Crohn Disease



Crohn Disease


Alexandros D. Polydorides, MD, PhD





Key Facts


Terminology



  • IBD discontinuously involving upper or lower GI


Etiology/Pathogenesis



  • Environmental trigger in genetically predisposed individuals leads to immunologically mediated injury


Clinical Issues



  • Peak: 2nd-3rd decade (smaller peak: 6th-7th decade)


  • Ileocolonic, small bowel only, or colon only


  • 5-30% of CD patients have upper GI disease


  • Abdominal pain, diarrhea, bleeding, obstruction


  • Most patients undergo surgery at some point


  • Drugs: Aminosalicylates, immunomodulators, antibiotics, corticosteroids


  • Recurrence: 94% within 10 years of diagnosis


  • Dysplasia/cancer: ˜ 5% patients develop GI cancer


Macroscopic Features



  • Skip lesions (uninvolved bowel), abrupt transition


  • Small aphthous or larger serpiginous/linear ulcers


  • “Cobblestone” mucosa, inflammatory pseudopolyps


  • Fat wrapping, mesenteric adhesions, abscesses


  • Sinus tracts, fistulas to other organs, skin


Microscopic Pathology



  • Basal lymphoplasmacytosis, crypt branching/dropout


  • Crypt abscesses, polypoid granulation tissue


  • Paneth cell and pseudopyloric gland metaplasia


  • Fissuring ulcers to muscularis propria


  • Transmural lymphoid aggregates


  • Submucosal fibrosis, muscle and nerve hypertrophy


  • Large, well-formed epithelioid cell granulomas



    • Mostly in submucosa, subserosa; ↑ distally







Gross photograph shows a “skip” lesion in Crohn disease. The ascending colon has a localized stricture image, whereas the distal and proximal bowel is mostly uninvolved image.






Hematoxylin & eosin shows a low-power view of Crohn disease in the small bowel with chronic mucosal changes image and transmural lymphoid aggregates image.


TERMINOLOGY


Abbreviations



  • Crohn disease (CD)


  • Inflammatory bowel disease (IBD)


  • Crohn colitis (CC)


Definitions



  • IBD = CD and ulcerative colitis (UC)


  • Involves any part of GI tract, mouth to anus


  • Characterized by patchy segmental transmural chronic inflammation with granulomas and associated fissures, fibrosis, neuromuscular hypertrophy, strictures, fistulas


ETIOLOGY/PATHOGENESIS


Environmental Exposure



  • Possible gut-specific sensitization to food antigens


  • Smoking: Exacerbates CD, ↑ risk of recurrence, relapse


  • Diet: Zinc deficiency may cause immune dysfunction



    • Elemental diet: ↓ intestinal permeability, symptoms


  • Increasing CD incidence in developing world



    • Better hygiene, vaccination, ↓ pathogen exposure


    • Possibly due to inadequate development of mucosal immunity


Infectious Agents



  • CD patients: ↑ incidence of childhood infections


  • ↑ serum levels of antibodies against enteric organisms


  • Mycobacterium paratuberculosis: Detected by PCR in some cases


  • Also implicated: Measles, Yersinia, indigenous flora


Genetic Predisposition



  • Clustering: Higher incidence in Ashkenazi Jews, Welsh


  • Familial risk: 10-25x higher incidence in 1° relatives



    • 5-10% of IBD patients have affected relatives


    • 25% of families: Discordant IBD type (CD vs. UC)


    • Suggests common & distinct genetic susceptibilities


  • Concordance: Mono- (50%) > di-zygotic (5%) twins



    • Significantly higher concordance rates than UC


    • Incomplete penetrance suggests additional factors


  • Polymorphisms (mutations) in NOD2 (CARD15)



    • Expressed in monocytes and enterocytes


    • Recognizes bacterial peptidoglycan, activates NF-κB


    • Mutations cause defective response to peptidoglycan



      • Ineffective innate, overactive adaptive immunity


      • ↑ bacterial survival, ↑ chronic inflammation


    • Maps to IBD1 susceptibility locus (chromosome 16)



      • Linkage to CD only (early onset, severe), not UC


Immunologic Factors



  • IBD: Disease of abnormal immune response regulation



    • Both innate (macrophages, neutrophils) and adaptive (lymphocytes, plasma cells) immunity


    • Excess stimulation (proinflammatory cytokines)


    • Upregulation: T-cell activation, antibody production


  • ↓ tolerance to luminal antigens, enteric commensals



    • Bacterial cell wall products, metabolites, and toxins


    • CD patients may have ↑ intestinal permeability



      • ↑ antigen absorption, bacterial invasion of mucosa


  • Increased activated dendritic cells in lamina propria



    • Toll-like receptors activate downstream NF-κB


    • ↑ TNF, IL-1β expression (pro-inflammatory activity)


  • Hyperactive CD4(+) T-cell response to normal flora



    • ↑ TH1 cytokine (IFN-γ, IL-12, IL-17) production


    • ↑ IgG production against commensal organisms



      • IBD flares may be ameliorated by antibiotics


  • Positive and negative associations with HLAs


Unknown Cause, Likely Multifactorial



  • Environmental trigger in genetically predisposed individuals leads to immunologically mediated injury


CLINICAL ISSUES


Epidemiology



  • Incidence



    • Increasing (˜ 0.01%), especially in Caucasians, Jews


  • Age




    • Peak: 2nd-3rd decade (smaller peak: 6th-7th decade)


  • Gender



    • IBD: Equal distribution; CD: Slightly more women


  • Ethnicity



    • Worldwide: More prevalent in USA, northern Europe


Site



  • 30-50%: Ileocolonic involvement



    • Distal 15-25 cm terminal ileum, right colon/cecum


  • 25-40%: Small intestine involvement only



    • Terminal ileum only > diffuse small bowel disease


  • 10-30%: Colonic disease only (isolated CC)


  • 5-30% of CD patients have upper GI disease


  • Colonic involvement: Variable, rectal sparing in ˜ 50%



    • More common in adults vs. children


    • R > L


    • Longer lengths involved (30-50 cm) vs. small bowel


Presentation



  • Often subtle: Diagnosis delayed after symptom onset


  • Depends on site involved, severity of inflammation


  • Intermittent, crampy, postprandial abdominal pain


  • Watery diarrhea or loose stools, especially at night


  • Perforation, bleeding (fissuring mucosal ulcers), fistula


  • Obstruction due to strictures (especially distal ileum)


  • Ileocecal disease mimics appendicitis, palpable mass


  • Malabsorption: Vitamins (B12, fat-soluble), zinc



    • May lead to growth retardation in pediatric patients


  • Colonic disease mimics UC (bloody, mucus diarrhea)


  • Sudden worsening: Superimposed infection (CMV) or ischemia (vasculitis), especially in immunosuppressed


  • Children may have predominance of systemic and extraintestinal symptoms, minimal GI signs


Endoscopic Findings



  • Colonoscopy with cannulation of terminal ileum


  • Increasing use of upper endoscopy in CD patients



    • Endoscopic findings do not reliably predict response


  • Early: Small aphthous lesions or erythematous ulcers


  • Late: Granularity, nodularity, “cobblestone” mucosa



    • Linear ulcers, rigidity of wall, stenosis, strictures


  • Surveillance for dysplasia/carcinoma is not as routine as it is for UC patients



    • Longstanding CC, strictures: Follow closely



      • Surveillance is difficult due to strictures


Laboratory Tests



  • Circulating antineutrophil cytoplasmic antibodies



    • Perinuclear staining pattern (p-ANCA)



      • Much more common and specific for UC


    • 25% of CD patients: Positive serum p-ANCA



      • Tend to have left-sided disease, similar to UC


Natural History



  • 2 forms of CD based on disease progression


  • Inherently indolent (nonperforating): Recurs slowly



    • Initially presents with inflammatory symptoms



      • Pain, diarrhea, weight loss, fever, GI bleeding


      • Exaggerated proinflammatory cytokine response


    • Can become fibrostenotic (obstruction, jaundice)


  • Inherently aggressive (perforating): Evolves rapidly



    • Prone to develop fistulizing disease and abscesses



      • Patients with small bowel disease or prior surgery


    • Up to 60% have internal or external fistulae



      • Spontaneously; to other bowel, vagina, bladder


    • Perforation in 1.5%



      • 2° to ischemia, infection, or spontaneous (abscess)


Treatment



  • Options, risks, complications



    • CC/UC patients after restorative proctocolectomy



      • Fecal stream diversion: Follicular hyperplasia, transmural inflammation, granulomas, fissures (difficult to distinguish from CD recurrence)


      • Ileostomy: Inflammatory polyps, prolapse, ulcers


      • Aphthous ulcer: 1st CD manifestation in neoileum


      • Pouchitis: Role of bacterial overgrowth from stasis


      • Resembles CD: Distortion, Paneth cell hyperplasia


      • Evaluate transmural disease far from anastomosis


    • Toxic megacolon: Mostly transverse, but not only



      • Complicates CD, UC; also seen in ischemic colitis and C. difficile colitis


      • Diameter > 6 cm without mechanical obstruction


      • Acutely ill patient: Fever, leukocytosis, distention


      • Mortality (25%), perforation → emergency surgery


      • Mucosal stripping, necrotic muscle with fissuring



  • Surgical approaches



    • Most patients will undergo surgery at some point



      • 20% in 1st year of diagnosis, 5% per year after


      • > 60%: Repeated operations → risk of short bowel


    • Balance: Disease resection vs. intestinal function


    • Indications: Abscess, fistula, bleeding, perforation, obstruction, intractable disease, dysplasia/carcinoma


    • Postoperative recurrence affected by



      • Indication, extent of disease at time of surgery


      • Smoking, failed therapy, perforating disease


  • Drugs



    • Inhibit inflammation, immune-mediated injury


    • Immunosuppression (cyclosporine), corticosteroids



      • Infection (CMV, C. difficile), osteonecrosis


    • Aminosalicylates (sulfasalazine, mesalazine)



      • Pneumonitis, hemolytic anemia, nephritis


    • Immunomodulators (azathioprine, mercaptopurine)



      • Lymphoproliferative disorders


    • Antibiotics (metronidazole, ciprofloxacin)


Prognosis



  • Recurrence common: 94% within 10 years of diagnosis



    • Mostly with ileocolonic disease or after surgery



      • Isolated ileal disease: Proximal to anastomosis


      • Ileocolitis, CC: Both sides of anastomosis


  • Regional jejunitis after surgery for ileal CD



    • Severe, sometimes fatal pattern of CD recurrence


  • Dysplasia/cancer: ˜ 5% patients develop GI carcinoma



    • May be multiple, usually preceded by dysplasia


    • Risk correlates with duration, anatomic extent



      • Median 15 years after diagnosis (75% > 8 years)


    • Risk of colorectal cancer reportedly less than in UC



      • Depends on extent, may be similar in cases of CC


    • Small bowel cancer: 10-20x ↑ risk (mostly distal)



      • Risk factors: > 20 years of disease, chronic fistulas


      • Poor prognosis: Difficult diagnosis, usually late


    • ↑ risk of anal squamous cell carcinoma, lymphoma


IMAGE FINDINGS


Radiographic Findings



  • Aphthous/deep ulcers, cobblestoning, fissures, fistulas, strictures, patchy involvement: Suggest CD over UC


  • Poor correlation with disease severity, activity


CT Findings



  • Useful to evaluate thickness, abscess, stricture, mass


MACROSCOPIC FEATURES


General Features



  • Skip lesions (uninvolved bowel) with abrupt transition


  • Intestinal mucosa



    • Small stellate aphthous ulcers



      • Erosions over lymphoid aggregates


    • Coalesce into “bear claw,” serpiginous, linear ulcers


    • Cobblestoning: Ulcers between uninvolved mucosa


    • Inflammatory pseudopolyps: Usually in transverse colon



      • Can be large (5 cm) or tall and narrow (filiform)


  • Intestinal wall



    • Sharp fissuring ulcers: Extend to muscularis propria



      • May lead to adhesions, fistulas, abscess


    • Submucosal fibrosis, muscular hypertrophy



      • Thick, firm, rigid bowel wall; can lead to stricture


  • Intestinal serosa



    • Exudate, serositis, many small nodules (granulomas)


    • Adhesions to other bowel, abdominal/pelvic organs


    • Fat wrapping (creeping fat substitution)



      • Adipose tissue expands toward antimesenteric surface


      • Partly or completely surrounds bowel


      • Associated with chronic transmural inflammation


    • Intramural or mesenteric abscesses and sinus tracts



      • Fistulas between organs, to skin (enterocutaneous)


    • Lymph nodes: Enlarged gray specks (granulomas)


  • Superficial CD



    • Classic CD but limited to mucosa and submucosa


    • Rare; diagnosis requires typical CD elsewhere


    • Minimal transmural inflammation



      • Bowel wall thin, pliable; strictures do not develop


    • In colon, superficial CC resembles UC


Extraintestinal Manifestations



  • Esophageal CD



    • Rare: < 1% of CD, less than oropharyngeal disease


    • Diagnosis of exclusion: Need evidence of distal CD


    • Aphthous ulcers, erosions, nonspecific esophagitis


    • Irregular stenosis, strictures: Simulate carcinoma


  • Gastric disease: Typically distal stomach



    • Antral stenosis and pyloric obstruction → vomiting


    • Diagnose only with concurrent intestinal disease



      • Important to exclude Helicobacter pylori gastritis


    • May present just as focally enhanced gastritis



      • Lymphocytes, neutrophils around single crypts


    • Isolated granulomatous gastritis: Early gastric CD?


  • Duodenal CD



    • Most have concomitant distal ileal or colonic disease



      • Can extend proximal (stomach), distal (jejunum)


      • Rarely, duodenum is only site involved by CD


    • Symptoms similar to distal disease (ulcers, strictures)



      • Epigastric pain, hemorrhage, nausea, vomiting


      • Obstruction, bleeding, duodenal-enteric fistulae


      • 30-60% of CD patients: Endoscopic/histologic involvement without upper GI symptoms


    • Diagnosis relies on finding patchy, segmental, inflammatory changes ± granulomas



      • No other cause for inflammation (peptic injury)


      • Focal neutrophils in lamina propria, epithelium


      • Intraepithelial lymphocytosis may be present, ± associated villous blunting


    • Distinguish from peptic duodenitis, ulcer, eosinophilic gastroenteritis, celiac disease


    • Gastroduodenal CD may be more common in children


  • Anorectal disease



    • Perirectal/perianal tags, scars, erosions, ulcers, blind sinus tracts, violaceous edema, fistulae, abscesses


    • Common in patients with colonic disease (˜ 75%)


    • Correlates with genital involvement (vulvar, vaginal)


    • May predate primary intestinal disease by years


  • Oral disease



    • 20-50% of CD patients: Lips, buccal mucosa, tongue


    • Vesicles, aphthous ulcers, polypoid inflammation


    • May herald unrecognized intestinal disease



  • Nonalimentary tract involvement



    • 25% of known CD patients: At least one extra-GI site



      • Colon involvement, longer disease predispose


    • Arthritis/arthralgia, ileitis, ankylosing spondylitis



      • Incidence varies, may predate intestinal symptoms


    • Hepatobiliary: Steatosis, pericholangitis, carcinoma



      • Primary sclerosing cholangitis: More often in UC


    • Skin: Erythema nodosum, pyoderma gangrenosum



      • Cutaneous CD: Around stoma or distant disease


    • Eye: Uveitis, conjunctivitis, iritis, orbital myositis


    • Vulva, vagina: Granulomatous inflammation


    • Genitourinary: Calculi, obstructive hydronephrosis


    • Vasculitis: Polyarteritis nodosa, giant cell arteritis


    • Venous thromboembolism: Hypercoagulable state


    • Anemia: B12 deficiency, ↓ erythropoietin, hemolysis

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Jul 6, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Crohn Disease

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