The active moiety of these drugs is 5-aminosalicylic acid (5-ASA). 5-ASA is absorbed in the small intestine (and may be nephrotoxic), so the design of the various aminosalicylate preparations is based on the binding of 5-ASA by an azo bond to sulfapyridine (sulfasalazine), 4-aminobenzoyl-â-alanine (balsalazide) or to 5-ASA itself (olsalazine), coating with a pH-sensitive polymer (Asacol) or packaging of 5-ASA in microspheres (Pentasa). The azo bonds are broken down by colonic bacteria to release 5-ASA within the colon. The pH-dependent forms are designed to release 5-ASA in the terminal ileum. Luminal pH profiles in patients with inflammatory bowel disease are abnormal and in some patients capsules of 5-ASA coated with pH-sensitive polymer may pass through into the faeces intact. 5-ASA is released from microspheres throughout the small intestine and colon. The mode of action of 5-ASA in inflammatory bowel disease is unknown, but the aminosalicylates have been shown to be effective in inducing remission in mild to moderately active disease and maintaining remission in all forms of disease. Sulfasalazine is being used less frequently because of its wider side-effect profile from the sulphonamide component
With an ileoanal anastomosis , a pouch of ileum is formed that acts as a reservoir. The pouch is anastomosed to the anus at the dentate line following endoanal excision of the mucosa of the distal rectum and anal canal. Continence is usually achieved. A third of patients, however, will experience ‘pouchitis’ in which there is inflammation of the pouch
About 7 of every 100,000 people in US have Crohn's disease.
These are among the highest rates in the world.
The incidence is about 1-3 per 100,000 in southern Europe, South Africa, and Australia, and is even lower, less than 1 per 100,000, in Asia and South America.
Environment Triggers Immunoregulatory Defects and Microbial Exposure Genetic Factor c)Occupation a)Dysfunctional immune host response to normal luminal components a)Westernization b)Sanitation and exposure to infection d)Diet c)Defective barrier function IBD-1 locus and NOD2/CARD15 gene e)Tobacco smoking b)Infection with a specific pathogen Etiology
Both UC and CD are more prevalent in white-collar compared with blue-collar occupations.
Higher mortality from IBD has been noted in managerial, clerical, and sales positions, which typically involve sedentary, indoor work.
In contrast, mortality resulting from IBD is low among farmers and construction workers.
outdoor air and physical activity is protective against IBD, whereas work in artificial venues confers an increased risk.
This theory could explain the higher risk for IBD in northern climates (e.g., more indoor exposure) and in immigrants to developed countries, as well as the varying rates among ethnic groups in different regions.
Numerous case-control studies have shown that current smoking is protective against UC (relative risk [RR], 40% of that of nonsmokers), with results that are consistent across diverse geographic regions.
The decreased risk for UC in smokers appears to be dose dependent
Paradoxically, ex-smokers are approximately 1.7 times more likely to develop UC than those who never smoked.
Ex-smokers also have a poorer disease course, with more frequent hospitalization than current smokers
as a group they are twice as likely as current smokers and those who have never smoked to require colectomy
the NOD2 mutation may increase susceptibility to chronic intracellular infection or prevent the development of tolerance to commensal microflora
In the absence of NOD2 expression by epithelial cells, microbial products that normally induce these cells to secrete chemokines fail to do so, leading to proliferation of bacteria and potential loss of barrier function
Immunoregulatory Defects and Microbial Exposure
In healthy gut epithelium, the presence of potentially proinflammatory luminal bacteria is tolerated without neutrophil recruitment into the epithelial surface
This may be caused in part by the unique phenotype of the resident macrophage population within the intestine
Triggering the receptor expressed on myeloid cells (TREM-1) is a cell surface molecule present on neutrophils, monocytes, and macrophages that amplifies the inflammatory response by enhancing degranulation and secretion of proinflammatory cytokines
Theories suggested concerning the pathogenesis of this process:
dysfunctional immune host response to normal luminal components,
infection with a specific pathogen
defective mucosal barrier to luminal antigens.
a) Dysfunctional immune host response to normal luminal components
normal relationship between commensal bacteria and the host is symbiotic
It is hypothesized that exposure to commensal bacteria down-regulates the inflammatory genes and blocks activation of the NF-kB pathway, thus inhibiting the inflammatory immune response of the gut to the myriad microbes and food antigens to which it is constantly exposed
In IBD, this tolerance is lost
Exposure to luminal microflora now triggers an inflammatory response by the cells lining the mucosa, leading to a chronic, destructive immune response
Variance in bacterial activation of the inflammatory immune response.
Antiinflammatory commensal bacteria (nonvirulent Salmonella strains) inhibit the NF-kB pathway via blockade of the inhibitor of NF-kB (IkB)–a degradation, which prevents subsequent nuclear translocation of the active NF-kB dimer
Although phosphorylation of IkB-a occurs, the subsequent polyubiquitination required for regulated IkB-a degradation is abrogated
Pathogenic bacteria activate the NF-kB pathway.
The bacteria bind to a cell-surface receptor, the toll-like receptor (TLR), which generates inflammatory factors connected to the NF-kB pathway.
They stimulate intermediate kinases, leading to phosphorylation (P) of the inhibitor of B kinase (IKK) and subsequent dissociation of NF-kB.
NF-kB is then able to travel to the nucleus, where it turns on inflammatory
If, however, bacterial products are able to cross the mucosal barrier, then they will come into direct contact with immune cells, resulting in a classic adaptive immune response
Avariety of inflammatory cytokines are produced, recruiting additional cells into the intestine wall
These include cytokines that reduce the tight junctions between the endothelial cells in the gut vasculature, which in turn facilitates recruitment of neutrophils to the mucosa from the peripheral blood
In CD, there is gross involvement of the small intestine alone in about 40%
colon alone in about 30%.
duodenum, stomach, esophagus, and mouth, are distinctly uncommon sites.
The serosa is granular and dull gray, and often the mesenteric fat wraps around the bowel surface (creeping fat).
The intestinal wall is rubbery and thick, caused by edema, inflammation, fibrosis, and hypertrophy of the muscularis propria.
As a result, the lumen is almost always narrowed; in the small intestine this is evidenced on x-ray as the "string sign," a thin stream of barium passing through the diseased segment.
A classic feature of CD is the sharp demarcation of diseased bowel segments from adjacent uninvolved bowel.
Endoscopic image of colon cancer identified in the sigmoid colon on screening colonoscopy for Crohn's disease.
Crohn's disease can mimic ulcerative colitis on endoscopy. This endoscopic image is of Crohn's colitis showing diffuse loss of mucosal architecture, friability of mucosa in sigmoid colon and exudate on wall, all of which can be found with ulcerative colitis.
Section of colectomy showing transmural inflammation
Endoscopy image of colon showing serpiginous ulcer, a classic finding in Crohn's disease
A key feature of UC is that the mucosal damage is continuous from the rectum and extending proximally. In CD, mucosal damage in the colon may be continuous but is just as likely to exhibit skip areas. It should be noted that quiescent UC, particularly treated disease in which active neutrophilic inflammation is not present, may appear virtually normal histologically.
Endoscopic image of a sigmoid colon afflicted with ulcerative colitis. Note the vascular pattern of the colon granularity and focal friability of the
Colonic pseudopolyps of a patient with intractable ulcerative colitis . Colectomy specimen
H&E stain of a colonic biopsy showing a crypt abscess, a classic finding in ulcerative colitis
Biopsy sample ( H&E stain ) that demonstrates marked lymphocytic infiltration (blue/purple) of the intestinal mucosa and architectural distortion of the crypts.
Inflammatory Bowel Disease Symptoms Because inflammatory bowel disease is a chronic disease (lasting a long time), you will go through periods in which the disease flares up and causes symptoms. These periods are followed by remission, in which symptoms disappear or decrease and good health returns. Symptoms may range from mild to severe and generally depend upon the part of the intestinal tract involved. They include the following :
Abdominal cramps and pain Bloody diarrhea Severe urgency to have a bowel movement Fever Loss of appetite Weight loss Anemia (due to blood loss)
Other Symptoms of IBD People with IBD may have symptoms outside the digestive tract, such as: Mouth sores and skin problems Arthritis Eye problems that affect vision
Symptoms in Crohn's disease vs. ulcerative colitis Crohn's disease Ulcerative colitis Defecation Often porridge-like sometimes steatorrhea Often mucus-like and with blood Tenesmus Less common More common Fever Common Indicates severe disease Fistulae Common Seldom Weight loss Often More seldom
Findings in diagnostic workup in Crohn's disease vs. ulcerative colitis Sign Crohn's disease Ulcerative colitis Terminal ileum involvement Commonly Seldom Colon involvement Usually Always Rectum involvement Seldom Usually Involvement around the anus Common Seldom Bile duct involvement No increase in rate of primary sclerosing cholangitis Higher rate
Distribution of Disease Patchy areas of inflammation (Skip lesions) Continuous area of inflammation Endoscopy Deep geographic and serpiginous (snake-like) ulcers Continuous ulcer Depth of inflammation May be transmural, deep into tissues Shallow, mucosal Stenosis Common Seldom Granulomas on biopsy May have non-necrotizing non-peri-intestinal crypt granulomas Non-peri-intestinal crypt granulomas not seen Sign Crohn's disease Ulcerative colitis
Pathological features of Crohn’s disease Any portion of small bowel: usually ileum may also involve: any segment of digestive tract Early stages: involved small bowel has soggy feeling mucosa: reddish purple may show pinpoint erosions known as ‘aphthoid ulcers’ Later stages: prominent ulceration
So-called ‘aphthoid ulcers’, an early feature of Crohn's disease.
Fig. 1: Gross appearance of Crohn's disease. There is a sharp demarcation between the involved and the uninvolved areas.
Fig. 2: Gross appearance of Crohn's disease. The combination of ulceration and elevated remnants of mucosa results in a typical cobblestone appearance. Fig. 3: Gross appearance of Crohn's disease. Another example of cobblestone appearance. Fig. 4: Gross appearance of Crohn's disease. Note the segmental nature of the inflammation, and rigidity of the wall, and flattening of the mucosa are characteristic.
Histopathology Submucosal lymphedema: early change accompanied by: lymphoid hyperplasia in lamina propria and submucosa scattering of chronic inflammatory cells, including: plasma cells: including some binucleated forms lymphocytes eosinophils Histiocytes: some containing prominent lysosomal inclusions mast cells Ulcerations: begin at top of lymphoid follicles preceded by patchy epithelial necrosis may have vascular pathogenesis
Whole mount specimen of Crohn's disease showing transmural inflammation with predominance of the inflammation in the mucosa and submucosa.
Signs and symptoms Diarrhea- patients often experience frequent loose or watery bowel movements. -stool is occasionally accompanied by thick, dark blood (not bright red smears of blood, which usually result from a bleeding hemorrhoid) -There is less mucus or pus in the stool than in cases of ulcerative colitis.
Patients may experience crampy, achy, or even sharp pain in the affected area.
Most often, patients with Crohn's disease feel pain on the lower right side of the abdomen (lower right quadrant) and just below the bellybutton- because the majority of cases of Crohn's disease involve disease in the terminal ileum, where the small intestine meets the large intestine.
terminal ileum crosses from left to right just above the beltline, and joins the large intestine in the lower right quadrant.
pain associated with Crohn's disease depends on what part of the GI tract is affected.
Disease in the terminal ileum generally causes sharp pain, while disease in the colon causes more crampy pain, similar to that that of ulcerative colitis. Pain is sometimes relieved (temporarily) after a bowel movement.
Most are adenocarcinomas of varying degrees of differentiation
Compared with carcinoma not associated with colitis:
higher proportion of:
poorly differentiated and mucinous carcinomas
usually in flat atrophic mucosa
distinguish from those due to regeneration atypia
should not be diagnosed in areas of active inflammation
evaluation difficult but successful in identifying those at high risk for colorectal carcinoma
Fig. 9: Adenocarcinoma with mucinous features arising in a colon affected by ulcerative colitis. This is a common tumor subtype in this particular setting. Fig. 10: Dysplasia in ulcerative colitis. Indefinite for dysplasia. Fig. 11: Dysplasia in ulcerative colitis. Low-grade dysplasia.
Fig. 12: Dysplasia in ulcerative colitis. High-grade dysplasia. Fig. 13: Dysplasia in ulcerative colitis. Dysplasia with papillary features.
Signs and Symptoms Diarrhea- frequent watery stools are the norm -stools are accompanied by thick blood (not bright red smears of blood, which usually occur from a bleeding hemorrhoid). -Mucus or pus also often passes with the stool. -Individual with ulcerative colitis will have stool of more normal consistency that contains pus or mucus.
Osteoporosis: Ulcerative colitis patients are at risk for low bone density, chiefly due to long-term use of some medications, such as steroids.
Venous thrombosis : most often in iliac vein
Strictures: Abnormal narrowing of the intestine.
Obstruction: Swelling and scarring obstructing the intestine.
Colon cancer: Ulcerative colitis patients have a higher risk of developing colon cancer. The risk increases when a greater proportion of the colon is affected, or if a patient has had ulcerative colitis for a prolonged period of time. Gastroenterologists may recommend that certain ulcerative colitis patients undergo periodic screening for colon cancer, based on disease duration.
Perforation: Extensive inflammation can lead to a tear in the intestinal wall, resulting in leakage of bowel contents outside the intestine. Categorized by sudden, severe abdominal pain, shock, and excessive abdominal tenderness.
Toxic megacolon: This serious complication may occur when inflammation spreads from the lining of the colon to involve the entire intestinal wall. Because this involvement temporarily stops the normal contractile movements of the intestine, the large intestine may greatly expand.
Fig. 6: Ulcerative colitis. Case complicated with toxic megacolon. Fig. 7: Ulcerative colitis complicated by toxic megacolon.
There are two types of laboratory tests, which IS routine tests and antibody tests.
• Stool culture to look for bacterial infection
• O&P (Ova and parasite) to detect parasites
• Clostridium difficile to detect toxin created by bacterial infection; may be seen following antibiotic therapy
• Fecal occult blood to look for blood in the stool
• Stool WBC to detect white blood cells in the stool
• Celiac Disease tests
Tests that are not specific for IBD but done to detect and evaluate the inflammation and anemia associated with IBD include:
• ESR (erythrocyte sedimentation rate) to detect inflammation
• CRP (C-reactive protein) to look for inflammation
Calprotectin is a protein associated with inflammation. Its use as an inflammatory marker to help diagnose and monitor IBD when measured in stool (fecal) samples is gaining attention. It may prove to be a useful test in predicting relapses in IBD patients.
Many patients with ulcerative colitis have the pANCA antibody in their blood, but not the ASCA antibody. For many Crohn's patients, the opposite is true: the ASCA antibody is present, while the pANCA is not.
Unfortunately, some patients have neither antibody in their blood, and some Crohn's patients may have only the "ulcerative colitis" pANCA antibody in their blood! Nevertheless, sometimes these blood tests help your doctor determine which condition is more likely, which may help in making decisions regarding medications or surgery.
Anti-CBir1 (Clostridium species antibodies), found to be associated with about 50% of Crohn’s disease cases.
Anti-Omp C (Escherichia coli antibodies), associated with rapidly progressing Crohn’s disease.
Endoscopy has four main procedures, or different types of "scopes", that are used to evaluate IBD. All use a thin, flexible tube with a lighted camera inside the tip, which allows your doctor to look directly at the lining of the gastrointestinal (GI) tract.
Types of Endoscopy
looks at the lower one-third of the colon. This makes it is a useful test when your physician wants to confirm the presence of inflammation or a source of bleeding (such as hemorrhoids) within the reach of the scope.
helps rule out infectious causes of inflammation, such as disease caused by bacteria, which may mimic IBD. It is also useful in evaluating symptoms that do not respond to your current treatment or that return despite treatment.
It is also useful for evaluating and taking biopsies of the distal small intestine (terminal ileum), which is important in the evaluation of Crohn's diseaseand chronic colitis.
When colonoscopy is performed to look for dysplasia, multiple biopsies are taken throughout the entire colon and rectum. Surveillance refers to routine examinations of the colon to minimize the risk of cancer by checking for dysplasia and monitoring any changes
It is designed to show images of sections of the small intestine that are beyond the reach of an EGD. This test is to determine obscure gastrointestinal bleeding. It takes approximately two hours for your doctor to review the images. The capsule is excreted in the stool normally and effortlessly. For patients with Crohn's disease, patients must be examined carefully to determine that there are no strictures or bowel obstructions before the capsule can be used.
A small percentage of patients with IBD also may have a liver disease called "primary sclerosing cholangitis," or PSC. A doctor may suspect PSC if repeatedly abnormal blood test results reflect the activity of enzymes in the liver. ERCP is a method that combines X-ray and endoscopy to look at your bile ducts and pancreatic ducts. As in an EGD, a tube is passed through your stomach and into your small bowel. The papilla, a small bump with a tiny opening in your duodenum, leads to your biliary and pancreatic ducts. A small catheter is introduced through the papilla into either your bile ducts or your pancreatic duct and contrast dye is injected.
is a relatively new technique that uses an ultrasound probe attached to an endoscope to obtain deep images of the gut below the surface. In IBD, this is most often used to look at fistulas in the rectal area. EUS can determine the depth and extent of the fistula and biopsies can be taken if needed.
Plain X-rays (without contrast) are a quick, inexpensive, and effective way of detecting blockage in the small or large intestine. Patients with Crohn's disease,have inflammation of the small bowel that narrows the intestine and prevents the easy passage of stool and air. The large bowel can also become blocked and dilated. People with ulcerative colitis develop widening of the large bowel called toxic megacolon.
Leukocyte scintigraphy or "tagged white blood cell scan" detects white blood cell accumulation in inflamed tissue.
Leukocyte scintigraphy has been used to detect the location of bowel inflammation and to evaluate treatment response in IBD. It is not useful in defining anatomic details or looking at inflammation in the rectum. It is a relatively safe test and entails less radiation exposure than contrast X-ray or CT scan.
The guidelines conform to the North of England evidence based guidelines development project. The grading of each recommendation is dependent on the category of evidence supporting it:
Grade A —requires at least one randomised controlled trial as part of a body of literature of overall good quality and consistency addressing the specific recommendation (evidence categories Ia and Ib).
Grade B —requires the availability of clinical studies without randomisation on the topic of consideration (evidence categories IIa, IIb, and III).
Grade C —requires evidence from expert committee reports or opinions or clinical experience of respected authorities, in the absence of directly applicable clinical studies of good quality (evidence category IV).