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Published: January, 2013

Crohn's Disease

Bret A. Lashner

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Crohn’s disease is characterized by recurring episodes of inflammation of any part of the gastrointestinal tract, from the mouth to the anus. This inflammation is transmural and can result in strictures, microperforations, and fistulae. The inflammation may not be contiguous and thus can produce skip lesions throughout the bowel. Histologically, Crohn’s disease can have transmural lymphoid aggregates, non-necrotizing granulomas, fissuring, or microscopic skip lesions. Although granulomas strongly suggest Crohn’s disease as the diagnosis, they are seen in only 10% of patients with Crohn’s disease and are sporadically distributed in biopsy specimens.

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Incidence and Prevalence

The annual incidence of Crohn’s disease ranges from 1 to 10 cases per 100,000 people annually depending on the region studied and the incidence appears to be rising 1. The peak age-specific incidence occurs between 10 and 20 years of age, and a second smaller peak occurs near age 50 years. Some have suggested that the second peak is due to more common diseases in this age group, like diverticulitis and ischemic disease. The prevalence of Crohn’s disease ranges from 10 to 70 per 100,000 people, but some North American studies have shown prevalence as high as 200 per 100,000 people. There also appears to be a north-south gradient worldwide, where populations in higher latitudes (i.e. Scandinavia, Canada, and Australia) have higher incidence rates than populations in lower latitudes (i.e. Southern U.S., Spain, and Italy). In the United States, males and females are equally affected, but both whites and Ashkenazi Jews are at much higher risk of developing Crohn’s disease than the rest of the population. Of note, migrants moving from a low-risk region to a high-risk region have a risk of developing Crohn’s disease that is similar to that in the high-risk region within one generation.

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The pathogenesis of Crohn’s disease is believed to be due to a dysregulated proinflammatory response to commensal gut bacteria.  Due to mutations, some mucosal defense mechanisms are disrupted.   Mucosal defense mechanisms include the presence of mucus-coated epithelium with tight junctions, IgA secretion, and defensins (naturally-occurring antibiotics that are produced by Paneth cells to maintain sterility of the crypt). Genome-wide association studies have shown that mutations in the NOD2/CARD15 gene and the autophagy gene, ATG16L1, are associated with Crohn’s disease 2,3.  The NOD2 gene is involved with recognition of bacterial peptidoglycans and mutations in the gene cause a decrease in defensin production and secretion.  Mutations in the ATG16L1 gene lead to a decrease in the exocytosis of secretory granules in Paneth cells, thereby decreasing concentrations in the crypt of defensins, lysozyme, and phospholipase A2.  When defense mechanisms are depressed, uncontrolled microbial proliferation can occur, and NF-kB-dependent genes are stimulated to produce pro-inflammatory cytokines like tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1), IL-6, and the chemokine IL-8.  Cytokines is a collective term for a group of low-molecular-weight peptides that are active at low concentrations and bind to specific receptors to produce autocrine, paracrine, and endocrine effects; chemokines are peptides that attract inflammatory cells.  Cytokine and chemokine production attract T-cell infiltration, which in Crohn’s disease patient are principally Th-1 cells, which in turn amplify the inflammatory response.

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Signs and symptoms

Patients with new-onset Crohn’s disease usually present with inflammatory-type symptoms, with such as diarrhea, abdominal pain, fever,  fatigue, stomatitis, anal fissures, and weight loss.  The abdominal pain usually is insidious, is in the right lower quadrant, occurs soon after eating, and may  be associated with a tender inflammatory mass.   When the inflammatory process affects the large bowel, there may be  hematochezia, but bleeding is much less common in Crohn’s disease patients than in ulcerative colitis patients.   Extra-intestinal manifesations of disease, such as  peripheral arthritis, axial arthritis, and erythema nodosum also may be presenting features. Cigarette smoking is seen much more commonly in Crohn’s disease patients (upwards of 50% of patients) compared to an unaffected adult population.

As Crohn’s disease becomes more advanced, strictures and fistulas may develop (Figure 1)4.  Patients with strictures often present the obstructive symptoms, such as severe abdominal pain, distension, bloating, and vomiting.   Patients who develop fistulas, or perforating-type complications, may present with perianal fistulas and abscesses, ventral wall drainage, pneumaturia, or intra-abdominal or retroperitoneal abscesses.  Children with extensive small bowel involvement with their Crohn’s disease can present with growth retardation and delayed puberty.  Interestingly, nutritional support can reverse some of manifestations of growth retardation.

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The diagnosis of Crohn’s disease is established by finding characteristic intestinal ulcerations and excluding alternative diagnoses, such as enteric infections, ischemia, diverticulitis, or NSAID-induced enteropathy (Table 1). 

Table 1: Principal Alternatives in the Differential Diagnosis of Inflammatory Bowel Disease—Crohn’s Disease
Crohn's Disease
Infectious colitis
Antibiotic-associated colitis
Bowel tuberculosis
Small bowel cancer
Nonsteroidal enteropathy
Celiac sprue
Postsurgical adhesions
Behcet's disease
Ischemic colitis
Radiation enteropathy

A tissue diagnosis is not necessary. The ulcerations of Crohn’s disease may appear aphthoid, but they could also be deep and serpiginous. Skip areas, a cobblestone appearance, pseudopolyps, and rectal sparing are characteristic findings (Figure 2). On a small bowel x-ray, Crohn’s disease often is manifested by separation of bowel loops and a narrowed terminal ileal lumen, the string sign (Figure 3).  Typical lesions of Crohn’s disease also may be seen in the upper gastrointestinal tract. The inflammation is localized in the ileocecal region in 45% of cases, in the small bowel in 22%, in  the colon in 32%, and in the upper gastrointestinal tract or perirectum in 6%.

The diagnosis of Crohn’s disease can be made only when other reasonable alternatives in the differential diagnosis have been excluded. The most common diagnoses that mimic Crohn’s disease are the infectious colitides. It is imperative to check stool for enteric pathogens, including ova and parasites, Escherichia coli O157:H7, and Clostridium difficile.  Infection with Yersinia enterocolitica or Mycobacterium tuberculosis can cause inflammation in the terminal ileum resembling Crohn’s disease. Other important diseases in the differential diagnosis of Crohn’s disease include intestinal lymphoma, celiac sprue, radiation enteropathy, and NSAID-induced enteropathy.

Natural History

Crohn's disease is a naturally recurring and remitting disease.  As intestinal disease progresses, fibrosis is left behind causing fixed narrowing of the bowel.  These strictures can lead to obstructive symptoms and even frank bowel obstruction.  Since there is little, if any, inflammation in these strictured segments, they do not usually respond to anti-inflammatory medications and will require surgery.  Surgery for intestinal strictures involves either a resection or a strictureplasty, or both 5.  Unfortunately, surgery for Crohn's disease is the rule rather than the exception – at least 80% will require at least one surgical procedure over the first 5 years of disease and many will need multiple abdominal surgeries over their lifetime.  Crohn's disease is characterized by transmural intestinal inflammation.  The inflammation can extend through the bowel wall and into adjacent organs and spaces causing fistulas and abscesses.  These complications are especially difficult to treat medically since anti-inflammatory medications can exacerbate septic complications.

There are many extraintestinal manifestations of Crohn's disease. Approximately 2% of inflammatory bowel disease patients develop primary sclerosing cholangitis, a cholestatic liver disease diagnosed by the appearance of extrahepatic and intrahepatic strictures on a cholangiogram. Primary sclerosing cholangitis is seen about 3-times more commonly in ulcerative colitis than in Crohn's disease patients and is not affected by anti-inflammatory therapy directed at the bowel. Other hepatic manifestations of inflammatory bowel disease include fatty liver, chronic active hepatitis, amyloidosis, and complications from medications used to treat inflammatory bowel disease (eg, steroids, azathioprine, 6-mercaptopurine [6-MP], sulfasalazine, infliximab).  Erythema nodosum, seen in up to 3% of patients, is characterized by raised tender, erythematous nodules appearing typically on the extremities and responding to anti-inflammatory therapy for the bowel. Pyoderma gangrenosum, a rare ulcerating necrotic lesion, is seen in both Crohn's disease and ulcerative colitis, and also usually responds to anti-inflammatory treatment  of the bowel.  Peripheral arthritis usually is seronegative, mono- or pauciarticular, and asymmetrical and is seen in approximately 25% of inflammatory bowel disease patients. The large joints are most often affected, and there is no synovial destruction. Human leukocyte antigen (HLA)-B27-positive axial arthritis is another extra-intestinal manifestation of inflammatory bowel disease patients seen in about 5% of patients.   Ocular manifestations of inflammatory bowel disease include blurred vision, eye pain, photophobia, and keratitic precipitates. Patients with uveitis often have HLA-B27 positivity, whereas patients with episcleritis and iritis usually do not. Cerebrovascular accidents and other thromboembolic events can result from hypercoagulability secondary to chronic inflammation or to other inherited syndromes, such as the factor V Leiden mutation. Crohn's disease patients, especially those with fat malabsorption are susceptible to nephrolithiasis from calcium oxalate stones.  Excess free fatty acids bind to calcium more avidly than dietary oxylate making oxylate readily available for absorption and concentration in the kidney.

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Therapy for Crohn's disease has been discussed in practice guidelines published in 2009 7. These guidelines set up a definition for the severity of a Crohn's disease flare. Mild to moderate disease is indicated when patients can tolerate oral intake without dehydration, high fever, abdominal pain, abdominal mass, or obstruction. Moderate to severe disease describes the disorder in patients who have failed to respond to therapy for mild or moderate disease or those with fevers, weight loss, abdominal pain, anemia, or nausea and vomiting without frank obstruction.  Severe to fulminate disease is found in patients with persisting symptoms despite the introduction of steroids on an outpatient basis or those presenting with high fever, persistent vomiting, obstruction, rebound tenderness, cachexia, or an abscess. In addition, it is important to distinguish between differing behaviors of disease: inflammatory, fistulizing, or fibrostenotic because different therapies are best suited for different disease behaviors regardless of disease severity.

For Crohn's disease patients with mildly to moderately active disease, oral mesalamine is only modestly effective and none of the mesalamine agents are approved for use. Sulfasalazine has some potential benefit in the treatment of colonic disease, but it is not useful for isolated small bowel disease. Budesonide is a topically active corticosteroid that, when given orally, is effective in treating mucosal inflammation of the distal ileum and proximal colon and is then inactivated through first-pass liver metabolism. The side-effect profile of budesonide is much better than that of oral corticosteroids. In patients with mildly to moderately active Crohn's disease, budesonide 9mg daily was found to be significantly better in inducing remission than 4g daily of a mesalamine preparation 7. Gastroduodenal Crohn's disease has been shown to improve with oral proton pump inhibitors.

For moderately to severely active Crohn's disease, oral steroids are often necessary. Prednisone is dosed as in ulcerative colitis patients at 40mg per day. It is important to rule out any concomitant infection or abscess before initiating steroid therapy. For patients who are steroid-resistant or who have become steroid-dependent, 6-MP,  azathioprine, or methotrexate may be used. These agents have  been shown to be safe and effective in Crohn's disease, enabling patients to avoid long-term use of corticosteroids.  Methotrexate also is effective as monotherapy.

Infliximab, a chimeric murine-human anti-tumor necrosis (TNF) antibody has been shown to be effective for induction and maintenance of remission for both inflammatory and fistulous Crohn's disease 8-10. Infliximab is given as a loading regimen of three doses over 6 weeks and then typically dosed at 5mg/kg over 2 hours and given every 8 weeks. Adverse side effects include infusion reaction, infections (including tuberculosis and other opportunistic infections), and lymphoma. Prior to initiation infliximab, testing for latent  tuberculosis and hepatitis B infection, since severe reactivation of these infections has been reported.   Adalimumub, a fully human anti-TNF antibody that is approved for induction and maintenance therapy for Crohn's disease, is given subcutaneously as a loading dose of 160mg at week 0 and 80mg at week 2 and then 40-mg every 2 weeks. Its effectiveness and toxicities are very similar to that of  infliximab (except injection reactions occur rather than infusion reactions)11.  Certolizumab, a pegylated Fab fragment of a humanized anti-TNF antibody, is also approved for induction and maintenance of Crohn's disease. Its effectiveness and toxicity is similar to that of infliximab and adalimumab, but injection reactions are much less frequent 12,13.  Certolizumab is given as a monthly subcutaneous injection after a loading dose. Natalizumab, an anti-integrin antibody, is another biologic agent approved for use in Crohn's disease. Its effectiveness appears to be similar to that of other biologic agents. Natalizumab, also approved for multiple sclerosis, has been rarely associated with progressive multifocal leukoencephalopathy (PML), a central nervous system infection with the JC virus, causing its use to be restricted to Crohn's disease patients who have failed to respond to an anti-TNF agent and who are enrolled into a national registry 14.

For Crohn's disease patients with severe or fulminate disease, hospitalization is advisable. An abdominal computed tomography (CT) scan should be obtained if an abscess is clinically suspected. Stool studies should be done to rule out infection, such as Clostridium  difficile and cytomegalovirus. Once abscess and infection have been excluded, intravenous steroids should be instituted. Surgical intervention is indicated for perforation, obstruction, abscess, or fulminate disease unresponsive to medical therapy.

Prior to initiating anti-inflammatory therapy, a thorough vaccine record should be obtained 15.  Vaccines given prior to immunosuppression will be more effective than those initiated after the start of such therapy.  In general, live vaccines (i.e. live attenuated influenza vaccine, measles-mumps-rubella, varicella-zoster vaccine, and oral polio live vaccine) should be avoided.  Fortunately, alternatives exist for the influenza vaccine, and some others.  Pneumococcus vaccine, meningococcus vaccine, human papillomavirus vaccine, and hapatitis B virus vaccine are all inactive vaccines and, therefore, should be administered when appropriate,


Patients with small bowel Crohn's disease have an increased risk of small bowel adenocarcinoma, likely related to chronic uncontrolled inflammation.  The distribution of small bowel cancer in Crohn's disease patients is mostly in the distal bowel, following the distribution of intestinal inflammation, while sporadic small bowel cancer occurs principally in the proximal small bowel.  Since the small bowel is not amenable to frequent endoscopic sampling, cancer surveillance is not practical.  However, surgeons always take a frozen section at the site of a small bowel stricture to rule out malignancy prior to resection or strictureplasty.

Patients with Crohn's disease who have at least 30% of the colon affected with inflammation have an increased risk of colonic epithelial dysplasia and adenocarcinoma. This risk of colon cancer is higher with both increasing duration and extent of disease, as well as with primary sclerosing cholangitis.  Entering at-risk patients into a cancer surveillance program is important, but the exact method and timing of surveillance are still matters of much debate. Most guidelines recommend beginning screening colonoscopies after 8 years of disease. Multiple biopsies should be taken at regular intervals throughout the colon and examined for the premalignant neoplastic lesion of dysplasia. All specimens with any grade of dysplasia should be reviewed by an expert gastrointestinal pathologist to confirm the findings.  It is generally agreed that high-grade dysplasia is an absolute indication for a colectomy because these patients have a high risk for concurrent or future cancer. Low-grade dysplasia in flat mucosa also is an indication for  surgery, because progression to more advanced neoplasia often occurs.


Crohn’s disease occurs in genetically-predisposed individuals, and mostly occurs in the second or third decade of life.  It is characterized by inflammation anywhere in the gastrointestinal tract from the mouth to the anus. Patients often develop extra-intestinal manifestations of disease in addition to diarrhea, abdominal pain, weight loss, fevers, and fatigue.    Treatment options are based on both the severity of disease as well as the behavior of disease (i.e. inflammatory, stricturing, or fistulizing disease).  Surgery in Crohn’s disease patients, both intestinal resection and strictureplasty, is the rule rather than the exception.

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  • Crohn’s disease is characterized by transmural inflammation involving any part of the gastrointestinal tract.
  • The diagnosis of Crohn’s disease is based on a constellation of clinical, endoscopic, radiographic, and histological findings, with negative stool cultures.
  • The differential diagnosis of Crohn’s disease includes infectious colitis, diverticulitis, celiac sprue, intestinal lymphoma, radiation enteropathy, NSAID use, and ischemic colitis.
  • Treatment options depend on the severity of disease as well as the behavior of disease.
  • First-line therapy for Crohn’s disease patients with inflammatory-type disease often includes budesonide, and some patients also need other corticosteroids agents, immunosuppressives, and biologic agents.
  • There are many extra-intestinal manifestations of Crohn’s disease and some respond to medications directed at bowel inflammation.
  • Colorectal cancer is an important concern for patients with extensive involvement of Crohn’s disease in the colon.

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Suggested Readings

  • Bayless TM, Hanauer SB, eds. Advanced Therapy in Inflammatory Bowel Disease: Volume II: IBD and Crohn's Disease. People's Medical Publising House, Shelton, CT, 2011
  • Bernstein CN, Fried M, Krabshuis JH, et al. World Gastroenterology Organization practice guidelines for the diagnosis and managment of IBD in 2010. Inflamm Bowel Dis 2010;16:112-24
  • Mowat G, Cole A, Windsor A, et al. Guidelines for the management of inflammatory bowel disease in adults. Gut 2011;60:571-6-7
  • Rivas MA, Beaudoin M, Gardet A, et al. Deep resequencing of GWAS loci identifies independent rare variants associated with inflammatory bowel disease. Nat Genet 2011;43:1066-73.
  • Lichtenstein GR, Hanauer SB, Sandborn WJ: Management of Crohn's disease in adults. Am J Gastroenterology 2009;104:465-483.


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