Crohn’s Disease

Crohn’s disease is a chronic, recurrent condition that causes patchy transmural inflammation that can involve any part of the gastrointestinal tract. It is a type of inflammatory bowel disease (IBD) along with ulcerative colitis (UC). The terminal ileum and proximal colon are usually affected. Crohn’s disease typically presents with intermittent, non-bloody diarrhea and crampy abdominal pain. Extraintestinal manifestations may include calcium oxalate renal stones, gallstones, erythema nodosum, and arthritis. Diagnosis is established via endoscopy with biopsy that shows transmural inflammation, characteristic “cobblestone” mucosa, and noncaseating granulomas. Management is with corticosteroids, azathioprine, antibiotics, and anti-TNF agents (infliximab and adalimumab). Complications include malabsorption, malnutrition, intestinal obstruction or fistula, and an increased risk of colon cancer.

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Epidemiology and Pathophysiology


  • Incidence: bimodal distribution
    • 15–25 years (slightly younger average than in ulcerative colitis [UC])
    • Smaller peak occurs between 50 and 70 years of age
  • Males and females are equally affected
  • Most common among whites and eastern European (Ashkenazi) Jews
  • In 2017, there were 6.8 million cases of inflammatory bowel disease (IBD) globally.
  • Prevalence of Crohn’s disease (CD) is approximately 200 per 100,000 adults
  • Incidence of CD is approximately 320 per 100,000 adults per year

Risk factors

  • Smoking (contrary to UC)
  • Genetics: 
    • HLA-B27 (encodes genes for the major histocompatibility complex [MHC])
    • NOD2 (affects the body’s ability to recognize and attack luminal pathogens)
  • Family history of IBS
    • Twin concordance rate is 55%
    • 15% of patients with CD have an affected first-degree relative
  • Decreased physical activity
  • Decreased fiber intake
  • Increased dietary fat intake


The exact pathophysiology is unknown but likely associated with a combination of dysregulation of the intestinal epithelium and the immune system.

  1. Mutations of the NOD2 gene → defects in the lamina propria and epithelial barrier of the gastrointestinal (GI) tract → more pathogens penetrate the GI tract → recruitment and activation of cytotoxic cells
  2. Activation of Th1-mediated cells in the GI wall → release of pro-inflammatory cytokines → intestinal inflammation 
  3. Lack of the down-regulation of immune responsiveness after an infection or initial flare → chronic inflammation → granulomas
  4. Intestinal tissue damage including edema, ulcerations, erosions, and necrosis
  5. Since the inflammation is transmural, it may lead to intestinal perforation and fistulas.
  6. Chronic and repetitive episodes → scarring, fibrosis, and obstruction of the intestinal wall

Location and pattern of inflammation:

  • May include any portion of the GI tract
  • The most common site is terminal ileum and proximal colon. 
  • Associated with skip lesions
  • The rectum is often spared.

Clinical Presentation

The typical presentation of Crohn’s disease is a relapsing disorder that includes:

  • GI manifestations:
    • Chronic, intermittent diarrhea that is usually non-bloody
    • Crampy abdominal pain (may be diffuse or localized to the right lower quadrant)
    • Odynophagia or dysphagia (secondary to esophageal involvement)
    • Flatulence and bloating
    • Fecal incontinence
    • Signs of malabsorption, with vitamin B12 and D deficiencies and iron deficiency anemia
  • General manifestations:
    • Low-grade fever
    • Signs of anemia: fatigue, pallor, dyspnea, palpitations
    • Loss of appetite
    • Weight loss
    • Failure to thrive or growth delay in children
  • Extraintestinal manifestations:
    • Aphthous ulcers
    • Gallstone formation (secondary to decreased bile acid reabsorption)
    • Kidney stones (usually calcium oxalate)
    • Pyoderma gangrenosum: rapidly progressive painful, red papules → pustules → deep ulcers with central necrosis
    • Erythema nodosum: painful, red nodules that usually appear on the shins
    • Eye inflammation (uveitis, iritis, episcleritis)
    • Peripheral arthritis, ankylosing spondylitis, or osteoporosis
    • Clubbing of the fingertips
    • Primary sclerosing cholangitis (much more common in UC than CD)

Reactivation of CD in an asymptomatic period can be triggered by physical or psychological stress, sudden or drastic changes in diet, and smoking.


The diagnosis of Crohn’s disease should be suspected if a patient presents with the above-noted symptoms of abdominal pain, chronic intermittent diarrhea, fatigue, and weight loss. The initial workup includes the following:

Laboratory studies

  • Complete blood count will show anemia, leukocytosis, and thrombocytosis.
  • Complete metabolic panel to check if chronic diarrhea has caused electrolyte imbalance 
  • Iron deficiency and vitamin B deficiency
  • ↑ ESR and CRP

Stool studies

  • May be used to exclude other causes of inflammatory diarrhea (e.g., infection)
  • Clostridioides difficile toxin studies in cases of recent antibiotic use
  • May show traces of blood in the stool

Abdominal computed tomography (CT), magnetic resonance imaging (MRI), or X-ray with barium swallow

  • Useful in assessing the extent and severity of disease as well as any complications, if present (e.g., perforation, fistulas, abscess, stenosis)
  • Signs of intestinal inflammation: wall thickening with mucosal enhancement, distortion, and hyperintensity
  • Mucosal ulcers that give a “cobblestone” appearance
  • Narrowing of the lumen can be seen as the “string sign” 
  • Loops of bowel appear to be widely separated due to fatty proliferation, known as “creeping fat”
  • Pseudodiverticula: areas of dilation after a site of localized contraction due to an ulcer

Colonoscopy with biopsy

  • Macroscopic findings:
    • Skip lesions in any portion of the GI tract, usually sparing the rectum
    • Ulcers, fissures, and fistulas (cobblestone appearance)
  • Microscopic findings:
    • Noncaseating granulomas
    • Lymphoid aggregates of the lamina propria
    • Transmural inflammation


Medical therapies for Crohn’s disease depend on the severity of the disease. The 2 main therapeutic goals are to terminate an acute, symptomatic attack and to prevent recurrent attacks.

In general, management consists of the following:

  • General measures: 
    • Smoking cessation
    • Vitamin B12 and D for severe disease or prior to ileal resection
    • Avoidance of lactose-containing foods
    • Antidiarrheal agents (e.g., loperamide, bile acid-binding agents)
  • Targeted medical therapy: 
    • Antibiotics 
      • Metronidazole or ciprofloxacin
      • Used for complications such as abscesses and fistulas
    • Corticosteroids 
      • Used for acute disease flare-ups
      • Duration is limited due to complications of long-term use
    • Immunomodulators 
      • Azathioprine or mesalamine
      • Used after corticosteroid induction therapy to allow tapering and withdrawal of corticosteroids 
      • Also used in combination with anti-TNF agents to induce remission and reduce the likelihood of treatment failure
    • Anti-TNF therapies 
      • Infliximab or adalimumab
      • For induction and maintaining remission
  • Surgical intervention: 
    • Intestinal resection, reserved for medical treatment failure
    • May also be necessary in case of complications such as fistulas, perforation, or obstruction
  • Preventative: colonoscopy to screen for colorectal cancer (higher risk in patients with UC)
    • 810 years after initial diagnosis 
    • Every 12 years thereafter


  • Small or large bowel obstruction:
    • Occurs due to transmural inflammation, lumen narrowing, and stricture formation
    • Presents with postprandial bloating, cramping abdominal pain, and high-pitched bowel sounds
  • Intestinal perforation: usually caused by performing a colonoscopy during an acute flare
  • Fistula:
    • Occurs secondary to transmural inflammation and perforation of intestinal wall
    • Symptoms vary based on organs involved. Fistulas may form between:
      • Loops of bowel (eneteroenteric)
      • Intestine and bladder (enterovesical); associated with recurrent urinary tract infections (UTI) and pneumaturia
      • Intestine and skin (enterocutaneous)
      • Intestine and vagina (enterovaginal)
  • Phlegmon/abscess:
    • Can penetrate through the intestinal wall resulting in an intra-abdominal or retroperitoneal abscess 
    • Associated with fevers, chills, tender abdominal mass, and leukocytosis
  • GI bleeding: 
    • Can occur acutely during a flare or chronically
    • May lead to anemia
  • Perianal disease: 
    • Skin tags
    • Anal fissures and fistulas
    • Perianal abscesses
  • Increased risk of colorectal cancer

Differential Diagnosis

The following conditions are differential diagnoses of Crohn’s disease:

  • Infectious colitis: presents with acute onset fever and diarrhea. Common causative enteric pathogens include Shigella, Salmonella, Campylobacter, Escherichia coli O157:H7, Yersinia, and C. difficile. These infections may be self-limiting or require antibiotic treatment and can be confirmed with stool cultures and polymerase chain reaction (PCR). 
  • Celiac disease: presents with abdominal pain and diarrhea following the consumption of gluten. Associated with IgA anti-tissue transglutaminase antibodies. Diagnosis is confirmed with intestinal biopsy demonstrating villous atrophy, crypt hyperplasia, and intraepithelial lymphocytosis. 
  • Irritable bowel syndrome (IBS): presents with recurrent abdominal pain; however, it requires 2 or more of the following: abdominal pain that improves with defecation, change in stool frequency, or change in stool consistency (diarrhea-predominant, constipation-predominant, or mixed). The diagnosis is clinical, and the condition is not associated with structural abnormalities. 
  • Lactose intolerance: presents with abdominal pain and diarrhea; however, symptoms also include flatulence and are associated with milk or milk-containing product consumption. Secondary lactose intolerance is often present in patients with Crohn’s disease.
  • Ulcerative colitis: presents with bloody diarrhea. Endoscopy and biopsy show continuous colonic lesions, mucosal and submucosal inflammation, ulcerations, and crypt abscess. The loss of haustra is also visible.
    One of the most effective ways to learn about Crohn’s disease is to compare and contrast it with ulcerative colitis, the other form of IBD. The table below provides a comparison.
Table: Inflammatory bowel disease
Crohn’s disease Ulcerative colitis
Pattern of involvement Skip lesions in any part of the GI tract:
  • Most commonly the terminal ileum and proximal colon
  • Rectal sparing
Continuous lesions:
  • More localized to the colon
  • Rectal involvement
GI symptoms Usually non-bloody diarrhea, may be bloody at times Bloody diarrhea
  • May present with mucus at times
  • Stool frequency: UC >> CD
Extraintestinal manifestations Cholelithiasis and nephrolithiasis with calcium oxalate stones Primary sclerosing cholangitis
  • Erythema nodosum
  • Pyoderma gangrenosum
  • Uveitis
  • Aphthous ulcers
  • Arthritis
  • Fistulas
  • Malabsorption or short bowel syndrome
  • Perianal fissures and fistulas
  • Toxic megacolon
  • Fulminant colitis
  • Gastrointestinal bleeding
  • Intestinal perforation
  • Bowel obstruction
  • Colorectal cancer
Macroscopic findings Transmural inflammation
  • Cobblestone mucosa
  • Bowel wall thickening (“string sign” on barium swallow study)
Mucosal and submucosal inflammation
  • Friable mucosa
  • Loss of haustra (“lead pipe” appearance on abdominal X-ray)
  • Broad-based ulcers
Microscopic findings
  • Non-caseating granulomas
  • Lymphoid aggregates of lamina propria
  • No granulomas
  • Crypt abscesses and ulcers
  • Epithelial metaplasia
  • Neutrophil infiltration
  • Corticosteroids
  • Antibiotics (ciprofloxacin, metronidazole)
  • Immunomodulators (azathioprine)
  • Anti-TNF agents (infliximab, adalimumab)
  • 5-ASA agents (mesalamine)
  • Immunomodulators (6-mercaptopurine)
  • Anti-TNF agents (infliximab)
  • Colectomy

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