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Lecturer: Ashlie L. Burkart Lecture: 3 “Bread and Butter” Pathology of the Small Bowel and Colon SMALL INTESTINE A. NORMAL HISTOLOGY OF THE SMALL INTESTINAL * Mucosa = the epithelium, lamina propria and muscularis mucosae. o Below the mucosa is the submucosa, muscularis propria, subserosal fat, the serosa or adventita depending on where in the GI tract you are. I. Major features o Plicae circulares: wave like projections formed by the mucosa and submucosa. o Villi: smaller undulations formed by only the mucosa o Crypts of lieberkuhn: crypt-like glands that extend into the mucosa between the villi. * Normal intestinal mucosa should have a villi height : crypt depth of 3:1. o A microvilli brush border along the epithelium. o Dispersed goblet cells. o Intraepithelial lymphocytes (EILs) dispersed throughout the epithelium. Normal = < 20 IEL / 100 enterocytes Normal = decrescendo pattern such that the IEL are less abundant near the tops of villi. o Lamina propria should have a normal, mild, mix of lymphocytes, plasma cells and some eosinophils. o Brunner’s Glands: Specific to the duodenum! Glands found below the muscularis mucosae. Produce an alkaline substance to help neutralize stomach acid. o Peyer’s Patches: Specific to the terminal Ilieum. Lymphoid aggregates that traverse the Muscularis mucosae. David Reilly 1 Lecturer: Ashlie L. Burkart Lecture: 3 2 B. CELIAC DISEASE (CD) I. General o Immune disorder d/t “gluten” sensitivity, or sensitivity to other proteins that resemble gluten. o Much like an allergic reaction in the intestine. II. Pathogenesis o Gluten and related proteins are digested in the small intestine gliadin peptide and a tissue transglutaminase (tTG) modified gliadin protein are formed reaction to these proteins especially effects the proximal small intestine. III. Gross o Scalloping of mucosa w/ loss of plicae circularis. IV. Histology o Biopsy best preformed in duodenum/proximal ilieum where concentration of gluten is highest. o Increased IEL cells with loss of “decrescendo” pattern. o Blunted villi w/ crypt elongation. Villi:Crypt ratio < 3:1 o Increased plasma cells and lymphocytes in lamina propria. * NOTE: histology is not specific to CD, must be corroborated with serology testing. V. Serologic Tests 1. Anti-tTG IgA: * Best screening test! Cheapest, least labor intensive, sensitivity and specificity = 90% 2. Serum IgA levels: o Must test serum IgA levels in general to ensure there is no IgA deficiency which may give false negative. 3. Other Serologic Testing: Anti-endomysial IgA: o Just as good as the Anti-tTG IgA test except more labor intensive. Anti-gliadin: o NOT sensitive or specific but may be used to follow up response to gluten free diet. VI. HLA testing of DQ2 and DQ8 * Almost all pts with CD carry the MHC class II HLA-DQ2 or HLA-DQ8 alleles!! o Not a good screening test since 20% of the population carry these alleles. But may be useful in diagnosing when other tests are not sufficient and you have a strong clinical suspicion. VII. GOLD STANDARD DIAGNOSIS AND TREATMENT * Gold standard Diagnosis: response to a gluten free diet. * Treatment: lifelong gluten free diet. VIII. Diseases that may mimic CD * Remember the histologic findings are NOT specific to CD, other conditions may have similar features: 1. Common Variable immunodeficiency (CVID): “acquired hypogammaglobinemia” o Result in villous blunting and increased IEL. o HOWEVER, most patients have very few (if any) plasma cells in the mucosa whereas in CD there is an elevated amount of plasma cells. 2. Infections o H. pylori gastritis, tropical sprue, bacterial overgrowth, viral gastroenteritis, giardia, cryptosporidium, cyclospora. 3. NSAID injury IX. Disease associated with CD o Dermatitis herpetiforme: Chronic blistering skin disease associated with a gluten allergy and CD. David Reilly Lecturer: Ashlie L. Burkart Lecture: 3 3 o Enteropathy-associated T-Cell lymphoma At much higher risk for this. Very aggressive. o Adenocarcinoma of the small intestine. COLON A. NORMAL HISTOLOGY OF THE COLON o Villi create a “test tubes in a rack” appearance where the bases of the intervening crypts touch the Muscularis mucosae. o Paneth cells are normally found in the RIGHT colon only! o Haustrau folds are unique to the colon o Other wise the histology is very similar to small intestine with lymphocytic presence in the mucosa, etc. B. MICROSCOPIC COLITIS I. General Features * Incorporates lymphocytic and collagenous colitis o Chronic watery (non-bloody) diarrhea with a normal endoscopic evaluation. o Cause usually unknown. o Typically in middle age elderly. * Both have no changes in mucosal architecture!! II. Lymphocytic Colitis o Female:male ratio of 3:1 o Increased IEL presence. o Increased presence of lymphocytes, plasma cells and eosinophils in the lamina propria. III. Collagenous colitis o F:M ratio of 8:1 o Increased IEL presence. o Increased presence of lymphocytes, plasma cells and eosinophils in the lamina propria. * Thickened subepithelial collagen band!!! C. INFLAMMATORY BOWEL DISEASE (IBD) Consists of 3 main subtypes: o Ulcerative Colitis (UC) o Crohn’s Disease o Indeterminate I. General Features of IBD*** 1. Chronicity (chronic changes) o 1) Architectural distortion: In Colon: crypts pull away from the MM, have unusual appearance- “pant leg” appearance. In Small Intestine: villi shortening, crypt elongation. o 2) Muscularis Hypertrophy and hyperplasia: Muscularis mucosa layer becomes hyperplastic and large. o 3) Metaplasia of cells: Cell types change, usually in an attempt to adapt to the new environment. Paneth cell metaplasia of the LEFT colon: Ulcerative Colitis! Normally paneth cells (antimicrobial, eosinophilic cells with granules that face TOWARD the lumen) are only found in the right colon. If found in the Left colon this is metaplasia and is highly suggestive of IBD. Pyloric Metaplasia: Crohn’s Disease! generation of glands that look similar to the pyloric glands of the stomach in the distal ileum. 2. Activity (acute inflammation) o 1) Cryptitis: neutrophils in the epithelium of crypts o 2) Crypt abscess: neutrophils accumulate in the lumen of crypts. II. Changes Specific to Ulcerative Colitis (UC) 1. Gross findings David Reilly Lecturer: Ashlie L. Burkart Lecture: 3 o Starts in the rectum and progresses continuously toward the right colon with NO breaks or patches! o Inflammatory polyps are common o Lead pipe colon: loss of haustral folds o Toxic megacolon: in severe cases of UC neural control is lost and the colon dilates. 2. Microscopic findings * Disease is LIMITED TO THE MUCOSA!!!! * Findings of Chronicity and activity esp. those related to colonic location. III. Changes Specific to Crohn Disease 1. Gross Findings o Distribution is patchy, most commonly involving the terminal ileum, but also has patchy distribution throughout the colon and even up to the stomach. Affects any part of the columnar GI tract. o Long Linear “Bear Claw like” ulcers o Cobblestone mucosa: long linear ulcers cross-hatched by normal plicae circularis * Strictures: d/t muscularis mucosae hypertrophy and hyperplasia. NOTE: strictures in an IBD patient is Crohn’s until proven otherwise. 2. Microscopic findings * Inflammatory changes involve THE ENTIRE WALL OF BOWEL!! o Knife like fissures cut into the mucosa o Granulomas are often found with multinucleated giant cells. o Combing fat: serosal/adventitial fat forms comb like projections into outer layers. o Lymphoid aggregates are common throughout the width of the entire wall. NOTE: All IBD patients must be routinely monitored for adenocarcinoma, dysplastic changes and malignancy. Risk is greatly increased even if IBD has resolved. IV. Algorithm for evaluating IBD 1. Look for features of “chronic” mucosal injury o Architectural distortion o Metaplasia: Pyloric metaplasia of terminal ileum or Paneth cell metaplasia of the left colon. o Hypertrophy/hyperplasia of MM. 2. Look for features of “activity” o Neutrophils in crypts or in crypt epithelium 3. Describe the disease distribution o Primarily involve the terminal ileum with patchy skip lesions: Crohn’s o Primarily involves the rectum and progresses proximal continuously: UC 4. Are there strictures? o Strictures in IBD are Crohn’s until proven otherwise. Strictures are only seen in UC with malignancy. 5. Does the process involve the mucosal layer only or the entire wall thickness? o Also identify classic histo. Features of the disease. 6. Follow up for dysplasia or signs of malignancy D. ACUTE SELF LIMITING COLITIS I. General o Transient, colitis with diarrhea (often bloody) o Common association: Bacterial enterocolitis o Usually not biopsied since diagnosis can be made clinically based on stool tests, etc… o If biopsy is taken, is used to rule out IBD: David Reilly 4 Lecturer: Ashlie L. Burkart Lecture: 3 * Will have features of acute inflammation (“activity”) but no features of “chronicity” E. C. DIFFICILE COLITIS I. General o Usually follows antibiotic exposure. o “pseudomembranous colitis”: pseudomembrane of fibrin, mucin and neutrophils covering the mucosa. Although it is classic of C. Difficile colitis it is NOT diagnostic (ischemia also has a pseudomembrane) * Defining feature is the dissolution of epithelial cells into the lumen d/t toxin produced by C. dif causing adhesion of cells to fail. F. ISCHEMIC BOWEL DISEASE I. Causes o Arterial occlusion: usually results in transmural infarction involving entire width of intestinal wall. o Occlusion of mesenteric veins: back up of deoxygenated blood ischemia o Luminal insult: pressure in lumen can blanche the mucosa reducing blood flow. o Non-occlusive ischemia: Hypoperfusion to bowel, possibly d/t shock results in mucosal ischemia. II. Pathogenesis o The mucosa gets blood last and is thus must sensitive to any decrease in blood flow or reduction in oxygenation. o Severity of ischemia determines how much of the intestine will be effected. III. Histology/types o Mucosal Ischemia: Hyalinization of the lamina propria (looks extra pink), withered crypts, may have pseudomembrane. Must distinguish from C. Dif colitis. **epithelial cells will not be falling off into the lumen as in C. Difficile colitis. o Mural infarct: damage to mucosa and submucosa o Transmural infarct: damage to entire width of wall. Most often d/t atherogenic infarction. o Chronic infarct: most often due to atherosclerosis leads to fibrosis and stricture. IV. ***Differential of bowel strictures: 1. Chronic ischemia from atherosclerosis fibrosis 2. Crohn’s disease hypertrophy and hyperplasia of MM 3. Tumor 4. Diverticulitis G. COLONIC DIVERTICULOSIS (“TICKS”) I. General o Uncommon in pt <40y/o o Caused by low fiber diet = much more common in western world o ~90% in sigmoid colon II. Characteristics * These are acquired pseudodiverticulum!! True diverticulum (ex. meckels’s) is far more rare. o Mucosa and submucosa herniate though the muscularis propria at a point of weakness (usually where a blood vessel penetrates) III. Complications and Associations 1. Complications o Diverticulitis: inflammation of the diverticulum from impaction, bacterial overgrowth, etc… o Perforation: leads to peritonitis, abscess formation and/or sepsis. 2. Associations o 1. Polypoid prolapsing mucosal folds (PPMFs)- prolapse related polyps that develop around diverticula o 2. Diverticular disease associated colitis- mimics IBD but has segmental distribution which is centered only around diverticula. David Reilly 5 Lecturer: Ashlie L. Burkart David Reilly Lecture: 3 6 Lecturer: Ashlie L. Burkart David Reilly Lecture: 3 7