Topic Editor: Grant E. Fraser, M.D., FRACGP, FACRRM, ASTEM

Review Date: 01/12/2012

Definition

Crohn's disease is a chronic, relapsing and remitting disorder of unknown etiology characterized by transmural granulomatous inflammation of the gastrointestinal tract, which often results in fibrosis, fistulae, and obstructive symptoms. It can affect any region of the gastrointestinal (GI) tract from the mouth to anus. 30% of cases involve only small bowel, 30% involve only colon and 40% of cases involve both large and small bowel.

Description

• Crohn's disease is a type of idiopathic inflammatory bowel disease (IBD) that can involve any part of gastrointestinal tract
• There is no curative intervention for Crohn's disease. The treatment goal is reduction of symptoms, complications, and improved quality of life
• Treatment approaches for Crohn's disease are individualized and based on severity, location and complications of the disease
• The Lennard-Jones criteria are internationally accepted criteria for the diagnosis of Crohn's disease:
• Infection, ischemia, malignancy, or damage from radiation must first be excluded as the cause of intestinal inflammation
• At least 3 of the following findings must be present. These items range from histology of specimens, to endoscopic, radiologic, or clinical findings:
• Chronic inflammatory lesions of the oral cavity, pylorus, small bowel, or anus
• Discontinuous disease distribution (areas of abnormal mucosa separated by normal mucosa)
• Fibrosis (stricture)
• Granulomata (noncaseating and not caused by foreign body)
• Lymphoid aggregates or aphthoid ulcers
• Retention of colonic mucin on biopsy in the presence of active inflammation
• Transmural inflammation (fissuring ulcer, abscess, or fistula)
• Items also considered diagnostic of Crohn's disease (but not part of these criteria) include cobblestoning, fat wrapping, and thickening of the intestinal wall

Epidemiology

Incidence/prevalence

• Incidence and prevalence data vary greatly due to multiple factors, including varying diagnostic criteria, varying access to medical care, and disease misclassification
• The annual incidence of Crohn's disease in the U.S. (1990-2000) was 7 cases per 100,000 persons
• Nearly 1.4 million individuals in the US and 2.2 million in Europe may be affected with IBD including Crohn's disease (2004 data)
• Traditionally low incidence areas of the world, such as Eastern Europe, Asia and South America are now showing increasing incidence of disease. Western countries have had increasing levels since the 1950's, but appear to have stabilized
• Crohn's disease is more common in the developed world
• Depending upon region of the world, rates are reported as low as 0.7/100,000 in Croatia to 15.6/100,000 in Manitoba, Canada

Age

• Onset of Crohn's disease is bimodal with the most common time of diagnosis being in late adolescence
• 10% of cases are diagnosed before age 18 years
• A peak onset occurs between age 15 to 25 years, and again at age 60 to 80 years

Gender

• Males and females are equally affected. Some research indicates a slight overall female predominance
• Pediatric cases have a moderate male predominance

Race

• The occurrence of Crohn's disease may be higher in patients of Jewish descent, particularly Ashkenazi Jews vs Shephardic Jews

Risk factors

• Caucasian ethnicity
• Cigarette smoking
• Diet rich in refined sugar
• Family history of Crohn's disease
• Non-breastfed children
• Nonsteroidal inflammatory disease (NSAID) use
• Oral contraceptive use

Etiology

The exact etiology of Crohn's disease remains unclear, with the best evidence pointing toward a combination of genetic components, environmental exposures, lifestyle, and immunologic irregularities.

• Genetic factors:
• Evidence exists for an inheritable risk for Crohn's disease
• Studies have identified IBD related genes including the IBD1 gene, which is located on chromosome 16 and involves mutations to the NOD2/CARD15 gene. Other regions of interest have been found on chromosomes 5q (IBD-5 gene), 6p (IBD-3 gene), and 19
• Environmental factors:
• Smoking doubles the risk of Crohn's disease. It is suggested that high-fat diets may possibly play a role in development of Crohn's disease
• Use of NSAIDs may be an exacerbating factor

History

• Abdominal pain, which can be crampy, intermittent or constant and may be generalized or localized. As the cecum is often involved - right lower quadrant or periumbilical pain is common
• Anorexia
• Constipation and obstipation
• Diarrhea - often intermittent
• Fatigue
• Fevers (usually low grade and intermittent)
• Stool abnormalities - pus, mucous, blood present intermittently Weight loss

Physical Findings

• Abdominal exam is variable depending upon the underlying complication. The range of possibilities includes bowel obstruction, intra-abdominal abscess, colitis, fistulae, among others. The examination will vary depending upon the nature of the underlying complicationsAphthous ulcers (oral)
• Extraintestinal manifestations can include inflammation of the eyes (uveitis, episcleritis, iritis), skin (erythema nodosum, pyoderma gangrenosum), or joints, and restricted growth or delayed maturation of secondary sexual features in children
• Fever may be present
• Heme positive stool may be present
• Hyperactive bowel sounds (if obstructed)
• Peri-anal examination may show fistulae, abscess or evidence of prior infection (scarring)

Blood test findings

• Complete blood count (CBC):
• Anemia and thrombocytosis are commonly found
• Anemia may be due to acute or chronic blood loss, or from chronic disease. Additional causes include malabsorption of vitamin B12, folate or iron
• Leukocytosis may be present, and can be due to infection or secondary to medications such as corticosteroids
• Chemistry:
• Renal function, liver enzymes, and electrolytes should be assessed
• Hypoalbuminemia is common in Crohn's disease
• Where indicated based upon CBC abnormalities, iron, folate, vitamin B12 levels
• Inflammatory markers:
• C-reactive protein is the best inflammatory marker to assess activity of disease
• Serologic testing:
• Serologic biomarkers used as adjuncts to other diagnostic modalities and clinical judgment and may predict disease behavior, but do not correlate with disease activity
• In 50% to 60% of patients, anti-saccharomyces cerevisiae antibodies (ASCA) are positive. These patients are likely to have more aggressive disease and more frequently (and at earlier age) require operative intervention

Other laboratory test findings

• Stool testing:
• In presence of diarrhea stool samples can be tested for the presence of occult blood, WBC (white blood cells), ova and parasites, bacterial pathogens, and Clostridium difficile toxin based upon clinical presentation and risk factors

Radiographic findings

• Barium Contrast Studies:
• Useful in determining the nature, distribution, and severity of Crohn's disease. Barium enema may have small bowel findings including loss of smooth mucosa, undermined ulcers, narrowed lumen (string sign), fistulae, and skip areas
• Computed tomography (CT) scan:
• CT scans may show bowel wall thickening, strictures, and dilatation. CT enterography (CTE) is superior to plain CT and has become the procedure of choice
• MRI abdomen/pelvis:
• MRI is superior to CT scanning in delineating pelvic lesions, bowel wall thickening, skip lesions, abscess and fistulae
• Ultrasound:
• Ultrasonography can evaluate some Crohn's disease complications. It has the advantage of being inexpensive, and avoids exposure to both contrast and radiation
• Ultrasound may identify bowel wall thickening, surrounding inflammation, abscess, and tubo-ovarian abscesses

Other diagnostic test findings

• Upper GI endoscopy:
• Upper GI endoscopy with biopsy can be helpful in differentiating Crohn's disease from peptic ulcer disease in patients with upper GI tract symptoms
• Colonoscopy:
• Colonoscopy with biopsy can confirm the diagnosis of Ulcerative Colitis or Crohn's disease. In patients with chronic disease, colonoscopy can effectively dilate fibrotic strictures

• Acute appendicitis
• Adhesions (generally postoperative)
• Amebiasis
• Behcet's disease
• Celiac disease
• Colitis - infectious or ischemic
• Diverticular disease (Diverticulosis or Diverticulitis)
• Ectopic pregnancy
• Endometriosis
• Gastroenteritis, bacterial or viral
• Giardiasis
• Hemorrhoids
• Intestinal carcinoid tumor
• Irritable bowel syndrome
• Ischemic colitis
• Lymphoma
• Malabsorption syndromes
• Malignancy - small or large bowel
• Nonsteroidal enteropathy
• Pelvic inflammatory disease
• Pseudomembranous colitis
• Radiation colitis
• Small bowel obstruction
• Tuberculosis of the bowel
• Ulcerative colitis
• Yersinia enterocolitica infection

General treatment items

• Approach consideration:
• Treatment of Crohn's disease is individualized to the patient's tolerance and response . As there is no cure for this condition, the goals of therapy are:
• Manage disease flare-ups (primarily medically, but where necessary surgically)
• Provide symptomatic relief
• Keep disease activity low (e.g. remission)
• Treat extra-intestinal manifestations when present (joints 25% of cases, skin 15% of cases, eye 5% of cases)
• Treat any nutritional deficiencies (folate, vitamin B12, iron, calcium, other fat soluble vitamins, etc)
• Management of diarrhea
• Loperamide or diphenoxylate with atropine can be used to control diarrhea and reduce its interference with day-to-day activities
• Patients with abdominal cramps can be treated with dicyclomine or hyoscyamine
• Mild to moderate disease
• Definition of mild to moderate disease: 'The patient is ambulatory and able to take oral alimentation. There is no dehydration, high fever, abdominal tenderness, painful mass, obstruction, or weight loss of more than 10 percent.'
• Salicylates are recommended
• Antibiotics may be useful in unresponsive patients
• Those who do not respond to therapy should be treated further for moderate to severe disease or treated with an alternate regimen
• Colonic, ileocolonic, or ileal disease have been generally treated with mesalamine or sulfasalazine; metronidazole and ciprofloxacin may be useful in unresponsive patients
• Moderate to severe disease:
• Definition of moderate to severe disease: 'Either the patient has failed treatment for mild to moderate disease OR has more pronounced symptoms including fever, significant weight loss, abdominal pain or tenderness, intermittent nausea and vomiting, or significant anemia.'
• Patients should be treated with prednisone until symptoms resolve. Note that budesonide is acceptable in moderate ileocaecal disease as it has little systemic absorption - but is slightly less effective
• Azathioprine/ mercaptopurine or methotrexate are administered to maintain remission
• Infliximab, a biologic, chimeric anti-tumor necrosis factor alpha antibody, administered IV, has shown promising results in treating patients with moderate to severe Crohn's disease refractory to first-line therapy with mesalamine and/or corticosteroids. Other biological therapies for Crohn's disease are currently under investigation
• Adalimumab is a human anti-TNF monoclonal antibody administered subcutaneously. It is useful in patients without experience of biologic therapy and in patients who are intolerant or resistant to infliximab
• Severe fulminant disease:
• Definition of severe fulminant disease: 'Either the patient has persistent symptoms despite outpatient steroid therapy OR has high fever, persistent vomiting, evidence of intestinal obstruction, rebound tenderness, cachexia, or evidence of an abscess.'
• Patients with severe Crohn's disease often require hospital admission. Patients with intestinal obstruction, abscesses, or fistula need urgent surgical evaluation
• Supportive treatment with fluid and electrolytes are indicated in dehydrated patients. Oral nutrition may be continued as tolerated in the absence of intestinal obstruction
• Broad spectrum antibiotics (gram negative plus anaerobic coverage) in combination with IV corticosteroids are indicated when an inflammatory mass is evident
• IV corticosteroids equivalent to 40-60 mg of prednisone are indicated in patients with severe fulminant disease
• Patients refractory to corticosteroid therapy may respond to IV tacrolimus or cyclosporine; however, the evidence for this is weak and such treatment may be harmful or ineffective
• Patients responsive to therapy for severe fulminant disease can often be transitioned in a stepwise manner to an oral regimen and eventually discharged
• Surgical intervention is frequently needed in cases of treatment failure
• Perianal Disease
• Surgical drainage may be required for perirectal or perianal abscesses
• Perianal non-suppurative complications typically respond well to metronidazole used alone or in combination with ciprofloxacin
• Maintenance therapy
• Aminosalicylates, namely mesalazine, is more effective than placebo in maintaining remission
• Methotrexate or infliximab are also felt to be beneficial in maintaining remission
• Azathioprine should not be first line, as there is a trade-off between harms and benefits - but may be appropriate in selected patients
• Both steroids and cyclosporine are likely to be ineffective or harmful as pharmacotherapy to maintain remission
• Mesalamine or azathioprine/mercaptopurine should be administered following ileocolonic resections to prevent recurrence

Medications indicated with specific doses

5-Aminosalicylic Acid Derivatives:

• Mesalamine [Oral]
• Adult Dosing
• Pediatric Dosing
• Sulfasalazine
• Adult Dosing
• Pediatric Dosing

• Prednisone
• Adult Dosing
• Pediatric Dosing

• Azathioprine [Oral]
• Adult Dosing
• Pediatric Dosing
• Mercaptopurine
• Adult Dosing
• Pediatric Dosing
• Methotrexate [Oral]
• Adult Dosing
• Pediatric Dosing

• Adalimumab [SC]
• Adult Dosing
• Infliximab [IV]
• Adult Dosing
• Pediatric Dosing

• Ciprofloxacin [Oral]
• Adult Dosing
• Pediatric Dosing
• Metronidazole [Oral]
• Adult Dosing
• Pediatric Dosing

• Loperamide
• Adult Dosing
• Pediatric Dosing

• Dicyclomine [Oral]
• Adult Dosing
• Hyoscyamine
• Adult Dosing
• Pediatric Dosing

Dietary and Activity restrictions

• Diet with high amounts of refined sugars and low amounts of raw vegetables and fruits has been implicated in the development of Crohn's disease
• Reduction in fat intake, use of unrefined carbohydrates, and inclusion of fiber rich foods are recommended in patients with significant diarrhea
• Fiber-rich foods should be avoided if continual obstruction or strictures are evident
• If fat malabsorption is evident, fat content in the diet should be reduced
• A protein-free elemental diet, usually administered through nasogastric feeding, or intravenously, has been known to effectively induce remission in patients with acute Crohn's disease. This diet can also be useful in correcting growth failure which complicates pediatric Crohn's disease

Disposition (admission vs. outpatient)

Admission Criteria

• Criteria for admission includes:
• Electrolyte disturbances
• Hemodynamic instability
• High-grade fever
• Pain not controlled by standard outpatient analgesics
• Severe fulminant disease
• Significant dehydration
• Significant hemorrhage
• Suspicion or proven need for surgical intervention
• Unable to maintain oral intake
• Criteria for surgical intervention includes
• Bowel obstruction or perforation
• Massive, refractory hemorrhage
• Strictureplasty is of unclear benefit
• Toxic dilation

• Mild to moderate aggravation of recognized disease without obstruction, severe pain, severe hemorrhage, or dehydration
• Outpatient follow-up arranged and appropriate step up therapy initiated (generally short term corticosteroids)
• Initial presentation of diarrhea, mild pain, without toxicity, with close outpatient follow-up

Monitoring

• Evaluation of weight, pain, diarrhea, hemoglobin and ESR is recommended every 3-6 months in stable patients
• Vitamin B12 levels should be measured periodically in patients with ileal disease or ileal resection
• An objective measure for recording disease activity is the Crohn's disease activity index (CDAI) score. It is also helpful in evaluating therapeutic response Surveillance colonoscopy is recommended, particularly for patients with colonic disease
• Annual liver function test (LFT) for all patients

Assessment of therapy

• Folate level should be assessed in patients on 5-aminosalicylate therapy
• Monitoring of LFTs, CBC and 6-MMP and 6-TG levels in patients on azathioprine or 6-mercaptopurine is essential
• LFTs should be regularly obtained on patients on methotrexate therapy

Complications

• Anemia and vitamin deficiency due to malabsorption of fat
• Colorectal cancer (some suggestion that folate supplementation decreases the risk)
• Extra-intestinal manifestations
• Fistula (to skin or other structures intra-abdominally)
• Intestinal obstruction
• Perforation of bowel
• Toxic megacolon

Prevention

• No specific prevention strategies for Crohn's disease have been documented
• Smoking cessation is important to reduce the risk for recurrence

Prognosis

• Crohn's disease is a chronic condition with variable but nearly certain progression, irrespective of site of occurrence
• Approximately 50% of patients need surgery during the first decade of the disease, and nearly 80% need surgery during their lifetime
• Weight loss >5 kg, perianal disease, strictures, or ongoing steroid requirement at the time of diagnosis have been associated with poor prognosis
• Following diagnosis of Crohn's disease, nearly 75% of patients remain employed; however, this condition has substantial implications, socially and economically

Pregnancy and pediatric effects of the condition

• In pregnancy, if the condition is in remission, prognosis is good for conception, full term birth, and a healthy fetus. Active disease at conception or during pregnancy has been associated with an increased risk of adverse pregnancy outcomes
• Low birth weight is the most significant adverse outcome of Crohn's disease during pregnancy
• The likelihood of disease relapse in pregnant women is comparable to that in the general population
• Generally, the pharmacological treatment of Crohn's disease in pregnant women is comparable to that in nonpregnant patients. Methotrexate is contraindicated during pregnancy and breastfeeding

Synonym

• Regional enteritis

ICD9-CM

• 555.0 Regional enteritis of small intestine
• 555.1 Regional enteritis of large intestine
• 555.2 Regional enteritis of small intestine with large intestine
• 555.9 Regional enteritis of unspecified site

ICD-10-CM

• K50 Crohn's disease [regional enteritis]
• K50.0 Crohn's disease of small intestine
• K50.1 Crohn's disease of large intestine
• K50.8 Crohn's disease of both small and large intestine
• K50.9 Crohn's disease, unspecified

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