarker for influenza infection: More questions than answers | journal = Journal of Emergencies, Trauma, and Shock | volume = 5 | issue = 2 | pages = 115–7 | date = April 2012 | pmid = 22787338 | pmc = 3391832 | doi = 10.4103/0974-2700.96477 }}</ref>


==Diagnostic use==
CRP is a more sensitive and accurate reflection of the acute phase response than the ESR<ref name="pmid23689052"/> ([[Erythrocyte sedimentation rate|Erythrocyte Sedimentation Rate]]). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.
CRP is used mainly as a marker of inflammation. Measuring and charting C-reactive protein 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 testing.


Various analytical methods are available for CRP determination, such as [[ELISA]], immunoturbidimetry, rapid [[immunodiffusion]] and visual [[agglutination (biology)|agglutination]].
The utility of CRP in differentiating inflammatory diseases (including [[inflammatory bowel disease]], [[intestinal lymphoma]], [[intestinal tuberculosis]], and [[Behçet's disease|Behcet's syndrome]]) has been investigated and compared to other inflammatory biomarkers, such as ESR and WBC.<ref name="pmid23689052"/>


Viral infections tend to give a lower CRP level than bacterial infection.
=== Cardiovascular disease ===


===Cardiology diagnostic test===
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of [[diabetes]],<ref name="pmid11466099">{{cite journal | vauthors = Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM | title = C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus | journal = JAMA | volume = 286 | issue = 3 | pages = 327–34 | date = July 2001 | pmid = 11466099 | doi = 10.1001/jama.286.3.327 }}</ref><ref name="pmid17327459">{{cite journal | vauthors = Dehghan A, Kardys I, de Maat MP, Uitterlinden AG, Sijbrands EJ, Bootsma AH, Stijnen T, Hofman A, Schram MT, Witteman JC | display-authors = 6 | title = Genetic variation, C-reactive protein levels, and incidence of diabetes | journal = Diabetes | volume = 56 | issue = 3 | pages = 872–8 | date = March 2007 | pmid = 17327459 | doi = 10.2337/db06-0922 }}</ref> [[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.<ref name="pmid15735094">{{cite journal | vauthors = Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, Willett WC, Hu FB | display-authors = 6 | title = Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction | journal = The Journal of Nutrition | volume = 135 | issue = 3 | pages = 562–6 | date = March 2005 | pmid = 15735094 | doi = 10.1093/jn/135.3.562 }}</ref> Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease,<ref name="pmid15070788">{{cite journal | vauthors = Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, Lowe GD, Pepys MB, Gudnason V | display-authors = 6 | title = C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease | journal = The New England Journal of Medicine | volume = 350 | issue = 14 | pages = 1387–97 | date = April 2004 | pmid = 15070788 | doi = 10.1056/NEJMoa032804 }}</ref> 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.<ref>Koenig, Wolfgang (2006). [http://www.crphealth.com/conf/hcp/5,59/doctor.wolfgang.koenig.c-reactive.protein.%96.a.critical.cardiovascular.risk.html "C-reactive protein - a critical cardiovascular risk marker"]. CRPhealth.com.</ref> Others have shown that CRP can exacerbate [[ischemic]] [[necrosis]] in a [[complement (biology)|complement]]-dependent fashion and that CRP inhibition can be a safe and effective therapy for [[Myocardial infarction|myocardial]] and [[Cerebral infarction|cerebral]] [[infarct]]s; so far, this has been demonstrated in animal models only.<ref name="pmid16642000">{{cite journal | vauthors = Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP | display-authors = 6 | title = Targeting C-reactive protein for the treatment of cardiovascular disease | journal = Nature | volume = 440 | issue = 7088 | pages = 1217–21 | date = April 2006 | pmid = 16642000 | doi = 10.1038/nature04672 }}</ref>
Arterial damage is thought to result from inflammation due to chemical insults. 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. Also, these values refer only to prolonged elevation, so a single measurement would be meaningless.


C-reactive protein blood test<ref>Torelli, Julius (2005), ''Beyond Cholesterol'', p.45. ISBN 0-312-34863-0</ref>
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.<ref name=Pepys/><ref name="pmid18997196">{{cite journal | vauthors = Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, Koenig W, Libby P, Lorenzatti AJ, MacFadyen JG, Nordestgaard BG, Shepherd J, Willerson JT, Glynn RJ | display-authors = 6 | title = Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein | journal = The New England Journal of Medicine | volume = 359 | issue = 21 | pages = 2195–207 | date = November 2008 | pmid = 18997196 | doi = 10.1056/NEJMoa0807646 }}</ref> Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins.<ref name="pmid22025854">{{cite journal | vauthors = Sindhu S, Singh HK, Salman MT, Fatima J, Verma VK | title = Effects of atorvastatin and rosuvastatin on high-sensitivity C-reactive protein and lipid profile in obese type 2 diabetes mellitus patients | journal = Journal of Pharmacology & Pharmacotherapeutics | volume = 2 | issue = 4 | pages = 261–5 | date = October 2011 | pmid = 22025854 | pmc = 3198521 | doi = 10.4103/0976-500X.85954 }}</ref><ref name="pmid11306519">{{cite journal | vauthors = Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S | title = Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels | journal = Circulation | volume = 103 | issue = 15 | pages = 1933–5 | date = April 2001 | pmid = 11306519 | doi = 10.1161/01.CIR.103.15.1933 }}</ref> A subsequent trial however failed to find that CRP was useful for determining statin benefit.<ref name="pmid21277016">{{cite journal | vauthors = ((Heart Protection Study Collaborative Group)), Emberson J, Bennett D, Link E, Parish S, Danesh J, Armitage J, Collins R | title = C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study | journal = Lancet | volume = 377 | issue = 9764 | pages = 469–76 | date = February 2011 | pmid = 21277016 | pmc = 3042687 | doi = 10.1016/S0140-6736(10)62174-5 }}</ref>
: Low risk: <1mg/L
: High risk: >3mg/L


== Differential Diagnosis ==
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.<ref name="pmid22520533">{{cite journal | vauthors = Swardfager W, Herrmann N, Cornish S, Mazereeuw G, Marzolini S, Sham L, Lanctôt KL | title = Exercise intervention and inflammatory markers in coronary artery disease: a meta-analysis | journal = American Heart Journal | volume = 163 | issue = 4 | pages = 666–76.e1-3 | date = April 2012 | pmid = 22520533 | doi = 10.1016/j.ahj.2011.12.017 }}</ref>


=== Most common ===
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.<ref name="pmid18971492">{{cite journal | vauthors = Zacho J, Tybjaerg-Hansen A, Jensen JS, Grande P, Sillesen H, Nordestgaard BG | title = Genetically elevated C-reactive protein and ischemic vascular disease | journal = The New England Journal of Medicine | volume = 359 | issue = 18 | pages = 1897–908 | date = October 2008 | pmid = 18971492 | doi = 10.1056/NEJMoa0707402 }}</ref> A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.<ref name="pmid19297430">{{cite journal | vauthors = St-Onge MP, Zhang S, Darnell B, Allison DB | title = Baseline serum C-reactive protein is associated with lipid responses to low-fat and high-polyunsaturated fat diets | journal = The Journal of Nutrition | volume = 139 | issue = 4 | pages = 680–3 | date = April 2009 | pmid = 19297430 | pmc = 2666362 | doi = 10.3945/jn.108.098251 }}</ref>
* Acute [[Pancreatitis|pancreatitis]]
* Bacteria
* [[Bechterew's Disease]]
* Degenerative joint diseases
* [[Dermatomyositis]]
* Fungi
* [[Inflammatory Bowel Disease]]
* [[Juvenile Arthritis]]
* [[Leukemia]]
* Malignant tumors
* [[Myocardial Infarction]]
* Parasites
* [[Polymyalgia Rheumatica]]
* [[Polymyositis]]
* Postoperatively
* Post Percutaneous Coronary Intervention (PCI)
* [[Pseudogout]]
* [[Psoriasis]] arthropathy
* [[Reiter's Syndrome]]
* [[Rheumatoid Arthritis]]
* [[Sjogren's Syndrome]]
* [[Systemic Lupus Erythematosus]]
* [[Vasculitis]]
* Viruses
* [[Wegener's Granulomatosis]]


===Complete Differential Diagnosis ===
=== Coronary heart disease risk ===
(By organ system)
{|style="width:50%; height:100px" border="1"
|style="height:100px"; style="width:25%" border="1" bgcolor="LightSteelBlue" | '''Cardiovascular'''
|style="height:100px"; style="width:75%" border="1" bgcolor="Beige" | [[Amyloidosis]],[[Catecholaminergic polymorphic ventricular tachycardia]],[[Myocarditis]],[[Ventricular Tachycardia Including Torsades De Pointes and Polymorphic Ventricular Tachycardia]],[[Abdominal Aortic Aneurysm]],[[Acute Coronary Syndromes]],[[Arrhythmogenic right ventricular dysplasia]],[[Atherosclerosis]],[[Brugada syndrome]],[[Cardiomyopathy]],[[Congestive Heart Failure]],[[Hypertrophic Cardiomyopathy]],[[Myocardial infarction]],[[Peripheral Arterial Disease]],[[Romano-Ward syndrome]],[[Shock (medical)]],[[Stress cardiomyopathy]],[[Subclavian Artery Disease]],[[Down syndrome]],[[Noonan syndrome]],[[Andersen-Tawil syndrome]],[[Pseudoxanthoma elasticum]],[[Rheumatic fever]],[[Homocystinuria]]
|-
|-bgcolor="LightSteelBlue"
| '''Chemical / poisoning'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Dermatologic'''
|bgcolor="Beige"| [[Acrodermatitis enteropathica]],[[Porphyria cutanea tarda]],[[Squamous cell carcinoma]],[[Acne vulgaris]],[[Contact dermatitis]],[[Eczema]],[[Pachyonychia congenita]],[[Pemphigus]],[[Scleroderma]]
|-
|-bgcolor="LightSteelBlue"
| '''Drug Side Effect'''
|bgcolor="Beige"|[[Abciximab]],[[Adalimumab]],[[Anakinra]],[[Aspirin]],[[Boldenone]],[[Clarithromycin]],[[Clindamycin]],[[Corticosteroid]],[[Demeclocycline]],[[Dexamethasone]],[[Doxycycline]],[[Drospirenone]],[[Erythromycin]],[[Estrogen]],[[Flunisolide Oral Inhalation]],[[Fluoxetine]],[[Fluticasone and Salmeterol Oral Inhalation]],[[Fluvoxamine]],[[Hydrocortisone Oral]],[[Ibuprofen]],[[Imatinib]],[[Ketamine]],[[Ketorolac]],[[Tacrolimus]],[[Triamcinolone Oral Inhalation]]
|-
|-bgcolor="LightSteelBlue"
| '''Ear Nose Throat'''
|bgcolor="Beige"| [[Collagenopathy, types II and XI]]
|-
|-bgcolor="LightSteelBlue"
| '''Endocrine'''
|bgcolor="Beige"| [[Diabetes mellitus]],[[Diabetic ketoacidosis]],[[Diabetic nephropathy]],[[Glucagonoma]],[[Graves' Disease]],[[Growth hormone deficiency]],[[Hypothyroidism]],[[Lipoid congenital adrenal hyperplasia]],[[McCune-Albright syndrome]],[[Catecholaminergic polymorphic ventricular tachycardia]],[[Wolfram syndrome]],[[Werner syndrome]],[[X-linked adrenal hypoplasia congenita]],[[Peroxisomal disorder]],[[Neuroendocrine tumors]],[[Thyroid Carcinoma]]
|-
|-bgcolor="LightSteelBlue"
| '''Environmental'''
|bgcolor="Beige"| [[Andrographis paniculata]],[[Nylon worker's lung]],[[Toxic and Nutritional Optic Neuropathy]]
|-
|-bgcolor="LightSteelBlue"
| '''Gastroenterologic'''
|bgcolor="Beige"| [[Ascites]],[[Autoimmune Hepatitis]],[[Budd-Chiari syndrome]],[[Celiac disease]],[[Cholecystitis]],[[Chronic pancreatitis]],[[Cirrhosis]],[[Colitis]],[[Crohn's disease]],[[Diarrhea]],[[Eosinophilic gastroenteritis]],[[Peutz-Jeghers syndrome]],[[Shwachman-Diamond syndrome]],[[Spontaneous bacterial peritonitis]],[[Typhoid fever]],[[Wilson's disease]],[[Amyloidosis]],[[Acrodermatitis enteropathica]],[[Wilson's disease]],[[Cystic Fibrosis]],[[Dubin-Johnson syndrome]],[[Primary biliary cirrhosis]],[[Hemochromatosis]],[[Zellweger syndrome]],[[Gaucher's disease]],[[Protein-Losing Enteropathy]],[[Gastrointestinal stromal tumor]],[[Hepatocellular carcinoma]],[[Ulcerative colitis]],[[Hepatitis B]],[[Hepatitis C/co-infection with HIV]],[[Hepatitis G]],[[Hepatitis]],[[Sarcoidosis]]
|-
|-bgcolor="LightSteelBlue"
| '''Genetic'''
|bgcolor="Beige"| [[Allan-Herndon-Dudley syndrome]],[[Alport syndrome]],[[Andersen-Tawil syndrome]],[[ASPM (Genetics)]],[[Ataxia Telangiectasia]],[[Atransferrinemia]],[[Bloom syndrome]],[[Cardiofaciocutaneous syndrome]],[[Chronic granulomatous disease]],[[Congenital Adrenal Hyperplasia]],[[Congenital muscular dystrophy]],[[Cystic Fibrosis]],[[Down syndrome]],[[Dubin-Johnson syndrome]],[[Familial Mediterranean fever]],[[Friedreich's ataxia]],[[Myotonia congenita]],[[Myotonic dystrophy]],[[Neurofibromatosis]],[[Niemann-Pick disease]],[[Noonan syndrome]],[[Osteogenesis imperfecta]],[[Otospondylomegaepiphyseal dysplasia]],[[Pachyonychia congenita]],[[Pendred syndrome]],[[Polycystic kidney disease]],[[Primary biliary cirrhosis]],[[Primary ciliary dyskinesia]],[[Pseudoxanthoma elasticum]],[[Rett syndrome]],[[Rubinstein-Taybi syndrome]],[[Salla disease]],[[Sickle-cell disease]],[[Stargardt's disease]],[[Tay-Sachs Disease]],[[Treacher Collins syndrome]],[[Usher syndrome]],[[Vitelliform macular dystrophy]],[[Von Hippel-Lindau disease]],,[[Von Willebrand disease]],[[Waldenstrom macroglobulinemia]],[[Walker-Warburg syndrome]],[[Werner syndrome]],[[Williams syndrome]],[[Wiskott-Aldrich syndrome]],[[Wolfram syndrome]],[[X-linked adrenal hypoplasia congenita]],[[X-linked alpha thalassemia mental retardation syndrome]],[[X-linked congenital stationary night blindness]],[[ZAP70 deficiency]],[[Norrie disease]],[[Shwachman-Diamond syndrome]],[[SADDAN]],[[Cystinuria]]
|-
|-bgcolor="LightSteelBlue"
| '''Hematologic'''
|bgcolor="Beige"| [[Abetalipoproteinemia]],[[Activated protein C resistance]],[[Acute myeloid leukemia]],[[Anemia]],[[Angiogenesis]],[[Angiopathy]],[[Antiphospholipid syndrome]],[[Arteriogenesis]],[[Blood transfusion]],[[Cryoglobulinemia]],[[Disseminated Intravascular Coagulation]],[[Fanconi anemia]],[[Fat Embolism Syndrome]],[[Hemochromatosis]],[[Hemoglobinuria]],[[Heparin Induced Thrombocytopenia]],[[Multiple myeloma]],[[Protein S deficiency]],[[Thrombocytopenia]],[[Thrombocytosis]],[[Thrombotic thrombocytopenic purpura]],[[Porphyria cutanea tarda]],[[Wiskott-Aldrich syndrome]],[[Atransferrinemia]],[[Sickle-cell disease]],[[Von Hippel-Lindau disease]],[[Von Willebrand disease]],[[Waldenstrom macroglobulinemia]],[[X-linked alpha thalassemia mental retardation syndrome]],[[Cavernous Sinus Thrombosis]]
|-
|-bgcolor="LightSteelBlue"
| '''Iatrogenic'''
|bgcolor="Beige"| [[Antithrombin Therapy During Percutaneous Coronary Intervention (PCI) (patient information)]],[[Heparin Induced Thrombocytopenia]]
|-
|-bgcolor="LightSteelBlue"
| '''Infectious Disease'''
|bgcolor="Beige"|
'''Bacterial:'''


'''Fungal:'''
Arterial damage results from [[macrophage|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 [[Sensitivity and specificity|specific]] prognostic indicator.<ref name="Lloyd-Jones">{{cite journal | vauthors = Lloyd-Jones DM, Liu K, Tian L, Greenland P | title = Narrative review: Assessment of C-reactive protein in risk prediction for cardiovascular disease | journal = Annals of Internal Medicine | volume = 145 | issue = 1 | pages = 35–42 | date = July 2006 | pmid = 16818927 | doi = 10.7326/0003-4819-145-1-200607040-00129 | url = http://annals.org/cgi/content/full/0000605-200607040-00129v1 | access-date = 2008-05-01 | archive-url = https://web.archive.org/web/20080417140838/http://www.annals.org/cgi/content/full/0000605-200607040-00129v1# | archive-date = 2008-04-17 | dead-url = yes | df =  }}</ref><ref>{{cite journal | vauthors = Bower JK, Lazo M, Juraschek SP, Selvin E | title = Within-person variability in high-sensitivity C-reactive protein | journal = Archives of Internal Medicine | volume = 172 | issue = 19 | pages = 1519–21 | date = October 2012 | pmid = 22945505 | pmc = 3613132 | doi = 10.1001/archinternmed.2012.3712 }}</ref> Nevertheless, a level above 2.4&nbsp;mg/L has been associated with a doubled risk of a coronary event compared to levels below 1&nbsp;mg/L;<ref name=Pepys/> 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.<ref name=Cecil>{{cite book |last1=Goldman |first1=Lee | name-list-format = vanc |title=Goldman's Cecil Medicine |publisher=Elsevier Saunders |location=Philadelphia |isbn=1437727883 |year=2011 |pages=54 |edition=24th }}</ref>


'''Helminthic:'''
The [[American Heart Association]] and U.S. [[Centers for Disease Control and Prevention]] have defined risk groups as follows:<ref>{{cite web |url=http://labtestsonline.org/understanding/analytes/hscrp/tab/test |title=hs-CRP |access-date=June 3, 2013}}</ref>
* Low Risk: less than 1.0&nbsp;mg/L
* Average risk: 1.0 to 3.0&nbsp;mg/L
* High risk: above 3.0&nbsp;mg/L
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.


'''Protozoal:'''
=== Fibrosis and inflammation ===


'''Viral:'''
[[Scleroderma]], [[polymyositis]], and [[dermatomyositis]] elicit little or no CRP response. CRP levels also tend not to be elevated in [[Systemic lupus erythematosus|SLE]] unless [[serositis]] or [[synovitis]] is present. Elevations of CRP in the absence of clinically significant inflammation can occur in [[Kidney failure|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 artery disease|peripheral vascular disease]].<ref name="Risk">{{cite journal | vauthors = Clearfield MB | title = C-reactive protein: a new risk assessment tool for cardiovascular disease | journal = The Journal of the American Osteopathic Association | volume = 105 | issue = 9 | pages = 409–16 | date = September 2005 | pmid = 16239491 | url = http://www.jaoa.org/content/105/9/409.full | access-date = 2013-02-10 | archive-url = https://web.archive.org/web/20120110071000/http://www.jaoa.org/content/105/9/409.full# | archive-date = 2012-01-10 | dead-url = yes | df = }}</ref> Elevated level of CRP can also be observed in [[inflammatory bowel disease]] (IBD), including [[Crohn's disease]] and [[ulcerative colitis]].<ref name="pmid23689052">{{cite journal | vauthors = Liu S, Ren J, Xia Q, Wu X, Han G, Ren H, Yan D, Wang G, Gu G, Li J | title = Preliminary case-control study to evaluate diagnostic values of C-reactive protein and erythrocyte sedimentation rate in differentiating active Crohn's disease from intestinal lymphoma, intestinal tuberculosis and Behcet's syndrome | journal = The American Journal of the Medical Sciences | volume = 346 | issue = 6 | pages = 467–72 | date = December 2013 | pmid = 23689052 | doi = 10.1097/MAJ.0b013e3182959a18 }}{{Unreliable medical source|date=August 2013|sure=y}}</ref>
|-
|-bgcolor="LightSteelBlue"
| '''Musculoskeletal / Ortho'''
|bgcolor="Beige"| [[Achondrogenesis]],[[Collagenopathy, types II and XI]],[[Duchenne's Muscular Dystrophy]],[[Dysarthria]],[[Ehlers-Danlos syndrome]],[[Emery-Dreifuss Muscular Dystrophy]],[[Fibrodysplasia ossificans progressiva]],[[Osteoarthritis]],[[Osteomalacia]],[[Osteoporosis]],[[SADDAN]],[[Still's disease]],[[McCune-Albright syndrome]],[[Rubinstein-Taybi syndrome]],[[Allan-Herndon-Dudley syndrome]],[[Congenital muscular dystrophy]],[[Myotonia congenita]],[[Myotonic dystrophy]],[[Osteogenesis imperfecta]],[[Otospondylomegaepiphyseal dysplasia]],[[Treacher Collins syndrome]],[[Gout]],[[Rheumatoid arthritis]],[[Polymyositis]]
|-
|-bgcolor="LightSteelBlue"
| '''Neurologic'''
|bgcolor="Beige"| [[Acute Disseminated Encephalomyelitis]],[[Adrenoleukodystrophy]],[[Amyotrophic Lateral Sclerosis]],[[Asceptic Meningitis]],[[Astrocytoma]],[[Benign familial neonatal convulsions]],[[Bovine spongiform encephalopathy]],[[Brain Abscess]],[[Cavernous angioma]],[[Cavernous Sinus Thrombosis]],[[Cerebral edema]],[[Cerebral hemorrhage]],[[Coccidioidal Meningitis]],[[Creutzfeldt-Jakob Disease]],[[Ddx:Meningitis]],[[Devic's disease]],[[Encephalitis]],[[Encephalopathy]],[[Epilepsy]],[[Experimental autoimmune encephalomyelitis]],[[Glioblastoma multiforme]],[[Juvenile myoclonic epilepsy]],[[Meningioma]],[[Multiple sclerosis]],[[Zellweger syndrome]],[[Walker-Warburg syndrome]],[[Friedreich's ataxia]],[[Williams syndrome]],[[Neurofibromatosis]],[[Pendred syndrome]],[[Rett syndrome]],[[Ataxia Telangiectasia]],[[Poliomyelitis]],[[Rabies]],[[Tick-borne meningoencephalitis]],[[Sandhoff disease]]
|-
|-bgcolor="LightSteelBlue"
| '''Nutritional / Metabolic'''
|bgcolor="Beige"| [[Biotinidase deficiency]],[[Carbamoyl phosphate synthetase I deficiency]],[[Carnitine palmitoyltransferase II deficiency]],[[Citrullinemia]],[[Cystinuria]],[[Gaucher's disease]],[Glutaric acidemia type 2]],[[Glutaric aciduria type 1]],[[Glycogen storage disease type I]],[[GM2-gangliosidosis, AB variant]],[[Gout]],[[High protein diet]],[[Homocystinuria]],[[Hurler's Syndrome]],[[Hyperlipidemia]],[[Hypermethioninemia]],[[Hyperprolinemia]],[[Isovaleric acidemia]],[[Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes]],[[Paraproteinemia]],[[Pellagra]],[[Peroxisomal disorder]],[[Phenylketonuria]],[[Propionic acidemia]],[[Protein-energy malnutrition]],[[Protein-Losing Enteropathy]],[[Sandhoff disease]],[[Tyrosinemia]],[[Urea cycle disorder]],[[Uremia]]
|-
|-bgcolor="LightSteelBlue"
| '''Obstetric/Gynecologic'''
|bgcolor="Beige"| [[Endometriosis]],[[Hydatidiform mole]]
|-
|-bgcolor="LightSteelBlue"
| '''Oncologic'''
|bgcolor="Beige"| [[Adenoid cystic carcinoma]],[[Breast cancer]],[[Cervical cancer]],[[Gastrointestinal stromal tumor]],[[Hepatocellular carcinoma]],[[Melanoma]],[[Mesothelioma]],[[Neuroendocrine tumors]],[[Paraneoplastic syndrome]],[[Thyroid Carcinoma]]
|-
|-bgcolor="LightSteelBlue"
| '''Opthalmologic'''
|bgcolor="Beige"| [[Arteritic anterior ischemic optic neuropathy]],[[Corneal ulcer]],[[Drusen]],[[Keratoconjunctivitis sicca]]
|-
|-bgcolor="LightSteelBlue"
| '''Overdose / Toxicity'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Psychiatric'''
|bgcolor="Beige"| [[Bipolar disorder]]


|-
High levels of CRP has been associated to point mutation '''Cys130Arg''' in '''''APOE''''' gene, coding for [[apolipoprotein E]], establishing a link between [[lipid]] values and inflammatory markers modulation.<ref>{{cite journal | vauthors = Sidore C, Busonero F, Maschio A, Porcu E, Naitza S, Zoledziewska M, Mulas A, Pistis G, Steri M, Danjou F, Kwong A, Ortega Del Vecchyo VD, Chiang CW, Bragg-Gresham J, Pitzalis M, Nagaraja R, Tarrier B, Brennan C, Uzzau S, Fuchsberger C, Atzeni R, Reinier F, Berutti R, Huang J, Timpson NJ, Toniolo D, Gasparini P, Malerba G, Dedoussis G, Zeggini E, Soranzo N, Jones C, Lyons R, Angius A, Kang HM, Novembre J, Sanna S, Schlessinger D, Cucca F, Abecasis GR | display-authors = 6 | title = Genome sequencing elucidates Sardinian genetic architecture and augments association analyses for lipid and blood inflammatory markers | journal = Nature Genetics | volume = 47 | issue = 11 | pages = 1272–1281 | date = November 2015 | pmid = 26366554 | pmc = 4627508 | doi = 10.1038/ng.3368 }}</ref>
|-bgcolor="LightSteelBlue"
| '''Pulmonary'''
|bgcolor="Beige"| [[Lung abscess]],[[Hypersensitivity Pneumonitis]],[[Atypical pneumonia]],[[Bird breeder's lung]],[[Bronchitis]],[[Byssinosis]],[[Cheese worker's lung]],[[Chemical worker's lung]],[[Emphysema]],[[Grain handler's lung]],[[Hot tub lung]],[[Humidifier lung]],[[Infant respiratory distress syndrome]],[[Loeffler's syndrome]],[[Malt worker's lung]]
|-
|-bgcolor="LightSteelBlue"
| '''Renal / Electrolyte'''
|bgcolor="Beige"| [[Nephrotic syndrome]],[[Acidosis]],[[Androgen insensitivity syndrome]],[[Chronic Renal Failure]],[[Hypercalcemia]],[[Focal segmental glomerulosclerosis]],[[Gitelman syndrome]],[[Glomerulonephritis]],[[Hyperammonemia]],[[Hyperkalemic periodic paralysis]],[[Hypernatremia]],[[Nephronophthisis]]
|-
|-bgcolor="LightSteelBlue"
| '''Rheum / Immune / Allergy'''
|bgcolor="Beige"| [[Ulcerative colitis]],[[Rheumatoid arthritis]],[[Soy allergy]]
|-
|-bgcolor="LightSteelBlue"
| '''Sexual'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Trauma'''
|bgcolor="Beige"| No underlying causes
|-
|-bgcolor="LightSteelBlue"
| '''Urologic'''
|bgcolor="Beige"|[[Bladder cancer]],[[Prostate cancer]]
|-
|-bgcolor="LightSteelBlue"
| '''Dental'''
|bgcolor="Beige"| [[Amelogenesis Imperfecta]]
|-
|-bgcolor="LightSteelBlue"
| '''Miscellaneous'''
|bgcolor="Beige"| [[Atrophy]],[[Bone healing]],[[Botulinum toxin]],[[Brachioradial pruritis]],[[Erythropoietin]],[[Excitotoxicity]],[[Snakebites]],[[Total Parenteral Nutrition]]


|-
=== Cancer ===
|}


=== Complete Differential Diagnosis ===
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.<ref>{{cite journal | vauthors = Lu H, Ouyang W, Huang C | title = Inflammation, a key event in cancer development | journal = Molecular Cancer Research | volume = 4 | issue = 4 | pages = 221–33 | date = April 2006 | pmid = 16603636 | doi = 10.1158/1541-7786.MCR-05-0261 }}</ref>  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.<ref name="pmid22035340">{{cite journal | vauthors = Allin KH, Nordestgaard BG | title = Elevated C-reactive protein in the diagnosis, prognosis, and cause of cancer | journal = Critical Reviews in Clinical Laboratory Sciences | volume = 48 | issue = 4 | pages = 155–70 | year = 2011 | pmid = 22035340 | doi = 10.3109/10408363.2011.599831 }}</ref>
(In alphabetical order)


# [[Abciximab (patient information)]]
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.<ref name="pmid14762037">{{cite journal | vauthors = Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ | title = C-reactive protein and the risk of incident colorectal cancer | journal = JAMA | volume = 291 | issue = 5 | pages = 585–90 | date = February 2004 | pmid = 14762037 | doi = 10.1001/jama.291.5.585 | url = http://jama.ama-assn.org/content/291/5/585.full.pdf }}</ref> 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 [[Non-steroidal anti-inflammatory drug|anti-inflammatory drugs]] could lower colon cancer risk.<ref name="pmid12621133">{{cite journal | vauthors = Baron JA, Cole BF, Sandler RS, Haile RW, Ahnen D, Bresalier R, McKeown-Eyssen G, Summers RW, Rothstein R, Burke CA, Snover DC, Church TR, Allen JI, Beach M, Beck GJ, Bond JH, Byers T, Greenberg ER, Mandel JS, Marcon N, Mott LA, Pearson L, Saibil F, van Stolk RU | display-authors = 6 | title = A randomized trial of aspirin to prevent colorectal adenomas | journal = The New England Journal of Medicine | volume = 348 | issue = 10 | pages = 891–9 | date = March 2003 | pmid = 12621133 | doi = 10.1056/NEJMoa021735 }}</ref>
# [[Abdominal Aortic Aneurysm]]
# [[Abetalipoproteinemia]]
# [[Achondrogenesis]]
# [[Acidosis]]
# [[Acne vulgaris]]
# [[Acrodermatitis enteropathica]]
# [[Activated protein C resistance]]
# [[Acute Coronary Syndromes]]
# [[Acute Disseminated Encephalomyelitis]]
# [[Acute myeloid leukemia]]
# [[Adalimumab]]
# [[Adenoid cystic carcinoma]]
# [[Adrenoleukodystrophy]]
# [[Allan-Herndon-Dudley syndrome]]
# [[Alport syndrome]]
# [[Amelogenesis Imperfecta]]
# [[Amyloidosis]]
# [[Amyotrophic Lateral Sclerosis]]
# [[Anakinra (patient information)]]
# [[Andersen-Tawil syndrome]]
# [[Androgen insensitivity syndrome]]
# [[Andrographis paniculata]]
# [[Anemia]]
# [[Angioedema]]
# [[Angiogenesis]]
# [[Angiopathy]]
# [[Ankylosing Spondylitis]]
# [[Anthrax]]
# [[Antiphospholipid syndrome]]
# [[Antithrombin Therapy During Percutaneous Coronary Intervention (PCI) (patient information)]]
# [[Aortic aneurysm]]
# [[Arrhythmogenic right ventricular dysplasia]]
# [[Arteriogenesis]]
# [[Arteritic anterior ischemic optic neuropathy]]
# [[Asceptic Meningitis]]
# [[Ascites]]
# [[Aspergillus clavatus]]
# [[Aspirin]]
# [[ASPM (Genetics)]]
# [[Astrocytoma]]
# [[Ataxia Telangiectasia]]
# [[Atherosclerosis]]
# [[Atransferrinemia]]
# [[Atrophy]]
# [[Atypical pneumonia]]
# [[Autoimmune Hepatitis]]
# [[Autoimmune polyendocrine syndrome]]
# [[Benign familial neonatal convulsions]]
# [[Biotinidase deficiency]]
# [[Bipolar disorder]]
# [[Bird breeder's lung]]
# [[Bladder cancer]]
# [[Blood transfusion]]
# [[Bloom syndrome]]
# [[Boldenone]]
# [[Bone healing]]
# [[Botulinum toxin]]
# [[Bovine spongiform encephalopathy]]
# [[Brachioradial pruritis]]
# [[Brain Abscess]]
# [[Breast cancer]]
# [[Bronchitis]]
# [[Brugada syndrome]]
# [[Budd-Chiari syndrome]]
# [[Byssinosis]]
# [[Carbamoyl phosphate synthetase I deficiency]]
# [[Cardiofaciocutaneous syndrome]]
# [[Cardiomyopathy]]
# [[Cardiovascular Effects of Cocaine]]
# [[Carnitine palmitoyltransferase II deficiency]]
# [[Catecholaminergic polymorphic ventricular tachycardia]]
# [[Cavernous angioma]]
# [[Cavernous Sinus Thrombosis]]
# [[Celiac disease]]
# [[Cerebral edema]]
# [[Cerebral hemorrhage]]
# [[Cervical cancer]]
# [[Cheese worker's lung]]
# [[Chemical worker's lung]]
# [[Cholecystitis]]
# [[Cholera]]
# [[Chronic granulomatous disease]]
# [[Chronic pancreatitis]]
# [[Chronic Renal Failure]]
# [[Cirrhosis]]
# [[Citrullinemia]]
# [[Cladosporium]]
# [[Clarithromycin]]
# [[Clindamycin]]
# [[Coccidioidal Meningitis]]
# [[Colitis]]
# [[Collagenopathy, types II and XI]]
# [[Congenital Adrenal Hyperplasia]]
# [[Congenital muscular dystrophy]]
# [[Congestive Heart Failure]]
# [[Contact dermatitis]]
# [[Corneal ulcer]]
# [[Corticosteroid]]
# [[Creutzfeldt-Jakob Disease]]
# [[Crohn's disease]]
# [[Cryoglobulinemia]]
# [[Cystic Fibrosis]]
# [[Cystinuria]]
# [[Ddx:Hypercalcemia]]
# [[Ddx:Meningitis]]
# [[Demeclocycline]]
# [[Devic's disease]]
# [[Dexamethasone]]
# [[Diabetes mellitus]]
# [[Diabetic ketoacidosis]]
# [[Diabetic nephropathy]]
# [[Diarrhea]]
# [[Disseminated Intravascular Coagulation]]
# [[Down syndrome]]
# [[Doxycycline]]
# [[Drospirenone]]
# [[Drusen]]
# [[Dubin-Johnson syndrome]]
# [[Duchenne's Muscular Dystrophy]]
# [[Dysarthria]]
# [[Eczema]]
# [[Ehlers-Danlos syndrome]]
# [[Emery-Dreifuss Muscular Dystrophy]]
# [[Emphysema]]
# [[Encephalitis]]
# [[Encephalopathy]]
# [[Endometriosis]]
# [[Eosinophilic gastroenteritis]]
# [[Epilepsy]]
# [[Erythromycin]]
# [[Erythropoietin]]
# [[Estrogen]]
# [[Excitotoxicity]]
# [[Experimental autoimmune encephalomyelitis]]
# [[Familial Mediterranean fever]]
# [[Fanconi anemia]]
# [[Fat Embolism Syndrome]]
# [[Fibrodysplasia ossificans progressiva]]
# [[Flunisolide Oral Inhalation (patient information)]]
# [[Fluoxetine]]
# [[Fluticasone and Salmeterol Oral Inhalation (patient information)]]
# [[Fluvoxamine]]
# [[Focal segmental glomerulosclerosis]]
# [[Food allergy]]
# [[Foot-and-mouth disease]]
# [[Friedreich's ataxia]]
# [[Gastrointestinal stromal tumor]]
# [[Gaucher's disease]]
# [[Gitelman syndrome]]
# [[Glioblastoma multiforme]]
# [[Glomerulonephritis]]
# [[Glucagonoma]]
# [[Glutaric acidemia type 2]]
# [[Glutaric aciduria type 1]]
# [[Glycogen storage disease type I]]
# [[GM2-gangliosidosis, AB variant]]
# [[Gout]]
# [[Graft-versus-host disease]]
# [[Grain handler's lung]]
# [[Graves' Disease]]
# [[Group A streptococcal infection]]
# [[Growth hormone deficiency]]
# [[Hantavirus pulmonary syndrome]]
# [[Hemochromatosis]]
# [[Hemoglobinuria]]
# [[Heparin Induced Thrombocytopenia]]
# [[Hepatitis]]
# [[Hepatitis B]]
# [[Hepatitis C/co-infection with HIV]]
# [[Hepatitis G]]
# [[Hepatocellular carcinoma]]
# [[Herpes simplex]]
# [[High protein diet]]
# [[HIV]]
# [[Homocystinuria]]
# [[Hookworm infection]]
# [[Hot tub lung]]
# [[Humidifier lung]]
# [[Hurler's Syndrome]]
# [[Hydatidiform mole]]
# [[Hydrocortisone Oral (patient information)]]
# [[Hyperammonemia]]
# [[Hypercalcemia]]
# [[Hyperimmunoglobulinemia D with recurrent fever]]
# [[Hyperkalemic periodic paralysis]]
# [[Hyperlipidemia]]
# [[Hypermethioninemia]]
# [[Hypernatremia]]
# [[Hyperprolinemia]]
# [[Hypersensitivity Pneumonitis]]
# [[Hypertrophic Cardiomyopathy]]
# [[Hypothyroidism]]
# [[Ibuprofen]]
# [[Imatinib (patient information)]]
# [[Infant respiratory distress syndrome]]
# [[Influenza]]
# [[Isovaleric acidemia]]
# [[Juvenile myoclonic epilepsy]]
# [[Keratoconjunctivitis sicca]]
# [[Ketamine]]
# [[Ketorolac]]
# [[Lactobacillus]]
# [[Lactobacillus reuteri]]
# [[LÃffler's syndrome]]
# [[Lassa Fever]]
# [[Latent tuberculosis]]
# [[Lentivirus]]
# [[Leptospira]]
# [[Lipoid congenital adrenal hyperplasia]]
# [[Lung abscess]]
# [[Malaria]]
# [[Malt worker's lung]]
# [[McCune-Albright syndrome]]
# [[Melanoma]]
# [[Meningioma]]
# [[Mesothelioma]]
# [[Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes]]
# [[Mollusk shell hypersensitivity]]
# [[Multiple myeloma]]
# [[Multiple sclerosis]]
# [[Myocardial infarction]]
# [[Myocarditis]]
# [[Myotonia congenita]]
# [[Myotonic dystrophy]]
# [[Nephronophthisis]]
# [[Nephrotic syndrome]]
# [[Neuroendocrine tumors]]
# [[Neurofibromatosis]]
# [[Niemann-Pick disease]]
# [[Non-Polio enterovirus infections]]
# [[Noonan syndrome]]
# [[Norrie disease]]
# [[Nylon worker's lung]]
# [[Osteoarthritis]]
# [[Osteogenesis imperfecta]]
# [[Osteomalacia]]
# [[Osteoporosis]]
# [[Otospondylomegaepiphyseal dysplasia]]
# [[Pachyonychia congenita]]
# [[Paraneoplastic syndrome]]
# [[Paraproteinemia]]
# [[Pellagra]]
# [[Pemphigus]]
# [[Pendred syndrome]]
# [[Peripheral Arterial Disease]]
# [[Peroxisomal disorder]]
# [[Peutz-Jeghers syndrome]]
# [[Phenylketonuria]]
# [[Pleural Effusion]]
# [[Pneumonia]]
# [[Poliomyelitis]]
# [[Polycystic kidney disease]]
# [[Polymyositis]]
# [[Porphyria cutanea tarda]]
# [[Primary biliary cirrhosis]]
# [[Primary ciliary dyskinesia]]
# [[Propionic acidemia]]
# [[Prostate cancer]]
# [[Protein S deficiency]]
# [[Protein-energy malnutrition]]
# [[Protein-Losing Enteropathy]]
# [[Pseudomonas aeruginosa]]
# [[Pseudoxanthoma elasticum]]
# [[Rabies]]
# [[Reactive Polyarticular Arthritis]]
# [[Relapsing fever]]
# [[Rett syndrome]]
# [[Rheumatic fever]]
# [[Rheumatoid arthritis]]
# [[Romano-Ward syndrome]]
# [[Rubinstein-Taybi syndrome]]
# [[Saccharopolyspora rectivirgula]]
# [[SADDAN]]
# [[Salla disease]]
# [[Sandhoff disease]]
# [[Sarcoidosis]]
# [[Schistosomiasis]]
# [[Scleroderma]]
# [[Sepsis]]
# [[Severe acute respiratory syndrome]]
# [[Shock (medical)]]
# [[Shwachman-Diamond syndrome]]
# [[Sickle-cell disease]]
# [[Sitophilus granarius]]
# [[Smallpox]]
# [[Snakebites]]
# [[Soy allergy]]
# [[Spontaneous bacterial peritonitis]]
# [[Squamous cell carcinoma]]
# [[Stargardt's disease]]
# [[Still's disease]]
# [[Streptococcus pneumoniae]]
# [[Stress cardiomyopathy]]
# [[Subclavian Artery Disease]]
# [[Syphillis]]
# [[Systemic lupus erythematosus]]
# [[Tacrolimus]]
# [[Tay-Sachs Disease]]
# [[Tetanus]]
# [[Thermoactinomyces sacchari]]
# [[Thermoactinomyces vulgaris]]
# [[Thrombocytopenia]]
# [[Thrombocytosis]]
# [[Thrombotic thrombocytopenic purpura]]
# [[Thyroid Carcinoma]]
# [[Tick paralysis]]
# [[Tick-borne meningoencephalitis]]
# [[Total Parenteral Nutrition (patient information)]]
# [[Toxic and Nutritional Optic Neuropathy]]
# [[Treacher Collins syndrome]]
# [[Triamcinolone Oral Inhalation (patient information)]]
# [[Tuberculosis]]
# [[Typhoid fever]]
# [[Tyrosinemia]]
# [[Ulcerative colitis]]
# [[Urea cycle disorder]]
# [[Uremia]]
# [[Usher syndrome]]
# [[Vaccinia]]
# [[Ventricular Tachycardia Including Torsades De Pointes and Polymorphic Ventricular Tachycardia]]
# [[Vitelliform macular dystrophy]]
# [[Vitiligo]]
# [[Von Hippel-Lindau disease]]
# [[Von Willebrand disease]]
# [[Waldenström macroglobulinemia]]
# [[Walker-Warburg syndrome]]
# [[Werner syndrome]]
# [[Williams syndrome]]
# [[Wilson's disease]]
# [[Wiskott-Aldrich syndrome]]
# [[Wolfram syndrome]]
# [[X-linked adrenal hypoplasia congenita]]
# [[X-linked alpha thalassemia mental retardation syndrome]]
# [[X-linked congenital stationary night blindness]]
# [[Yellow fever]]
# [[ZAP70 deficiency]]
# [[Zellweger syndrome]]


== Role in cardiovascular disease ==
=== Obstructive sleep apnea ===
Recent research suggests that patients with elevated basal levels of CRP are at an increased risk for [[diabetes]],<ref>{{cite journal | author=Pradhan AD | title=C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus| journal=JAMA | year=2001 | volume=286 | pages= 327&ndash;334 | url= http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=pubmed| id=PMID  11466099}}</ref><ref>{{cite journal | author=Dehghan A| title=Genetic variation, C-reactive protein levels, and incidence of diabetes. | journal=Diabetes | year=2007 | volume=56 | pages= 872|id=PMID 17327459 }}</ref> [[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 C-reactive protein (CRP, a pro-inflammatory [[cytokine]] which is a [[cardiovascular disease]] risk factor) that were 73% higher than those in the lowest quartile.<ref>{{cite journal | author=Esther Lopez-Garcia | title=Consumption of Trans Fatty Acids Is Related to Plasma Biomarkers of Inflammation and Endothelial Dysfunction | journal=The Journal of Nutrition | year=2005 | volume=135 | issue=3 | pages= 562&ndash;566 | url=http://jn.nutrition.org/cgi/content/full/135/3/562 | id=PMID  15735094}}</ref> Although one group of researchers indicated that CRP may only be a moderate risk factor for cardiovascular disease,<ref>{{cite journal | author=John Danesh | title=C-Reactive Protein and Other Circulating Markers of Inflammation in the Prediction of Coronary Heart Disease| journal=New England Journal of Medicine | year=2004 | volume=350 | issue=14 | pages= 1387&ndash;1397 | url=http://content.nejm.org/cgi/content/abstract/350/14/1387 | id=PMID 15070788}}</ref> 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.<ref>Koenig, Wolfgang (2006). ''C-Reactive Protein – A Critical Cardiovascular Risk Marker'' [http://www.crphealth.com/conf/hcp/5,59/doctor.wolfgang.koenig.c-reactive.protein.%96.a.critical.cardiovascular.risk.html]</ref>  Others have shown that CRP can exacerbate [[ischemic]] [[necrosis]] in a [[complement (biology)|complement]]-dependent fashion and that CRP inhibition can be a safe and effective therapy for [[myocardial]] and [[cerebral]] [[infarct]]s.<ref>{{cite journal | author=Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, Hawkins PN, Myers RM, Smith MD, Polara A, Cobb AJ, Ley SV, Aquilina JA, Robinson CV, Sharif I, Gray GA, Sabin CA, Jenvey MC, Kolstoe SE, Thompson D, Wood SP | title=Targeting C-reactive protein for the treatment of cardiovascular disease.| journal=Nature | year=2006 | volume=440 | pages=1217&ndash;1221 |  id=PMID 16642000}}</ref>


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.
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.<ref name="pmid23533751">{{cite journal | vauthors = Latina JM, Estes NA, Garlitski AC | title = The Relationship between Obstructive Sleep Apnea and Atrial Fibrillation: A Complex Interplay | journal = Pulmonary Medicine | volume = 2013 | issue =  | pages = 621736 | year = 2013 | pmid = 23533751 | pmc = 3600315 | doi = 10.1155/2013/621736 }}</ref> 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.<ref name="pmid23533751"/>


==Role in colon cancer==
=== Rheumatoid arthritis ===
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.<ref>{{cite journal | author=Erlinger TP, Platz EA, Rifai N, Helzlsouer KJ | title=C-reactive protein and the risk of incident colorectal cancer | journal=Journal of the American Medical Association | volume=291 | issue=Feb. 4 | year=2004 | pages=585-590 | id=PMID 14762037 }}</ref> These findings concur with previous studies that indicate that [[Non-steroidal anti-inflammatory drug|anti-inflammatory drugs]] could lower colon cancer risk.<ref> {{ cite journal | author=Baron JA, et al | title = A randomized trial of aspirin to prevent colorectal adenomas | journal = New England Journal of Medicine | volume = 348 | year=2003 | pages=891-899 | id=PMID 12621133 }}</ref>
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.<ref name="pmid25359432">{{cite journal | vauthors = Ammitzbøll CG, Steffensen R, Bøgsted M, Hørslev-Petersen K, Hetland ML, Junker P, Johansen JS, Pødenphant J, Østergaard M, Ellingsen T, Stengaard-Pedersen K | display-authors = 6 | title = CRP genotype and haplotype associations with serum C-reactive protein level and DAS28 in untreated early rheumatoid arthritis patients | journal = Arthritis Research & Therapy | volume = 16 | issue = 5 | pages = 475 | date = October 2014 | pmid = 25359432 | pmc = 4247621 | doi = 10.1186/s13075-014-0475-3 }}</ref> 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.


==Related chapters==
== See also ==
* acute phase
* [[acute phase]]
* [[erythrocyte sedimentation rate]]
* [[erythrocyte sedimentation rate]]
* [[immunology]]
* [[Cardiology diagnostic tests and procedures]]


==Additional images==
==Additional images==
<gallery>
<gallery>
  Image:C-reactive protein.png|C-reactive protein
  Image:C-reactive protein.png|C-reactive protein
Image: 1lj7.jpg|C-reactive protein
</gallery>
</gallery>


==References==
== References ==
{{Reflist|2}}
{{Reflist|35em}}


==Resources==
== External links ==
* {{MedlinePlus|003356}}
* {{MedlinePlusEncyclopedia|003356|C-reactive protein}}
* [http://www.americanheart.org/presenter.jhtml?identifier=4648 Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein] ([[American Heart Association]])
* [http://www.americanheart.org/presenter.jhtml?identifier=4648 Inflammation, Heart Disease and Stroke: The Role of C-Reactive Protein] ([[American Heart Association]])
* {{MeshName|C-Reactive+Protein}}
* {{MeshName|C-Reactive+Protein}}
* CRP at [http://labtestsonline.org/understanding/analytes/crp/tab/test Lab Tests Online]
* [http://www.acb.org.uk/Nat%20Lab%20Med%20Hbk/CRP.pdf CRP: analyte monograph] - The Association for Clinical Biochemistry and Laboratory Medicine
*[http://epubs.scu.edu.au/hahs_pubs/2234/ George Vrousgos, N.D. - Southern Cross University]
* {{UCSC gene info|CRP}}


{{PDB Gallery|geneid=1401}}
{{Albumins}}
{{Albumins}}
{{Acute phase proteins}}  
{{Acute phase proteins}}
{{SIB}}
{{Immunologic techniques and tests}}


{{DEFAULTSORT:C-Reactive Protein}}
[[Category:Acute phase proteins]]
[[Category:Acute phase proteins]]
[[Category:Blood tests]]
[[Category:Chemical pathology]]
[[Category:Chemical pathology]]
[[Category:Blood tests]]
[[Category:Intensive care medicine]]
 
[[Category:Immunologic tests]]
[[da:CRP]]
[[Category:Biomarkers]]
[[de:C-reaktives Protein]]
[[es:Proteína C reactiva]]
[[fr:Protéine C réactive]]
[[it:Proteina C-reattiva]]
[[he:חלבון מגיב C]]
[[nl:C-reactief proteïne]]
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C-reactive protein (CRP) is an annular (ring-shaped), pentameric protein found in blood plasma, whose levels rise in response to inflammation. It is an acute-phase protein of hepatic origin that increases following interleukin-6 secretion by macrophages and T cells. Its physiological role is to bind to lysophosphatidylcholine expressed on the surface of dead or dying cells (and some types of bacteria) in order to activate the complement system via C1q.[1]

CRP is synthesized by the liver[2] in response to factors released by macrophages and fat cells (adipocytes).[3] It is a member of the pentraxin family of proteins.[2] It is not related to C-peptide (insulin) or protein C (blood coagulation). C-reactive protein was the first pattern recognition receptor (PRR) to be identified.[4]

History and nomenclature

Discovered by Tillett and Francis in 1930,[5] it was initially thought that CRP might be a pathogenic secretion since it was elevated in a variety of illnesses, including cancer.[2] The later discovery of hepatic synthesis (made in the liver) demonstrated that it is a native protein.[6][7][8] Initially, CRP was measured using Quellung reaction which gave a positive or a negative reaction. More precise methods nowadays is using dynamic light scattering on antibodies specific to CRP.[9]

CRP was so named because it was first identified as a substance in the serum of patients with acute inflammation that reacted with the antibody against the somatic capsular polysaccharide (C-polysaccharide) of pneumococcus.[10][11]

Genetics and structure

The CRP gene is located on chromosome 1 (1q23.2[12]). It is a member of the small pentraxins family. The monomer has 224 amino acids,[13] and molecular mass of 25,106 Da. In serum, it assembles into stable pentameric structure with a discoid shape.

Function

CRP binds to the phosphocholine expressed on the surface of dead or dying cells and some bacteria. This activates the complement system, promoting phagocytosis by macrophages, which clears necrotic and apoptotic cells and bacteria.[9]

This so-called acute phase response occurs as a result of a rise in the concentration of IL-6, which is produced by macrophages[2] as well as adipocytes[3] in response to a wide range of acute and chronic inflammatory conditions such as bacterial, viral, or fungal infections; rheumatic and other inflammatory diseases; malignancy; and tissue injury and necrosis. These conditions cause release of interleukin-6 and other cytokines that trigger the synthesis of CRP and fibrinogen by the liver.

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.[9]

Serum levels

In healthy adults, the normal concentrations of CRP varies between 0.8 mg/L to 3.0 mg/L. However, some healthy adults show elevated CRP at 10 mg/L. When there is a stimulus, the CRP level can rise 10,000-fold from less than 50 μg/l to more than 500 mg/L. Such levels can rise to 5 mg/L by 6 hours and peaks at 48 hours. The plasma half-life of CRP is 19 hours. Such half-life is constant in all medical conditions. Therefore, the only factor that affects the level of CRP in blood is its rate of production. The rate of CRP production increases with inflammation, infection, trauma, necrosis, malignancy, and allergic reaction. The CRP level also increases with age, possibly due to increasing subclinical condition. There is also no seasonal variations of CRP levels. Gene polymorphism of interleukin-1 family, interleukin 6, and polymorphic GT repeat of the CRP gene do affects the usual CRP levels when a person does not have any medical illnesses.[2] Other inflammatory mediators that can cause a rise in CRP are TGF beta 1, and tumor necrosis factor alpha. In acute inflammation, CRP can raise as much as 50 to 100 mg/dL within 4 to 6 hours in mild to moderate inflammation or insult such as skin infection, cystitis, or bronchitis. It can double every 8 hours and reaches its peak at 36 to 50 hours following injury or inflammation. CRP between 100 to 500 mg/dL is considered as bacterial inflammation. CRP concentrations between 2 to 10 mg/dL are considered as metabolic inflammation (metabolic pathways that causes arteriosclerosis and type II diabetes mellitus). Once inflammation subsides, CRP level falls quickly because of its relatively short half-life.[9]

Clinical significance

Diagnostic use

CRP is used mainly as a marker of inflammation. Apart from liver failure, there are few known factors that interfere with CRP production.[2] 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 [14]

Measuring and charting CRP values can prove useful in determining disease progress or the effectiveness of treatments. ELISA, immunoturbidimetry, nephelometry, rapid immunodiffusion, and visual agglutination are all methods used to measure CRP.

File:Blood values sorted by mass and molar concentration.png
Reference ranges for blood tests, showing C-reactive protein in brown-yellow in center.

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.

The risk of developing cardiovascular disease is quantified as follows:[15]

  • low: hs-CRP level under 1.0 mg/L
  • average: between 1.0 and 3.0 mg/L
  • high: above 3.0 mg/L

Normal levels increase with aging.[16] 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 burns (>200 mg/L).[17]

CRP is a more sensitive and accurate reflection of the acute phase response than the ESR[18] (Erythrocyte Sedimentation Rate). ESR may be normal while CRP is elevated. CRP returns to normal more quickly than ESR in response to therapy.

The utility of CRP in differentiating inflammatory diseases (including inflammatory bowel disease, intestinal lymphoma, intestinal tuberculosis, and Behcet's syndrome) has been investigated and compared to other inflammatory biomarkers, such as ESR and WBC.[18]

Cardiovascular disease

Recent research suggests that patients with elevated basal levels of CRP are at an increased risk of diabetes,[19][20] 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.[21] Although one group of researchers indicated that CRP may be only a moderate risk factor for cardiovascular disease,[22] 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.[23] 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.[24]

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.[2][25] Studies comparing effect of various statins in hs-CRP revealed similar effects of different statins.[26][27] A subsequent trial however failed to find that CRP was useful for determining statin benefit.[28]

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.[29]

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.[30] A study published in 2011 shows that CRP is associated with lipid responses to low-fat and high-polyunsaturated fat diets.[31]

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.[32][33] 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;[2] 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.[34]

The American Heart Association and U.S. Centers for Disease Control and Prevention have defined risk groups as follows:[35]

  • Low Risk: less than 1.0 mg/L
  • Average risk: 1.0 to 3.0 mg/L
  • High risk: above 3.0 mg/L

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.

Fibrosis and inflammation

Scleroderma, polymyositis, and dermatomyositis 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.[36] Elevated level of CRP can also be observed in inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis.[18]

High levels of CRP has been associated to point mutation Cys130Arg in APOE gene, coding for apolipoprotein E, establishing a link between lipid values and inflammatory markers modulation.[37]

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.[38] 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.[39]

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.[40] 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.[41]

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.[42] 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.[42]

Rheumatoid arthritis

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.[43] 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.

See also

Additional images

References

  1. ↑ Thompson D, Pepys MB, Wood SP (February 1999). "The physiological structure of human C-reactive protein and its complex with phosphocholine". Structure. 7 (2): 169–77. doi:10.1016/S0969-2126(99)80023-9. PMID 10368284.
  2. ↑ 2.0 2.1 2.2 2.3 2.4 2.5 2.6 2.7 Pepys MB, Hirschfield GM (June 2003). "C-reactive protein: a critical update". The Journal of Clinical Investigation. 111 (12): 1805–12. doi:10.1172/JCI18921. PMC 161431. PMID 12813013.
  3. ↑ 3.0 3.1 Lau DC, Dhillon B, Yan H, Szmitko PE, Verma S (May 2005). "Adipokines: molecular links between obesity and atheroslcerosis". American Journal of Physiology. Heart and Circulatory Physiology. 288 (5): H2031–41. doi:10.1152/ajpheart.01058.2004. PMID 15653761.
  4. ↑ Mantovani A, Garlanda C, Doni A, Bottazzi B (January 2008). "Pentraxins in innate immunity: from C-reactive protein to the long pentraxin PTX3". Journal of Clinical Immunology. 28 (1): 1–13. doi:10.1007/s10875-007-9126-7. PMID 17828584.
  5. ↑ Tillett WS, Francis T (September 1930). "Serological reactions in pneumonia with a nonprotein somatic fraction of pneumococcus". The Journal of Experimental Medicine. 52 (4): 561–71. doi:10.1084/jem.52.4.561. PMC 2131884. PMID 19869788.
  6. ↑ Kennelly PJ, Murray RF, Rodwell VW, Botham KM (2009). Harper's illustrated biochemistry. McGraw-Hill Medical. ISBN 0-07-162591-7.
  7. ↑ Pincus MR, McPherson RA, Henry JB (2007). Henry's clinical diagnosis and management by laboratory methods. Saunders Elsevier. ISBN 1-4160-0287-1.
  8. ↑ Ratey JJ, Noskin GA, Braun R, Hanley EN Jr, McInnes IB, Ruddy S (2008). Kelley's Textbook of Rheumatology: 2-Volume Set, Expert Consult: Online and Print (Textbook of Rheumatology (Kelley's)(2 Vol)). Philadelphia: Saunders. ISBN 1-4160-3285-1.
  9. ↑ 9.0 9.1 9.2 9.3 Bray C, Bell LN, Liang H, Haykal R, Kaiksow F, Mazza JJ, Yale SH (December 2016). "Erythrocyte Sedimentation Rate and C-reactive Protein Measurements and Their Relevance in Clinical Medicine" (PDF). Wisconsin Medical Journal (WMJ). 115 (6): 317–21. PMID 29094869.
  10. ↑ Ananthanarayan R, Paniker CJ (1978). Ananthanarayan and Paniker's Textbook of Microbiology (7th ed.). Himayatnagar, Hyderabad: Orient Longman. p. 218. ISBN 9788125028086.
  11. ↑ Levine M (2011). "Chapter 13: Chronic Periodontitis". Topics in Dental Biochemistry. Berlin, Heidelberg: Springer. ISBN 978-3-540-88115-5. C-reactive protein (CRP) was originally identified as binding to the phosphocholine attachment site of capsular polysaccharide (C-polysaccharide) from Streptococcus pneumoniae.
  12. ↑ "CRP C-reactive protein [Homo sapiens]". Entrez Gene. National Center for Biotechnology Information (NCBI), U.S. National Library of Medicine.
  13. ↑ "#CAA39671". NCBI Entrez Protein.
  14. ↑ Enocsson H, Sjöwall C, Skogh T, Eloranta ML, Rönnblom L, Wetterö J (December 2009). "Interferon-alpha mediates suppression of C-reactive protein: explanation for muted C-reactive protein response in lupus flares?". Arthritis and Rheumatism. 60 (12): 3755–60. doi:10.1002/art.25042. PMID 19950271.
  15. ↑ "Normal results". C-reactive protein. MedlinePlus. Retrieved 23 April 2015.
  16. ↑ Thomas, Lothar, Labor und Diagnose. TH-Books, Frankfurt, 2008, p. 1010
  17. ↑ Chew KS (April 2012). "What's new in Emergencies Trauma and Shock? C-reactive protein as a potential clinical biomarker for influenza infection: More questions than answers". Journal of Emergencies, Trauma, and Shock. 5 (2): 115–7. doi:10.4103/0974-2700.96477. PMC 3391832. PMID 22787338.
  18. ↑ 18.0 18.1 18.2 Liu S, Ren J, Xia Q, Wu X, Han G, Ren H, Yan D, Wang G, Gu G, Li J (December 2013). "Preliminary case-control study to evaluate diagnostic values of C-reactive protein and erythrocyte sedimentation rate in differentiating active Crohn's disease from intestinal lymphoma, intestinal tuberculosis and Behcet's syndrome". The American Journal of the Medical Sciences. 346 (6): 467–72. doi:10.1097/MAJ.0b013e3182959a18. PMID 23689052.[unreliable medical source]
  19. ↑ Pradhan AD, Manson JE, Rifai N, Buring JE, Ridker PM (July 2001). "C-reactive protein, interleukin 6, and risk of developing type 2 diabetes mellitus". JAMA. 286 (3): 327–34. doi:10.1001/jama.286.3.327. PMID 11466099.
  20. ↑ Dehghan A, Kardys I, de Maat MP, Uitterlinden AG, Sijbrands EJ, Bootsma AH, et al. (March 2007). "Genetic variation, C-reactive protein levels, and incidence of diabetes". Diabetes. 56 (3): 872–8. doi:10.2337/db06-0922. PMID 17327459.
  21. ↑ Lopez-Garcia E, Schulze MB, Meigs JB, Manson JE, Rifai N, Stampfer MJ, et al. (March 2005). "Consumption of trans fatty acids is related to plasma biomarkers of inflammation and endothelial dysfunction". The Journal of Nutrition. 135 (3): 562–6. doi:10.1093/jn/135.3.562. PMID 15735094.
  22. ↑ Danesh J, Wheeler JG, Hirschfield GM, Eda S, Eiriksdottir G, Rumley A, et al. (April 2004). "C-reactive protein and other circulating markers of inflammation in the prediction of coronary heart disease". The New England Journal of Medicine. 350 (14): 1387–97. doi:10.1056/NEJMoa032804. PMID 15070788.
  23. ↑ Koenig, Wolfgang (2006). "C-reactive protein - a critical cardiovascular risk marker". CRPhealth.com.
  24. ↑ Pepys MB, Hirschfield GM, Tennent GA, Gallimore JR, Kahan MC, Bellotti V, et al. (April 2006). "Targeting C-reactive protein for the treatment of cardiovascular disease". Nature. 440 (7088): 1217–21. doi:10.1038/nature04672. PMID 16642000.
  25. ↑ Ridker PM, Danielson E, Fonseca FA, Genest J, Gotto AM, Kastelein JJ, et al. (November 2008). "Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein". The New England Journal of Medicine. 359 (21): 2195–207. doi:10.1056/NEJMoa0807646. PMID 18997196.
  26. ↑ Sindhu S, Singh HK, Salman MT, Fatima J, Verma VK (October 2011). "Effects of atorvastatin and rosuvastatin on high-sensitivity C-reactive protein and lipid profile in obese type 2 diabetes mellitus patients". Journal of Pharmacology & Pharmacotherapeutics. 2 (4): 261–5. doi:10.4103/0976-500X.85954. PMC 3198521. PMID 22025854.
  27. ↑ Jialal I, Stein D, Balis D, Grundy SM, Adams-Huet B, Devaraj S (April 2001). "Effect of hydroxymethyl glutaryl coenzyme a reductase inhibitor therapy on high sensitive C-reactive protein levels". Circulation. 103 (15): 1933–5. doi:10.1161/01.CIR.103.15.1933. PMID 11306519.
  28. ↑ Heart Protection Study Collaborative Group, Emberson J, Bennett D, Link E, Parish S, Danesh J, Armitage J, Collins R (February 2011). "C-reactive protein concentration and the vascular benefits of statin therapy: an analysis of 20,536 patients in the Heart Protection Study". Lancet. 377 (9764): 469–76. doi:10.1016/S0140-6736(10)62174-5. PMC 3042687. PMID 21277016.
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