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Inflammatory intestinal disease

In general, diverticular disease refers to acquired pseudodiverticular outpouchings of the colonic mucosa and submucosa. Such colonic diverticula are rare in individuals younger than 30 years of age, but the prevalence approaches 50% in Western adult populations older than 60 years of age. Diverticula generally are multiple, and the condition is referred to as diverticulosis. This disease is much less common in developing countries, probably because of dietary differences.
Pathogenesis

Colonic diverticula tend to develop under conditions of elevated intraluminal pressure in the sigmoid colon.
This is facilitated by the unique structure of the colonic muscularis propria, where nerves, arterial vasa recta, and their connective tissue sheaths penetrate the inner circular muscle coat to create discontinuities in the muscle wall. In other parts of the intestine, these gaps are reinforced by the external longitudinal layer of the muscularis propria, but in the colon, this muscle layer is discontinuous, being gathered into three bands termed taeniae coli.
High luminal pressures may be generated by exaggerated peristaltic contractions, with spasmodic sequestration of bowel segments that may be exacerbated by diets low in fiber, which reduce stool bulk.
Morphology
Anatomically, colonic diverticula are small, flask like outpouchings, usually 0.5 to 1 cm in diameter, that occur in a regular distribution in between the taeniae coli.
They are most common in the sigmoid colon, but other regions of the colon may be affected. Colonic diverticula have a thin wall composed of a flattened or atrophic mucosa, compressed submucosa, and attenuated muscularis propria—often, this last component is totally absent Obstruction of diverticula with stasis of contents, leads to inflammatory changes, producing diverticulitis and peridiverticulitis. Because the wall of the diverticulum is supported only by the muscularis mucosa and a thin layer of subserosal adipose tissue, inflammation, increased pressure, and mucosal ucleration within an obstructed diverticulum can readily result in perforation. With or without perforation, recurrent diverticulitis may cause segmental colitis, fibrotic thickening in and around the colonic wall, or stricture formation.

Ulcerative colitis

Ulcerative colitis is a severe ulcerating inflammatory disease that is limited to the colon and rectum and extends only into the mucosa and submucosa.
Crohn disease, also been referred to as “regional enteritis” (because of frequent ileal involvement) may involve any area of the GI tract and is typically transmural.

Pathogenesis

IBD is an idiopathic disorder. Although there is limited epidemiologic association of IBD with autoimmunity, neither Crohn disease nor ulcerative colitis is thought to be an autoimmune disease.
Most investigators believe that the two diseases result from a combination of defects in host interactions with intestinal microbiota, intestinal epithelial dysfunction, and aberrant mucosal immune responses.
Genetic factors contribute to IBD.
Risk of disease is increased when there is an affected family member and, in Crohn disease, the concordance rate for monozygotic twins is approximately 50%.
The same factors may also contribute to disease phenotype, because twins affected by Crohn disease tend to present within 2 years of each other and develop disease in similar regions of the GI tract.
The concordance of monozygotic twins for ulcerative colitis is only 16%, suggesting that genetic factors are less dominant than in Crohn disease. Concordance for dizygotic twins is less than 10% for both Crohn disease and ulcerative colitis.
Molecular linkage analyses of affected families have identified NOD2 (nucleotide oligomerization binding domain 2) as a susceptibility gene in Crohn disease. Specific NOD2 polymorphisms confer at least a four-fold increase in Crohn disease risk among Caucasians of European ancestry.
NOD2 encodes a protein that binds to intracellular bacterial peptidoglycans and subsequently activates NF-κB “transcription factors”. It has been postulated that disease-associated NOD2 variants are less effective at recognizing and combating luminal microbes, which are then able to enter the lamina propria and trigger inflammatory reactions. Other data suggest that NOD2 may regulate immune responses to prevent excessive activation by luminal microbes.
IBD-associated genes has used genome-wide association studies (GWAS) that assess single-nucleotide polymorphisms.
The number of genes identified by GWAS is increasing rapidly (already numbering more than 30).
polymorphisms of the IL-23 receptor are protective in both Crohn disease and ulcerative colitis
Mucosal immune responses
Although the mechanisms by which mucosal immunity contributes to ulcerative colitis and Crohn disease pathogenesis are still being obscured, immunosuppression remains the mainstay of IBD therapy.
Epithelial defects
A variety of epithelial defects have been described in both Crohn disease and ulcerative colitis. For example, defects in intestinal epithelial tight junction barrier function are present in Crohn disease patients and a subset of their healthy first-degree relatives
Microbiota
The abundance of microbiota in the GI lumen is overwhelming, amounting to as much as 1012 organisms per milliliter in the colon and 50% of fecal mass.
In total, these organisms greatly outnumber human cells in our bodies, meaning that, at a cellular level, we are only about 10% human.
Although the composition of this dense microbial population tends to be stable within individuals over at least several years, it can be modified by diet and there is significant variation between individuals. In addition to the luminal microbiota, the more limited microbial population that inhabits the intestinal mucous layer may have the greatest impact on health.
One model that unifies the roles of intestinal microbiota, epithelial function, and mucosal immunity suggests a cycle by which transepithelial flux of luminal bacterial components activates innate and adaptive immune responses.
In a genetically susceptible host, the subsequent release of TNF and other immune-mediated signals direct epithelia to increase tight junction permeability, which causes further increases in the flux of luminal material. These events may establish a self-amplifying cycle in which a stimulus at any site may be sufficient to initiate IBD. Although this model is helpful in advancing our understanding of IBD pathogenesis, it is important to recognize that a variety of factors are associated with disease for unknown reasons. For example, an episode of appendicitis is associated with reduced risk of developing ulcerative colitis. Tobacco also modifies IBD epidemiology, but, paradoxically, the risk of Crohn disease is increased by smoking while that of ulcerative colitis is reduced.
Feature
MACROSCOPIC
Bowel region
Distribution
Stricture
Wall appearance
MICROSCOPIC
Inflammation
Pseudopolyps
Ulcers
Lymphoid reaction
Fibrosis
Serositis
Granulomas
Fistulae/sinuses
CLINICAL
Perianal fistula
Fat/vitamin malabsorption
Malignant potential
Recurrence after surgery
Toxic megacolon
The associated carcinomas are often infiltrative without obvious exophytic masses, further underscoring the importance of early diagnosis.
Historically, the risk of cancer is highest in patients with pancolitis of 10 or more years' duration, in whom it is 20- to 30-fold higher than in a control population.



رفعت المحاضرة من قبل: Hatem Saleh
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