Crohn's disease causes: Difference between revisions

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[[Image:NOD2 CARD15.svg|center|thumb|200px|Schematic of NOD2 CARD15 gene, which is associated with certain disease patterns in Crohn's disease]]
[[Image:NOD2 CARD15.svg|center|thumb|200px|Schematic of NOD2 CARD15 gene, which is associated with certain disease patterns in Crohn's disease]]


The exact cause of Crohn's disease is unknown. However, genetic and environmental factors have been invoked in the [[pathogenesis]] of the disease. Research has indicated that Crohn's disease has a strong genetic link. <ref>[http://www.ccfa.org/reuters/genelic link Crohn's disease has strong genetic link: study]</ref> The disease runs in families and those with a sibling with the disease are 30 times more likely to develop it than the normal population. Ethnic background is also a risk factor. Until very recently, whites and European Jews accounted for the vast majority of the cases in the United States, and in most industrialized countries, this demographic is still true. 
The exact cause of Crohn's disease is unknown. However, genetic and environmental factors have been invoked in the [[pathogenesis]] of the disease. Research has indicated that Crohn's disease has a strong genetic link. <ref>[http://www.ccfa.org/reuters/genelic link Crohn's disease has strong genetic link: study]</ref> The disease runs in families and those with a sibling with the disease are 30 times more likely to develop it than the normal population.


[[Mutation]]s in the [[NOD2|CARD15]] gene (also known as the NOD2 [[gene]]) are associated with Crohn's disease<!-- --><ref>Ogura Y, Bonen DK, Inohara N, ''et al.''  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.  ''Nature''. 2001 May 31;411(6837):603-6.</ref> and with susceptibility to certain phenotypes of disease location and activity.<ref><!--  
[[Mutation]]s in the [[NOD2|CARD15]] gene (also known as the NOD2 [[gene]]) are associated with Crohn's disease<!-- --><ref>Ogura Y, Bonen DK, Inohara N, ''et al.''  A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease.  ''Nature''. 2001 May 31;411(6837):603-6.</ref> and with susceptibility to certain phenotypes of disease location and activity.<ref><!--  
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A handful of cases of Crohn's Disease cases were reported at the turn of the 20th century, but since then, the disease has continued to increase in prevalence dramatically. Some argue that this increase has been the result of a genetic shift in the population caused by conditions favoring individuals carrying the genes linked with the disease. These conditions could be a lower infant mortality rate or better health care in the nations that have the highest incidence of disease (industrialized nations).   
A handful of cases of Crohn's Disease cases were reported at the turn of the 20th century, but since then, the disease has continued to increase in prevalence dramatically. Some argue that this increase has been the result of a genetic shift in the population caused by conditions favoring individuals carrying the genes linked with the disease. These conditions could be a lower infant mortality rate or better health care in the nations that have the highest incidence of disease (industrialized nations).   


Others argue that Crohn's Disease is caused by a combination of environmental and genetic factors. Many environmental factors have also been hypothesized as causes or risk factors for Crohn's disease. Proven environmental risk factors include living in an industrialized country, smoking, and living in an urban area. Diets high in sweet, [[fat]]ty or [[Food processing|refined foods]] may also play a role. A retrospective Japanese study found that those diagnosed with Crohn's disease had higher intakes of sugar, fat, fish and shellfish than controls prior to diagnosis.<!--
Others argue that Crohn's Disease is caused by a combination of environmental and genetic factors.
--><ref>{{cite journal | author = Sakamoto N, Kono S, Wakai K, ''et al.'' | title = Dietary risk factors for inflammatory bowel disease: a multicenter case-control study in Japan. | journal = Inflamm Bowel Dis | volume = 11 | issue = 2 | pages = 154-63 | year = 2005 | id = PMID 15677909}}</ref> A similar study in Israel also found higher intakes of fats (especially chemically modified fats) and [[sucrose]], with lower intakes of [[fructose]] and fruits, water, [[potassium]], [[magnesium]] and vitamin C in the diets of Crohn's disease sufferers before diagnosis,<!--
--><ref>{{cite journal | author = Reif S, Klein I, Lubin F, Farbstein M, Hallak A, Gilat T | title = Pre-illness dietary factors in inflammatory bowel disease. | journal = Gut | volume = 40 | issue = 6 | pages = 754-60 | year = 1997 | id = PMID 9245929| url = http://gut.bmj.com/cgi/reprint/40/6/754 | format = PDF }}</ref> and cites three large European studies in which sugar intake was significantly increased in people with Crohn's disease compared with controls. Certain chemicals in the diet, known as microparticles, are also hypothesized as a risk factor for the disease, as well as a poor imbalance of omega-6 to healthy omega-3 fatty acids that emerging research shows helps to improve all types of inflammatory disease. The most common forms of microparticles include titanium dioxide, aluminosilicates, anatase, calcium phosphate, and soil residue. These substances are ubiquitous in processed food and most toothpastes and lip glosses. Soil residue is found on fresh fruits and vegetables unless carefully removed.
 
[[Tobacco smoking|Smoking]] has been shown to increase the risk of the return of active disease, or "flares".<ref>{{cite journal | author = Cosnes J | title = Tobacco and IBD: relevance in the understanding of disease mechanisms and clinical practice. | journal = Best Pract Res Clin Gastroenterol | volume = 18 | issue = 3 | pages = 481-96 | year = 2004 | id = PMID 15157822}}</ref>
The introduction of [[hormonal contraception]] in the United States in the 1960's is linked with a dramatic increase in the incidence rate of Crohn's disease. Although a causal linkage has not been effectively shown, there remain fears that these drugs work on the digestive system in similar ways to smoking.<ref><!--
-->{{cite journal | author = Lesko S, Kaufman D, Rosenberg L, ''et al.'' | title = Evidence for an increased risk of Crohn's disease in oral contraceptive users. | journal = Gastroenterology | volume = 89 | issue = 5 | pages = 1046-9 | year = 1985 | id = PMID 4043662}}</ref>
 
Additionally, many in the scientific community believe that early childhood exposure to illness is necessary to the creation of a proper immune system for those with the genetic suseptibility for Crohn's Disease. Like Polio, higher incidences of Crohn's Disease are associated with cleaner living conditions. Throughout the early and mid-20th century in the United States, the disease was strongly associated with upper-class populations, and today the disease does not yet exist in the many Third World countries, despite the fact that it occurs in all races. CD is also associated with first born and single children (because  they would have less exposure to childhood illness from siblings) and in populations that have low incidences of gastric cancer. Gastric cancer is most often caused by the bacterium Helicobacter pylori that flourishes in cramped and unsanitary conditions.<ref>{{cite journal|last=Morris|first= Danielle L|coauthors=Scott M Montgomery|date=2000-11-18|title=Early environmental factors may have role in both Crohn's disease and gastric carcinoma - Letter to the Editor|journal=British Medical Journal|url=http://findarticles.com/p/articles/mi_m0999/is_7271_321/ai_67708495/|accessdate=2008-01-16}}</ref>


Abnormalities in the immune system have often been invoked as being causes of Crohn's disease. It has been hypothesized that Crohn's disease involves augmentation of the [[T helper cell#Th1.2FTh2 Model for helper T cells|T<sub>h</sub>1]] of [[cytokine]] response in inflammation.<ref>Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn's disease.  ''Immunol Rev.'' 2005 Aug;206:277-95.  PMID 16048555</ref> The most recent gene to be implicated in Crohn's disease is ATG16L1, which may reduce the effectiveness of [[autophagy]], and hinder the body's ability to attack invasive bacteria.<ref>Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, Bagnall R, Mirza MM, Sanderson J, Forbes A, Mansfield JC, Lewis CM, Schreiber S, Mathew CG. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. ''Gastroenterology.'' 2007 May;132(5):1665-71. PMID: 17484864.</ref>
Abnormalities in the immune system have often been invoked as being causes of Crohn's disease. It has been hypothesized that Crohn's disease involves augmentation of the [[T helper cell#Th1.2FTh2 Model for helper T cells|T<sub>h</sub>1]] of [[cytokine]] response in inflammation.<ref>Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn's disease.  ''Immunol Rev.'' 2005 Aug;206:277-95.  PMID 16048555</ref> The most recent gene to be implicated in Crohn's disease is ATG16L1, which may reduce the effectiveness of [[autophagy]], and hinder the body's ability to attack invasive bacteria.<ref>Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, Bagnall R, Mirza MM, Sanderson J, Forbes A, Mansfield JC, Lewis CM, Schreiber S, Mathew CG. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. ''Gastroenterology.'' 2007 May;132(5):1665-71. PMID: 17484864.</ref>

Revision as of 15:21, 12 August 2012

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

Overview

Causes

Schematic of NOD2 CARD15 gene, which is associated with certain disease patterns in Crohn's disease

The exact cause of Crohn's disease is unknown. However, genetic and environmental factors have been invoked in the pathogenesis of the disease. Research has indicated that Crohn's disease has a strong genetic link. [1] The disease runs in families and those with a sibling with the disease are 30 times more likely to develop it than the normal population.

Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's disease[2] and with susceptibility to certain phenotypes of disease location and activity.[3] In earlier studies, only two genes were linked to Crohn's, but scientists now believe there are over eight genes that show genetics play a crucial role in the disease.

A handful of cases of Crohn's Disease cases were reported at the turn of the 20th century, but since then, the disease has continued to increase in prevalence dramatically. Some argue that this increase has been the result of a genetic shift in the population caused by conditions favoring individuals carrying the genes linked with the disease. These conditions could be a lower infant mortality rate or better health care in the nations that have the highest incidence of disease (industrialized nations).

Others argue that Crohn's Disease is caused by a combination of environmental and genetic factors.

Abnormalities in the immune system have often been invoked as being causes of Crohn's disease. It has been hypothesized that Crohn's disease involves augmentation of the Th1 of cytokine response in inflammation.[4] The most recent gene to be implicated in Crohn's disease is ATG16L1, which may reduce the effectiveness of autophagy, and hinder the body's ability to attack invasive bacteria.[5]

A variety of pathogenic bacteria were initially suspected of being causative agents of Crohn's disease. However, the current consensus is that a variety of microorganisms are simply taking advantage of their host's weakened mucosal layer and inability to clear bacteria from the intestinal walls, both symptoms of the disease. [6] Some studies have linked Mycobacterium avium subsp. paratuberculosis to Crohn's disease, in part because it causes a very similar disease, Johne's disease, in cattle. [7] The mannose bearing antigens, mannins, from yeast may also elicit pathogenic anti saccharomyces cerevisiae antibodies.[8] Newer studies have linked specific strains of enteroadherent E. coli to the disease but failed to find evidence of contributions by other species. [9]

References

  1. ↑ link Crohn's disease has strong genetic link: study
  2. ↑ Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn's disease. Nature. 2001 May 31;411(6837):603-6.
  3. ↑ Cuthbert A, Fisher S, Mirza M; et al. (2002). "The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease". Gastroenterology. 122 (4): 867–74. PMID 11910337.
  4. ↑ Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn's disease. Immunol Rev. 2005 Aug;206:277-95. PMID 16048555
  5. ↑ Prescott NJ, Fisher SA, Franke A, Hampe J, Onnie CM, Soars D, Bagnall R, Mirza MM, Sanderson J, Forbes A, Mansfield JC, Lewis CM, Schreiber S, Mathew CG. A nonsynonymous SNP in ATG16L1 predisposes to ileal Crohn's disease and is independent of CARD15 and IBD5. Gastroenterology. 2007 May;132(5):1665-71. PMID: 17484864.
  6. ↑ Sartor, R. (2006). "Mechanisms of Disease: pathogenesis of Crohn's disease and ulcerative colitis". Nature Clinical Practice Gastroenterology & Hepatology (3): 390–407. doi:10.1038 Check |doi= value (help).
  7. ↑ Naser SA, Collins MT. Debate on the lack of evidence of Mycobacterium avium subsp. paratuberculosis in Crohn's disease. Inflamm Bowel Dis. 2005 Dec;11(12):1123. PMID 16306778
  8. ↑ Giaffer MH, Clark A, Holdsworth CD (1992). "Antibodies to Saccharomyces cerevisiae in patients with Crohn's disease and their possible pathogenic importance". Gut. 33 (8): 1071–5. PMID 1398231.
  9. ↑ Baumgart, M.; et al. (2007). "Culture independent analysis of ileal mucosa reveals a selective increase in invasive Escherichia coli of novel phylogeny relative to depletion of Clostridiales in Crohn's disease involving the ileum (advance online publication)". The ISME Journal. doi:10.1038 Check |doi= value (help).

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