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  Disease summary:

  
  
  
  
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    The inflammatory bowel diseases (IBDs) are prototypic complex genetic disorders, involving multiple interacting genetic loci and environmental factors that trigger disease.

    
    
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    IBD is comprised of two inter-related disorders, Crohn disease (CD), and ulcerative colitis (UC), as well as indeterminate colitis (IC). IC describes the 5% to 10% of IBD involving only the colon and is neither classic CD nor UC.

    
    
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    Clinical presentations of UC and CD overlap; both present with diarrhea, bloody diarrhea, abdominal pain, most extraintestinal manifestations, weight loss, and fever.

    
    
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    Anatomic involvement: CD can involve any portion of the gastrointestinal (GI) tract, most commonly the terminal ileum (5%-75%) and colon (20%-50%). CD causes transmural inflammation in all four layers of bowel wall; extension through the bowel wall can cause fistulae, abscesses, or perianal complications. Strictures secondary to fibrosis are relatively common. UC is localized to varying lengths of continuous inflammation proceeding proximally from the rectum; a discontinuous cecal patch may be present. UC is limited to mucosal and submucosal inflammation, and does not cause perianal or intra-abdominal disease; strictures are much less common than in CD.

  
  
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  Differential diagnosis:

  
  
  
  
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    Infectious colitis (bacterial, viral, protozoal), pseudomembranous colitis (Clostridium difficile toxin), and ischemic colitis

  
  
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  Monogenic forms:

  
  
  
  
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    No single gene cause of IBD is known to exist except perhaps for a rare form of CD (see IL-10 pathway later).

  
  
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  Family history:

  
  
  
  
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    An affected first-degree relative confers a relative risk of 30 to 40 for CD and 10 to 20 for UC. Overlapping risk occurs since first-degree relatives of patients with CD have relative risk of 3.9 for developing UC.

  
  
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  Twin studies:

  
  
  
  
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    Monozygotic twins have a 20% to 50% concordance rate in CD, much lower in UC.

  
  
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  Environmental factors:

  
  
  
  
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    Luminal microbes or microbial products are implicated as “environmental” triggers for IBD.

  
  
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  Genome-wide associations:

  
  
  
  
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    Many associations exist. Disease-associated genetic variants (single-nucleotide polymorphisms [SNPs]) provide insight into disease pathogenesis; testing for SNPs is not yet clinically validated to diagnose or guide management of IBD.

  
  
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  Pharmacogenomics:

  
  
  
  
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    Testing for common thiopurine S-methyltransferase (TPMT) variants to guide management has proven validity in some clinical circumstances.

Diagnostic Criteria for IBD

Diagnostic evaluation should include

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  Stool studies including fecal leukocytes, culture for appropriate bacterial and parasitic cultures, assays for C difficile toxin, appropriate tests for possible viral etiologies (cytomegalovirus) and Mycobacterium tuberculosis.

  
  
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  Colonoscopy with biopsy and ileum cannulation. Granulomas are present on endoscopic biopsies in approximately 10% of CD, crypt abscesses are indicative of UC.

  
  
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  Serologic markers may be helpful; anti-Saccharomyces cerevisiae antibodies (ASCA) and antineutrophil cytoplasmic antibodies with perinuclear staining (p-ANCA) have high sensitivity for IBD in combination compared to other causes of intestinal inflammation, but sensitivity varies for different ethnic groups (much lower, eg, in regions endemic for tuberculosis). ASCA shows high specificity for CD, and p-ANCA for UC, although patients with CD limited to the colon may be positive for p-ANCA. Prognostic use of antibody concentrations in IBD remains under investigation.

  
  
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  Upper GI imaging to assess for signs of ileal or other upper GI tract involvement.

  
  
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  Workup for extraintestinal manifestations if clinically indicated.

Clinical Characteristics

Patterns of Disease in CD

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  Fibrostenotic CD can present with right lower quadrant pain as the most common symptom and can mimic acute appendicitis and present with pain, fever, and a palpable mass; alternatively, the pain may be colicky in nature, recurrent or progressive and associated with abdominal bloating, nausea, vomiting, and weight loss.

  
  
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  Penetrating CD can present with an intra-abdominal abscess with complications of fistulae to the perianal region, abdominal wall or bladder with associated drainage, urinary tract infections, pneumaturia or even fecaluria. Anal fissures are also specific for CD.

  
  
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  Inflammatory colonic CD can present identically to UC (see later).

Patterns of Disease in UC

UC presentation is less variable and is characterized by mucosal or submucosal inflammation of varying lengths of the colon but always involves the rectum. As such, clinical presentations include diarrhea that may be bloody, tenesmus, urgency, and crampy abdominal pain. Fever and weight loss may accompany severe disease.

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  Extraintestinal manifestations of IBD: Nonintestinal manifestations are similar for both CD and UC.

  
  
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  Dermatologic manifestations include the relatively common erythema nodosum that often correlate with acute flares. The more problematic pyoderma gangrenosum is much more common in UC than CD, and its course is independent of IBD activity.

  
  
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  Joint manifestations include peripheral arthritis that correlates with exacerbations of bowel disease, and central arthritis (ankylosing spondylitis or sacroiliitis) that does not correlate with bowel activity.

  
  
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  Ocular complications include conjunctivitis, episcleritis, and uveitis and may occur independent of bowel activity.

  
  
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  Hepatobiliary complications include nonalcoholic fatty liver disease, cholestasis, gallstones (CD>UC, particularly with ileal disease due to decreased bile acid reabsorption), and primary sclerosing cholangitis (UC>>CD), a fibrotic disorder of intra- and extrahepatic bile ducts that does not correlate with bowel disease activity.

  
  
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  Renal complications include kidney stones that are more common in CD than in UC. Oxalate absorption is increased in bowel inflammation leading to calcium oxalate stones. Uric acid stones also occur with increased frequency in CD.

Screening

No clear evidence for screening of family members exists. Genetic testing for disease-associated SNPs is not clinically validated. While suggestions of specific phenotypes related to specific SNPs exist such as stricturing ileal CD for the three most common NOD2 SNPs, no current therapy for primary prophylaxis against IBD development is known, so these tests have no clinical utility at present.

Counseling

Familial clustering is common but not universal. Mendelian inheritance for a rare form of enterocolitis may exist but is exceedingly rare. Nevertheless, many patients want to know the risk for offspring during family planning and the risk for siblings of affected individuals. If a patient has IBD, the lifetime risk of a first-degree relative developing IBD is 10%; if two parents have IBD, the lifetime risk for each offspring may be as high as 36%. Genetic risk is much higher for CD than for UC with a relative risk of 3 to 40 for CD and 10 to 20 for UC. A first-degree relative of a proband with CD has a relative risk for developing UC of 3.9, while the relative risk of a UC proband developing CD is only 1.8.

Aminosalicylates

For both forms of IBD, the aminosalicylates remain the most common first-line therapy in mild to moderate disease. Sulfasalazine, balsalazide, and olsalazine depend on colonic bacteria to release the active salicylate making them an effective treatment for UC and CD limited to the colon but much less effective in small intestinal involvement. Mesalamine is used preferentially in small intestinal CD. In addition to treating mild to moderate disease, salicylates reduce the incidence and severity of recurrence after surgical resection or medically induced remission. In UC, distal colonic inflammation can be treated with salicylate suppositories (proctitis) or enemas (proctosigmoiditis).

Antibiotics and Probiotics

Antibiotics have also shown to improve mild to moderate CD, particularly metronidazole and ciprofloxacin. Metronidazole also helps in the treatment of fistulous complications of CD but its use is limited by upper GI side effects and peripheral neuropathy. With recent understanding of the importance of the gut microflora, new strategies to eliminate or reduce proinflammatory bacteria or replace them with anti-inflammatory bacteria, also known as probiotics, should provide new treatment options. Clinical applications for using the microflora to treat IBD has not yet been optimized.

Immune Modulating Agents