Basics
Description
Crohn disease (CD) is a chronic inflammatory bowel disease (IBD) affecting any part of the gastrointestinal (GI) tract from the mouth to the anus. Crohn disease is generally characterized by transmural skip lesions, as well as periods of exacerbations and quiescence.
Epidemiology
- ~20-25% of patients are diagnosed with CD in childhood or adolescence.
- Family history is present in 30% of patients <30 years old.
- In adulthood, male = female; in childhood, male > female (1.6:1)
- Highest frequency in Caucasian populations; however, CD can be diagnosed in patients of all racial backgrounds
Risk Factors
Genetics
- 1st-degree relatives have a 5-25% higher risk of developing CD than the normal population.
- Children of 1 parent with CD have a 7-16% risk of developing either CD or ulcerative colitis.
- Siblings of patients with IBD are at 30 times higher risk of developing the disease.
- Concordance in monozygotic twins is 50%; in dizygotic twins, 38%
- CD is complex genetic disease:
- Over 100 gene loci have been associated with CD.
- Gene mutations in CD involve pathways responsible for microbe recognition and autophagy.
- The first gene association was with NOD2/CARD15, a protein important in innate immunity.
- CARD15 mutation is present in ~14-18% of patients. Homozygotes carry 2-4% lifetime risk of developing CD.
- Additional genetic links found to possibly predict responses to corticosteroids, anti-TNF agents.
Pathophysiology
- Interaction and combination of environmental factors, genetic susceptibility, host's intestinal microbiota, and a yet, unspecified triggering factor (likely bacterial products) lead to a dysregulated immune response, causing chronic intestinal inflammation.
- CD pathogenesis is now attributed to dysfunction of both innate and adaptive immunity.
- Innate immunity: Defects have been identified in epithelial barrier, microbial sensing, and autophagy in CD, for example, patients with the CARD15/NOD2 mutation have dysregulated response to bacterial products.
- Adaptive immunity: abnormal activation of T-helper-1 and Th17 lymphocytes leads to overproduction of inflammatory cytokines such as IL-2, interferon g, IL-6, TNF-Ī±, and IL-17 which cause invasive intestinal inflammation in CD.
- IL-23 is a significant cytokine in CD. Polymorphisms in the IL-23R gene have been associated with aberrant responses of both the innate and adaptive immune systems. In the GI tract, release of inflammatory cytokines causes transmural inflammation with cryptitis, crypt abscesses and distortion of crypt architecture, and pathognomonic formations called granulomas (in 20-40% of biopsies).
- Macroscopically, the following are characteristics of CD:
- Ulcerations
- "Creeping fat"¯ (increased mesenteric fat surrounding inflamed small intestinal loops)
- Sinus tracts (extension of deep ulcerations beyond the intestinal wall)
- Fistulae (communications between intestine and skin, other intestinal loops or other organs)
- Strictures
- The most common site to be affected in the GI tract is the terminal ileum. Other sites most often affected, in decreasing frequency, are right colon, isolated colon, proximal small bowel, and upper GI tract (i.e., stomach, duodenum, esophagus).
Diagnosis
History
- Diarrhea (80%)
- Weight loss (85%)
- Abdominal pain (85%)
- Rectal bleeding (50%)
- Fever (40%)
- Growth failure (35%)
- Perianal disease (25%)
- Nausea and vomiting (25%)
- Delayed puberty
- Menstrual irregularity
- Extraintestinal disease (25%)
- Arthritis
- Erythema nodosum
- Pyoderma gangrenosum
- Mouth ulcers
- Episcleritis
- Uveitis
- Thromboembolic disease
- Vasculitis
- Renal stones
- Amyloidosis
- Sclerosing cholangitis
- Pancreatitis
- Other history could include the following:
- Enteric infection (including Clostridium difficile)
Physical Exam
- Growth delay and weight loss, delayed puberty
- Abdominal examination:
- Hyperactive bowel sounds
- Right lower quadrant (RLQ) mass and tenderness
- Palpable thickened loop of intestine
- Rectal and perianal examination: skin tag, fissure, fistula, and abscess
Diagnostic Tests & Interpretation
Lab
- CBC; common to see microcytic anemia (due to iron deficiency); can also see a normocytic anemia due to chronic disease or a macrocytosis (suggesting nutrient deficiency, especially iron, B12, folate, zinc)
- Elevated ESR, C-reactive protein, stool calprotectin (disease activity)
- Electrolytes (reflect hydration, renal function)
- Transaminases, alkaline phosphatase, Ī³-glutamyl transpeptidase (hepatobiliary disease)
- Stool for occult blood and presence of white cells
- Stool cultures, Clostridium difficile toxin A and B
- Serologic profiles, including perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti Saccharomyces cerevisiae antibody (ASCA), may be helpful in differentiating among types of IBD.
- Genetic screening among healthy, asymptomatic patients is not recommended.
Imaging
- Consider plain abdominal x-ray in acute presentation to rule out obstruction or perforation.
- MRI enterography to assess disease extent and activity is radiation-paring and provides information about small bowel and colonic disease, including abscesses and fistula.
- Barium upper GI and small bowel follow-through may also be used to evaluate extent of disease in small bowel not accessible to endoscopy-involves exposure to radiation.
- CT scan and ultrasound may be necessary to evaluate complications (abscess, phlegmon).
- Colonoscopy and upper endoscopy with multiple biopsies are the gold standard tests for initial evaluation and diagnosis of CD.
- Video capsule endoscopy can be used to access small bowel not visualized at the time of endoscopy.
- Balloon-assisted enteroscopy is useful in the evaluation of small intestinal lesions and has the advantage of providing biopsies for diagnostic purposes.
Differential Diagnosis
- Ulcerative colitis
- Appendicitis
- Infection:
- Mycobacterium tuberculosis
- Salmonella, Shigella dysenteriae
- Campylobacter jejuni, Aeromonas spp.
- Yersinia enterocolitica, Clostridium difficile
- Escherichia coli, Giardia lamblia, Cryptosporidium, Strongyloides
- Hemolytic uremic syndrome
- Henoch-Sch ¶nlein purpura
- Irritable bowel syndrome
- Peptic ulcer disease
- Autoimmune enteropathy, immunodeficiency
- Cow's milk protein allergy
- Small intestinal lymphoma
- Functional disorders
Treatment
Medication
- The goal of therapy is resolution of all symptoms in the acute phase (induction), microscopic healing of the intestinal mucosa, steroid-free long-term remission, appropriate growth, and good quality of life. The therapy is used in a stepwise fashion.
- Several 5-aminosalicylic acid (5-ASA) preparations can be trialed according to their intestinal site of activation. These medications can be used for both induction and maintenance of remission of mild to moderate disease but have modest efficacy:
- Mesalamine (Asacol; terminal ileum, colon): 50-100 mg/kg/24 h (max 4.8 g/24 h for active disease and 3.2 g/24 h to maintain remission)
- Mesalamine (Pentasa; duodenum, jejunum, ileum, colon): 50-100 mg/kg/24 h (max 4 g/24 h for active disease and 3 g/24 h to maintain remission)
- Sulfasalazine (Azulfidine): 40-60 mg/kg/24 h (max 4 g/24 h) for active disease, and 30 mg/kg/24 h (max 2 g/24 h) for maintenance of remission (liquid preparation available)
- Balsalazide (Colazal; 6.75 g/24 h; 110-170 mg/kg/24 h): can be given to small children as liquid preparation
- Mesalamine (Rowasa): 4-g enemas and 500-mg suppositories daily to b.i.d. PR
- Corticosteroids can control intestinal inflammation in the acute setting; however, they should not be used long-term for maintenance of remission due to their side-effect profile. An effective starting dose to treat CD is 1-2 mg/kg/24 h IV methylprednisolone or oral prednisone (max 60 mg). Initially, patient is treated for 10 days to 2 weeks and tapered off within several weeks. Topical hydrocortisone is useful in localized left-sided colonic disease and is available in liquid and foam enemas. Corticosteroid with controlled ileal release, budesonide (9 mg/24 h) is available.
- Exclusive enteral nutrition (EEN): This approach is frequently used in Europe and Canada as a 1st-line therapy to induce remission in lieu of steroids. With EEN, an exclusive elemental or polymeric diet has been reported to be effective in inducing remission, especially in active small bowel disease. Nutritional supplementation in addition to other treatment is also used to correct growth failure. In this setting, it can be given as overnight nasogastric feeding if not tolerated orally. EEN has the appeal of being drug-free but does involve a large commitment from the patient and may be difficult to maintain long-term.
- Azathioprine, 2-3 mg/kg/24 h PO, and its metabolite 6-mercaptopurine, 1-1.5 mg/kg/24 h, PO are immunomodulators used as maintenance treatment to prevent exacerbations in patients who have been placed in remission with steroids, or biologics and other agents. Adverse events include liver toxicity, leukopenia, and slightly increased risk of malignancy, specifically lymphoma.
- Methotrexate, another immunomodulator is also used for the maintenance of remission, at the dose of 10-25 mg IM or PO once a week. Adverse effects are similar to azathioprine and 6-mercaptopurine, with the addition of nausea and vomiting, and pulmonary fibrosis.
- Frequent laboratory follow-up is necessary when immunomodulators are used. WBC and platelet count should be monitored carefully. In the case of azathioprine and 6-mercaptopurine, thiopurine methyltransferase (TPMT)-an enzyme catabolizing these drugs-activity or genotype should be determined prior to its use. If TPMT activity is absent (homozygous), these immunomodulators should not be used due to severe risk of myelosuppression via reduced drug clearance. If TPMT activity is intermediate (heterozygous), they should be used in adjusted doses with close monitoring of WBC count.
- Other immunomodulatory therapy used infrequently: cyclosporine, tacrolimus (FK-506), thalidomide, etc.
- Antibiotics can be used for induction of remission, fistulizing disease, or postoperative maintenance of remission; however, their efficacy is modest, and side effects frequently preclude their long-term use.
- Metronidazole: 15 mg/kg/24 h
- Ciprofloxacin: 20 mg/kg/24 h
- Rifaximin: 200 mg t.i.d.-800 mg b.i.d.
- Infliximab, a biologic, chimeric anti-tumor necrosis factor-Ī± antibody (5 mg/kg IV infusion, given every 2-3 months, after initial 3-dose induction therapy at 0, 2, and 6 weeks) for severe and fistulizing disease unresponsive to other therapy. Adalimumab, a humanized anti-TNF-Ī± antibody, was recently approved for use in children with moderate to severe CD (80-160 mg SC at week 0, 40-80 mg at week 2, and 20-40 mg at week 4, and bimonthly thereafter). Both agents can be used for both induction and maintenance of remission. Their side effects include serious infections, anaphylactic reactions, and slightly increased risk of malignancy (lymphoma).
- Other biologic therapies including anti-TNF-Ī± antibody certolizumab and the antiadhesion molecule natalizumab are available but not yet approved for use in pediatric CD.
- Complementary therapy (probiotics, prebiotics)
Surgery/Other Procedures
- Surgery is reserved for patients with localized CD that is unresponsive to other therapy and that is causing intractable bleeding.
- Surgery may be necessary in stricturing disease, especially in case of proximal intestinal dilatation, and perforation.
- Several types of procedures are available: strictureplasty, abscess drainage, and intestinal resection (side-to-side anastomosis is widely accepted).
- Surgery for CD is not curative, and postoperative recurrence at the site of anastomosis is common.
Ongoing Care
Follow-up Recommendations
Patient Monitoring
- The morbidity of CD is high. The majority of patients experience recurring disease.
- Most patients have good general health in between episodes and go on to lead productive lives.
- Carcinoma surveillance is necessary on a regular basis.
- After 5 and 20 years of disease, the probability of survival is 98% and 89% of expected survival, respectively.
- Death is a rare complication (2.4% in a large series).
Complications
- Intestinal obstruction due to strictures, or adhesions
- Abscess or phlegmon formation
- Enteroenteric, enterovesical, enterovaginal, and enterocutaneous fistulas
- Perforation
- Gallstones, kidney stones
- Intestinal lymphoma, colon cancer
- Malabsorption resulting in deficiency (e.g., vitamin B12 and bile salt deficiency, iron deficiency)
- Short bowel syndrome due to repeated bowel resections
- Massive hemorrhage is rare (1%).
- Growth failure is frequent; final height is reduced, and puberty is delayed in CD affecting prepubertal children.
- Future infertility due to inflammation involving the fallopian tubes and ovaries
- Osteopenia and osteoporosis secondary to inflammation, nutritional deficiency, and therapeutic side effects (corticosteroids)
- Toxic megacolon is a rare but serious complication.
Additional Reading
- Benchimol EI, Fortinsky KJ, Gozdyra P, et al. Epidemiology of pediatric inflammatory bowel disease: a systematic review of international trends. Inflamm Bowel Dis. 2011;17(1):423-439. [View Abstract]
- Cabr © E, Gassull MA. Nutritional and metabolic issues in inflammatory bowel disease. Curr Opin Clin Nutr Metab Care. 2003;6(5):569-576. [View Abstract]
- Day AS, Ledder O, Leach ST, et al. Crohn's and colitis in children and adolescents. World J Gastroenterol. 2012;18(41):5862-5869. [View Abstract]
- Henderson P, van Limbergen JE, Wilson DC, et al. Genetics of childhood-onset disease. Curr Opin Pediatr. 2014;26(5):590-596. [View Abstract]
- Hildebrand H, Karlberg J, Kristiansson B. Longitudinal growth in children and adolescents with inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 1994;18(2):165-173. [View Abstract]
- Kugathasan S, Baldassano RN, Bradfield JP, et al. Loci on 20q13 and 21q22 are associated with pediatric-onset inflammatory bowel disease. Nat Genet. 2008;40(10):1211-1215. [View Abstract]
- Maltz R, Podberesky DJ, Saeed SA. Imaging modalities in pediatric inflammatory bowel disease. Curr Opin Pediatr. 2014;26(5):590-596. [View Abstract]
- Rufo PA, Denson LA, Sylvester FA, et al. Health supervision in the management of children and adolescents with IBD: NASPGHAN recommendations. J Pediatr Gastroenterol Nutr. 2012;55(1):93-108. [View Abstract]
Codes
ICD09
- 555.9 Regional enteritis of unspecified site
- 555.0 Regional enteritis of small intestine
- 555.1 Regional enteritis of large intestine
- 555.2 Regional enteritis of small intestine with large intestine
ICD10
- K50.90 Crohn's disease, unspecified, without complications
- K50.913 Crohn's disease, unspecified, with fistula
- K50.911 Crohn's disease, unspecified, with rectal bleeding
- K50.919 Crohn's disease, unspecified, with unspecified complications
- K50.912 Crohn's disease, unspecified, with intestinal obstruction
- K50.918 Crohn's disease, unspecified, with other complication
- K50.914 Crohn's disease, unspecified, with abscess
SNOMED
- 34000006 Crohn's disease (disorder)
- 56689002 Crohn's disease of small intestine
- 7620006 Crohn's disease of large bowel
- 38106008 Crohn's disease of ileum (disorder)
FAQ
- Q: Should the diet of patients with CD be restricted?
- A: One approach to inducing remission in active disease can be to use EEN. However, this approach can be difficult to maintain long-term and should be reserved for those patients who are committed to excluding all other foods. In general, a careful, balanced approach to nutrition in children with CD is required to assure appropriate growth and development. The only foods not recommended are "high-residue foods,"¯ including poorly digestible vegetables (if eaten raw), nuts, and popcorn, which can cause obstruction in the narrowed, inflamed intestine. Patients with secondary lactose intolerance should use lactase supplements or avoid milk products while ensuring adequate calories and calcium intake.