Crohn's disease pathophysiology: Difference between revisions

Jump to navigation Jump to search
VisualWikitext
m (Bot: Removing from Primary care)
 
(21 intermediate revisions by 4 users not shown)
Line 1: Line 1:
<div style="-webkit-user-select: none;">
{| class="infobox" style="position: fixed; top: 65%; right: 10px; margin: 0 0 0 0; border: 0; float: right;"
|-
| {{#ev:youtube|https://https://www.youtube.com/watch?v=thzOJV-CHRo|350}}
|-
|}
__NOTOC__
__NOTOC__
{{Crohn's disease}}
{{Crohn's disease}}
{{CMG}}
{{CMG}}; {{AE}} {{ADG}}
==Overview==
[[Genetic]] and environmental factors play a key role in the pathogenesis of Crohn's disease. [[Mutation]]s in the [[NOD2|CARD15]] gene (also known as the NOD2 [[gene]]) are associated with Crohn's disease and with susceptibility to certain phenotypes of disease location and activity. Environmental factors include autoimmune Disease and dysregulated Immune Response to Commensal Bacteria. Characteristic features of the [[pathology]] that point toward Crohn's disease are transmural pattern of [[inflammation]] and skip lesions. Under microscopy [[Granuloma]]s are seen, which are aggregates of [[macrophage]] derivatives known as giant cells, are found in 50% of cases and are most specific for Crohn's disease.
==Pathophysiology==
==Pathophysiology==
Genetic and environmental factors play a key role in the pathogenisis of Crohn's disease.
The exact pathogenesis of Crohn's disease is not clearly understood. However, 4 components have been proved to play a key role in the pathogenesis of Crohn's disease.
===Genetics===
*Genetic component
*[[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><!--  
*Stress and environmental component
-->{{cite journal | author = Cuthbert A, Fisher S, Mirza M, ''et al.'' | title = The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. | journal = Gastroenterology | volume = 122 | issue = 4 | pages = 867-74 | year = 2002 | id = PMID 11910337}}</ref>  
*Microbial component
*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.
*Inflammatory component
*Abnormalities in the immune system have often been invoked as being causes of Crohn's disease.  
===Genetic Component===
*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>  
There are several genes involved in the pathogenesis of Crohn's disease. Mutation of any of these genes disrupts the normal function of cells triggering an inflammatory response. Some common and most important genes are as follows:.<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>
-->{{cite journal | author = Cuthbert A, Fisher S, Mirza M, ''et al.'' | title = The contribution of NOD2 gene mutations to the risk and site of disease in inflammatory bowel disease. | journal = Gastroenterology | volume = 122 | issue = 4 | pages = 867-74 | year = 2002 | id = PMID 11910337}}</ref><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><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><ref>Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn's disease.  ''Immunol Rev.'' 2005 Aug;206:277-95.  PMID 16048555</ref>
*NOD2/CARD15 gene
*OCTN1 gene
*DLG5 gene
*TLR4 gene
<u>'''The following tables summarizes the most important genes involved in the pathogenesis of Crohn's disease'''</u>
{| class="wikitable"
!Genes
! colspan="2" |Chromosome
!Function
!Mutation
|-
|NOD2/CARD15
|16
|16q12.1
|Encodes a scaffolding protein important for maintaining epithelial integrity
|Disrupts normal epithelial integrity
|-
|OCTN1
|05
|5q31
|Ecodes an ion channel
|Alters the function of cation transporters and cell-to-cell signaling
|-
|DLG5
|10
|10q22.3
|Interact additively with the NOD2/CARD15 gene
|Iincrease susceptibility to CD along with CARD15
|-
|TLR4
|09
|9q33.1
|Lipopolysaccharide signaling, bacterial recognition, and subsequent immune response
|Altered immune response to pathogens and a subsequent increase in inflammation.
|}
* 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
 
===Stress and Environmental Component===
*Stress signals are perceived by the central nervous system (CNS), triggering the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis.
*Neuroendocrine mediators released in response to stress not only modulate secretory, absorptive, and barrier functions in the gut but also increase the gut permeability.
*Stress increases gut permeability along with other factors which inlude
**Corticotropin-releasing factor
**Autonomic nervous system
**Enteric nervous system
 
===Microbial Component===
The possible mechanisms for a bacterial etiology in the development of CD include:
*Initial immune response to a specific pathogen resulting in intestinal infection
*Alterations in normal bacterial flora of the intestinal tract
*Defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins
*Alterations to the intestinal immune response
 
{| border="1" cellpadding="5" cellspacing="0" align="center" |class="wikitable"
! style="background:#efefef;" |Infectious Pathogens Implicated in Crohn’s Disease
|-
|
*Escherichia coli<br>
*Listeria monocytogenes<br>
*Yersinia enterocolitica<br>
*Mycobacterium avium subspecies paratuberculosis<br>
*Measles virus
|}
 
=== Immune Component ===
*'''<u>Altered immune response</u>''':
** An abnormal antibody response to an unspecified bacterial antigen is mainly responsible for inflammation in Crohn's disease.
** The inflammatory response is believed to be triggered when elimination of specified microbial antigen was unsuccessful leading to altered immune response
** Dysregulation of normal mucosal immune response results in failure of phagocytosis leading to antigen persistence.
** Antigen persistance leads to antibodies production against all the normal gut flora.
** Activation resulted in secretion of tumor necrosis factor-alpha (TNF-alpha) and subsequent epithelial changes.
*'''<u>Cytokine response</u>''':
**The primary precipitating event in Crohn's disease is T-cell  mediated immune response.
**Activated T cells are responsible for the release of cytokines.
**The production of inflammatory cytokines results in ulceration and increased intestinal permeability.
**The characteristic granulomatous lesion seen in Crohn’s disease is evidence of a cell-mediated immune response.
**The early lesions of Crohn's disease are characterized by elevations in interleukin-4 (IL-4) and decrease in IFN-gamma, a pattern more consistent with an overactive Th2 immune response.
**Chronic lesions are associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma), TNF-alpha, and interleukin-12 and -18 (IL-12 and IL-18) consistent with an Th1 immune response.
**Tumor necrosis factor appears to play a significant role in the pathogenesis of CD.
***TNF-alpha induces expression of adhesion factors that allow for inflammatory cells to infiltrate and activates macrophages to promote release of other pro-inflammatory mediators such as IFN-gamma.
***Neutralization of TNF resulted in significant decrease in inflammation.
***TNF-alpha concentrations in the stool can be used to monitor disease activity in both CD and UC.


===Gross Pathology===
===Gross Pathology===
There are certain characteristic features of the [[pathology]] seen that point toward Crohn's disease. Crohn's disease shows a transmural pattern of [[inflammation]], meaning that the inflammation may span the entire depth of the intestinal wall. Grossly, [[ulcer]]ation is an outcome seen in highly active disease.  There is usually an abrupt transition between unaffected tissue and the ulcer.
Characteristic features of Crohn's disease on gross pathology include:
* Creeping fat
* Thick/rubbery intestinal wall
* [[Strictures]] (string sign on barium enema)
* Skip areas
* [[Aphthous ulcers|Aphthous mucosal ulcers]]


===Microscopic Pathology===
===Microscopic Pathology===
Under a microscope, biopsies of the affected colon may show [[mucosa]]l inflammation. Transmural inflammation results in formation of lymphoid aggregates throughout the wall of the colon. This inflammation is characterized by focal infiltration of [[neutrophils]], a type of inflammatory cell, into the [[epithelium]]. This typically occurs in the area overlying [[lymphoid tissue|lymphoid]] aggregates. These neutrophils, along with [[lymphocyte|mononuclear cells]], may infiltrate into the [[Crypts of Lieberkühn|crypts]] leading to inflammation (crypititis) or abscess (crypt abscess).  [[Granuloma]]s, aggregates of [[macrophage]] derivatives known as giant cells, are found in 50% of cases and are most specific for Crohn's disease. The granulomas of Crohn's disease do not show "caseation", a cheese-like appearance on microscopic examination that is characteristic of granulomas associated with infections such as [[tuberculosis]]. Biopsies may also show chronic mucosal damage as evidenced by blunting of the intestinal [[villus|villi]], atypical branching of the crypts, and change in the tissue type ([[metaplasia]]). One example of such metaplasia, ''Paneth cell metaplasia'', involves development of Paneth cells (typically found in the small intestine) in other parts of the gastrointestinal system.<ref name=Robbins>Crawford JM.  "The Gastrointestinal tract, Chapter 17".  In Cotran RS, Kumar V, Robbins SL. ''Robbins Pathologic Basis of Disease: 5th Edition''.  W.B. Saunders and Company, Philadelphia, 1994.</ref>
On microscopic analysis of the affected colon may show [[mucosa]]l inflammation. Histo-pathological finding include
*Transmural [[inflammation]]
*Lymphoid aggregates throughout the wall of the colon.
*Focal infiltration of [[neutrophils]] along with [[lymphocyte|mononuclear cells]], may infiltrate into the [[Crypts of Lieberkühn|crypts]] leading to inflammation (crypititis) or abscess (crypt abscess).   
*Non- caseating [[Granuloma]]s (aggregates of [[macrophage]] derivatives) known as giant cells, are found in 50% of cases and are most specific for Crohn's disease.
*Blunting of the intestinal [[villus|villi]]
*Atypical branching of the crypts
*''Paneth cell metaplasia'' <ref name="Robbins">Crawford JM.  "The Gastrointestinal tract, Chapter 17".  In Cotran RS, Kumar V, Robbins SL. ''Robbins Pathologic Basis of Disease: 5th Edition''.  W.B. Saunders and Company, Philadelphia, 1994.</ref>


[[Image:Crohn's transmural path.jpg|thumb|center|120px|H and E section of [[colectomy]] showing transmural inflammation.]]
[[Image:Crohn's transmural path 1.png|thumb|center|400px|H and E section of [[colectomy]] showing transmural inflammation.<br>Source:By The original uploader was Samir at English Wikipedia [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons]]


==References==
==References==
{{reflist|2}}
{{reflist|2}}
{{WH}}
{{WS}}
[[Category:Disease]]
[[Category:Disease]]
[[Category:Autoimmune diseases]]
[[Category:Autoimmune diseases]]
Line 30: Line 134:
[[Category:Conditions diagnosed by stool test]]
[[Category:Conditions diagnosed by stool test]]
[[Category:Abdominal pain]]
[[Category:Abdominal pain]]
[[Category:Primary care]]
[[Category:Needs overview]]
[[Category:Needs overview]]
{{WH}}
{{WS}}

Latest revision as of 21:10, 29 July 2020

https://https://www.youtube.com/watch?v=thzOJV-CHRo%7C350}}

Crohn's disease

Home

Patient Information

Overview

Historical Perspective

Classification

Pathophysiology

Causes

Differentiating Crohn's Disease from other Diseases

Epidemiology and Demographics

Risk Factors

Screening

Natural History, Complications and Prognosis

Diagnosis

History and Symptoms

Physical Examination

Laboratory Findings

CT

MRI

Other Imaging Findings

Other Diagnostic Studies

Treatment

Medical Therapy

Surgery

Prevention

Cost-Effectiveness of Therapy

Future or Investigational Therapies

Case Studies

Case #1

Crohn's disease pathophysiology On the Web

Most recent articles

Most cited articles

Review articles

CME Programs

Powerpoint slides

Images

American Roentgen Ray Society Images of Crohn's disease pathophysiology

All Images
X-rays
Echo & Ultrasound
CT Images
MRI

Ongoing Trials at Clinical Trials.gov

US National Guidelines Clearinghouse

NICE Guidance

FDA on Crohn's disease pathophysiology

CDC on Crohn's disease pathophysiology

Crohn's disease pathophysiology in the news

Blogs on Crohn's disease pathophysiology

Directions to Hospitals Treating Crohn's disease

Risk calculators and risk factors for Crohn's disease pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Aditya Ganti M.B.B.S. [2]

Overview

Genetic and environmental factors play a key role in the pathogenesis of Crohn's disease. Mutations in the CARD15 gene (also known as the NOD2 gene) are associated with Crohn's disease and with susceptibility to certain phenotypes of disease location and activity. Environmental factors include autoimmune Disease and dysregulated Immune Response to Commensal Bacteria. Characteristic features of the pathology that point toward Crohn's disease are transmural pattern of inflammation and skip lesions. Under microscopy Granulomas are seen, which are aggregates of macrophage derivatives known as giant cells, are found in 50% of cases and are most specific for Crohn's disease.

Pathophysiology

The exact pathogenesis of Crohn's disease is not clearly understood. However, 4 components have been proved to play a key role in the pathogenesis of Crohn's disease.

  • Genetic component
  • Stress and environmental component
  • Microbial component
  • Inflammatory component

Genetic Component

There are several genes involved in the pathogenesis of Crohn's disease. Mutation of any of these genes disrupts the normal function of cells triggering an inflammatory response. Some common and most important genes are as follows:.[1][2][3][4]

  • NOD2/CARD15 gene
  • OCTN1 gene
  • DLG5 gene
  • TLR4 gene

The following tables summarizes the most important genes involved in the pathogenesis of Crohn's disease

Genes Chromosome Function Mutation
NOD2/CARD15 16 16q12.1 Encodes a scaffolding protein important for maintaining epithelial integrity Disrupts normal epithelial integrity
OCTN1 05 5q31 Ecodes an ion channel Alters the function of cation transporters and cell-to-cell signaling
DLG5 10 10q22.3 Interact additively with the NOD2/CARD15 gene Iincrease susceptibility to CD along with CARD15
TLR4 09 9q33.1 Lipopolysaccharide signaling, bacterial recognition, and subsequent immune response Altered immune response to pathogens and a subsequent increase in inflammation.
  • 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

Stress and Environmental Component

  • Stress signals are perceived by the central nervous system (CNS), triggering the hypothalamic-pituitary-adrenal axis and the sympathetic-adrenal-medullary axis.
  • Neuroendocrine mediators released in response to stress not only modulate secretory, absorptive, and barrier functions in the gut but also increase the gut permeability.
  • Stress increases gut permeability along with other factors which inlude
    • Corticotropin-releasing factor
    • Autonomic nervous system
    • Enteric nervous system

Microbial Component

The possible mechanisms for a bacterial etiology in the development of CD include:

  • Initial immune response to a specific pathogen resulting in intestinal infection
  • Alterations in normal bacterial flora of the intestinal tract
  • Defective mucosal barrier and overwhelming exposure to resident bacteria and their antigens and endotoxins
  • Alterations to the intestinal immune response
Infectious Pathogens Implicated in Crohn’s Disease
  • Escherichia coli
  • Listeria monocytogenes
  • Yersinia enterocolitica
  • Mycobacterium avium subspecies paratuberculosis
  • Measles virus

Immune Component

  • Altered immune response:
    • An abnormal antibody response to an unspecified bacterial antigen is mainly responsible for inflammation in Crohn's disease.
    • The inflammatory response is believed to be triggered when elimination of specified microbial antigen was unsuccessful leading to altered immune response
    • Dysregulation of normal mucosal immune response results in failure of phagocytosis leading to antigen persistence.
    • Antigen persistance leads to antibodies production against all the normal gut flora.
    • Activation resulted in secretion of tumor necrosis factor-alpha (TNF-alpha) and subsequent epithelial changes.
  • Cytokine response:
    • The primary precipitating event in Crohn's disease is T-cell mediated immune response.
    • Activated T cells are responsible for the release of cytokines.
    • The production of inflammatory cytokines results in ulceration and increased intestinal permeability.
    • The characteristic granulomatous lesion seen in Crohn’s disease is evidence of a cell-mediated immune response.
    • The early lesions of Crohn's disease are characterized by elevations in interleukin-4 (IL-4) and decrease in IFN-gamma, a pattern more consistent with an overactive Th2 immune response.
    • Chronic lesions are associated with high levels of interleukin-2 (IL-2), interferon gamma (IFN-gamma), TNF-alpha, and interleukin-12 and -18 (IL-12 and IL-18) consistent with an Th1 immune response.
    • Tumor necrosis factor appears to play a significant role in the pathogenesis of CD.
      • TNF-alpha induces expression of adhesion factors that allow for inflammatory cells to infiltrate and activates macrophages to promote release of other pro-inflammatory mediators such as IFN-gamma.
      • Neutralization of TNF resulted in significant decrease in inflammation.
      • TNF-alpha concentrations in the stool can be used to monitor disease activity in both CD and UC.

Gross Pathology

Characteristic features of Crohn's disease on gross pathology include:

Microscopic Pathology

On microscopic analysis of the affected colon may show mucosal inflammation. Histo-pathological finding include

  • Transmural inflammation
  • Lymphoid aggregates throughout the wall of the colon.
  • Focal infiltration of neutrophils along with mononuclear cells, may infiltrate into the crypts leading to inflammation (crypititis) or abscess (crypt abscess).
  • Non- caseating Granulomas (aggregates of macrophage derivatives) known as giant cells, are found in 50% of cases and are most specific for Crohn's disease.
  • Blunting of the intestinal villi
  • Atypical branching of the crypts
  • Paneth cell metaplasia [5]
H and E section of colectomy showing transmural inflammation.
Source:By The original uploader was Samir at English Wikipedia [GFDL (http://www.gnu.org/copyleft/fdl.html) or CC-BY-SA-3.0 (http://creativecommons.org/licenses/by-sa/3.0/)], via Wikimedia Commons

References

  1. ↑ 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.
  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. ↑ 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.
  4. ↑ Cobrin GM, Abreu MT. Defects in mucosal immunity leading to Crohn's disease. Immunol Rev. 2005 Aug;206:277-95. PMID 16048555
  5. ↑ Crawford JM. "The Gastrointestinal tract, Chapter 17". In Cotran RS, Kumar V, Robbins SL. Robbins Pathologic Basis of Disease: 5th Edition. W.B. Saunders and Company, Philadelphia, 1994.

Template:WH Template:WS

Retrieved from "https://www.wikidoc.org/index.php?title=Crohn%27s_disease_pathophysiology&oldid=1636636"