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Crohn Disease
Eric Ji-Yuan Mao, MD
Samir A. Shah, MD, FACG, FASGE, AGAF
image BASICS
DESCRIPTION
A chronic, relapsing inflammatory GI tract disorder, most commonly involving the terminal ileum (80%)
  • Hallmark features
    • Transmural inflammation which can result in fibrosis, stricture formation, and fissures leading to sinus tracts, abscesses, or fistulas.
    • Noncaseating granulomas (30%), crypt abscesses
    • Skip lesions: patchy, segmental distribution of disease; lesions may affect multiple bowel segments, interspersed with areas of normal mucosa; disease can also be continuous, potentially mimicking ulcerative colitis (UC).
    • Diverse presentations: ileocolitis (50%); isolated colitis (20%) are most common. In cases of isolated colitis, 10% involve the rectum and 33% involve the anorectal area.
  • Early disease
    • Ulcerations: focal lesions with surrounding edema, resembling aphthous ulcers
    • Perianal disease (pain, anal fissures, perirectal abscess) may precede intestinal disease.
    • May present as wasting illness or anorexia
  • Developed disease
    • Mucosal cobblestoning; luminal stenosis; creeping fat; fissures between mucosal folds result in strictures/adhesions and/or fistulae
EPIDEMIOLOGY
Incidence
  • In North America, 8 to 15 cases/100,000 adults; incidence is rising in North America and Western Europe.
  • Bimodal age distribution: Predominant age is 15 to 25 years, with a second smaller peak at 50 to 70 years.
  • Women slightly more affected than men; increased incidence in northern climates
  • Increased risk in whites versus non-whites: 2 to 5 times
  • Increased risk in Ashkenazi Jews: 3 to 5 times
Prevalence
U.S. adults: 100 to 200 cases/100,000
ETIOLOGY AND PATHOPHYSIOLOGY
  • General: Clinical manifestations result from activation of inflammatory cells, whose by-products produce nonspecific tissue injury.
  • Mechanism of diarrhea: excess fluid secretion and impaired fluid absorption; bile salt malabsorption in inflamed ileum, with steatorrhea, bacterial overgrowth
  • Multifactorial: Genetic, environmental triggers, and immunologic abnormalities result in inflammation and tissue injury in genetically predisposed individuals.
Genetics
Of CD patients, 15% have a first-degree relative with inflammatory bowel disease (IBD); first-degree relative of an IBD patient has 3 to 30 times increased risk of developing IBD by age 28 years. At least 163 different genes associated with IBD.
  • Mutations in susceptibility loci
    • Ileal CD: IBD1 gene (chromosome 16)
    • Early-onset CD (age ≤15 years): mutations in 5q31-33 (IBD5), 21q22, and 20q13
    • North American white men with CD: 30% have HLA-DR7 and DQ4.
    • Extraintestinal manifestations of CD: mutations in HLA-A2, HLA-DR1, HLA-DQw5
    • Others: IL-10, IL-23 receptors; ATG16L1; IRGM
  • Genetic syndromes associated with IBD: Turner and Hermansky-Pudlak syndromes, glycogen storage disease type 1b
RISK FACTORS
  • Environmental factors
    • Cigarette smoking doubles the risk of developing CD; tobacco cessation may reduce frequency of flares and reduce relapses after surgery.
    • Dietary factors: higher incidence if diet high in refined sugars, animal fat, protein (meat, fish)
    • Salmonella or Campylobacter increase risk of developing IBD
    • Clostridium difficile infection may trigger flare of IBD and make treatment more difficult.
  • Immunologic abnormalities: an aggressive immune response against commensal enteric bacteria
    • Tumor necrosis factor (TNF): upregulation of inflammatory Th1 cytokines
    • Tissue inflammation may result from increased secretion of cytokine IL-17 by Th17 subset of CD4+ T cells.
COMMONLY ASSOCIATED CONDITIONS
  • Extraintestinal manifestations
    • Arthritis (20%): seronegative, primarily involving large joints; axial arthritis or ankylosing spondylitis (AS), and sacroiliitis (SI).
    • Skin disorders (10%): erythema nodosum, pyoderma gangrenosum, psoriasis
    • Ocular disease (5%): uveitis, iritis, episcleritis
    • Kidney stones: calcium oxalate stones (from steatorrhea and diarrhea) or uric acid stones (from dehydration and metabolic acidosis)
    • Fat-soluble vitamin deficiency (A, D, E, K), B12
    • Osteopenia and osteoporosis; hypocalcemia
    • Hypercoagulability: venous thromboembolism prophylaxis essential in hospitalized patients
    • Gallstones: cholesterol stones resulting from impaired bile acid reabsorption
    • Primary sclerosing cholangitis (5%): more common in men with UC; asymptomatic, elevated alkaline phosphatase as marker
    • Autoimmune hemolytic anemia
  • Conditions correlated with increased disease activity
    • Peripheral arthropathy (but not SI and AS)
    • Episcleritis (but not uveitis)
    • Oral aphthous ulcers and erythema nodosum
    • SI, AS, and uveitis are associated with HLA-B27.
  • Other significant complications: GI bleed, toxic megacolon, bowel perforation/peritonitis, malignancy, sclerosing cholangitis, rectovaginal fistula
image DIAGNOSIS
PHYSICAL EXAM
Presentation varies with location of disease.
  • General: signs of sepsis/disease activity (fever, tachycardia, hypotension) or wasting/malnutrition
  • Abdominal: focal or diffuse tenderness, distension, rebound/guarding; rectal bleeding
  • Perianal: fistulae, fissures
  • Skin: erythema nodosum; psoriasis
DIFFERENTIAL DIAGNOSIS
  • Acute, severe abdominal pain: perforated viscus, pancreatitis, appendicitis, diverticulitis, bowel obstruction, kidney stones, ovarian torsion
  • Chronic diarrhea with crampy pain (colitis-like): UC, radiation colitis, infection, drugs, ischemia, microscopic colitis, IBD, celiac disease, malignancy (lymphoma, carcinoma), carcinoid
  • Wasting illness: malabsorption, malignancy, psychiatric illness
DIAGNOSTIC TESTS & INTERPRETATION
Initial Tests (lab, imaging)
  • CBC, chem 10, LFTs, erythrocyte sedimentation rate, C-reactive protein, serum iron, vitamin B12, vitamin D-25 OH
  • If diarrhea, stool specimen for routine culture, fecal leukocytes, C. difficile, and ova and parasites
  • In hospitalized patients with severe flare-ups, KUB to rule out toxic megacolon
  • Colonoscopy with ileoscopy provides the greatest diagnostic sensitivity and specificity for colonic disease.
  • Small bowel: sensitivity of CT or magnetic resonance enterography (MRE) better than small bowel follow through. MRE has no radiation exposure (important in younger patients). Capsule endoscopy allows small bowel visualization but no biopsy (1)[A].
    • Signs of small bowel disease: narrowed lumen with nodularity and/or string sign; cobblestone appearance, fistula and abscess formation, bowel loop separation (transmural inflammation)
  • Gastroduodenal: upper GI endoscopy
    • Signs of gastroduodenal disease: antral narrowing and segmental duodenal stricturing; inflammatory mucosal disease on endoscopy
  • Perirectal complications: combination of endoscopic ultrasound (EUS) or MRI with exam under anesthesia
  • Contraindications to endoscopy: perforated viscus, recent myocardial infarction, severe diverticulitis, toxic megacolon, or inability to undergo appropriate bowel preparation. In most cases, unprepared limited sigmoidoscopy allows adequate visualization to assess severity, extent, and aspirate stool for C. difficile, obtain biopsies to assess histologic severity, and exclude other disorders (e.g., cytomegalovirus).
Follow-Up Tests & Special Considerations
Evidence of complications
  • Stricture: obstructive signs such as nausea, vomiting, pain, weight loss, diarrhea, or inability to pass gas/feces
  • Abscess/phlegmon: localized abdominal peritonitis with fever and abdominal pain; diffuse peritonitis suggests intestinal perforation or abscess rupture (may be masked by steroids, opiates).
  • Fistulae (33-50% of patients, after 10 to 20 years of disease, respectively)
    • Enteroenteric: asymptomatic or a palpable, commonly indolent abdominal mass
    • Enterovesical: pneumaturia, recurrent polymicrobial UTI
    • Retroperitoneal: psoas abscess, ureteral obstruction
    • Enterovaginal: vaginal passage of gas or feces; clear, nonfeculent drainage from ileal fistula may be misdiagnosed as primary vaginal infection.
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Diagnostic Procedures/Other
How to distinguish CD from UC
  • CD: small bowel disease, rectal sparing; skip lesions; granulomas, perianal disease, and/or fistulae; no gross bleeding: RLQ pain is common.
    • Commercially available antibody tests (overall 70% sensitive): anti-Saccharomyces cerevisiae antibody (ASCA), Cbir-1, OmpC, I2
  • UC: diffuse, continuous involving the rectum; loss of vascularity, friable tissue; perinuclear antineutrophil cytoplasmic antibody (pANCA); LLQ pain; typically only affects colon; rectal bleeding common
image TREATMENT
  • Disease severity: Crohn Disease Activity Index (CDAI)
    • Asymptomatic: spontaneously, after medical/surgical intervention, or while on steroids (CDAI <150)
    • Mild to moderate CD: ambulatory patients able to tolerate PO intake without dehydration, obstruction, or >10% weight loss. No abdominal tenderness, toxicity, or mass (CDAI 150 to 220)
    • Moderate to severe CD: Patients who have failed initial treatment or who continue to have mild symptoms such as fever, weight loss, and abdominal pain (CDAI 220 to 450).
    • Severe: persistent symptoms despite outpatient therapy with glucocorticoids and/or biologics, or fulminant disease (peritonitis, cachexia, intestinal obstruction, abscess) (CDAI >450)
  • General strategies
    • Step-up approach: Begin treatment with milder therapy (5-ASA, antibiotics) followed by more aggressive agents (steroids, immunomodulators, anti-TNF agents), as needed.
    • Top-down approach: Early management with immunomodulators and/or anti-TNF agents before patients receive steroids, become steroid-dependent, or require surgery.
GENERAL MEASURES
Additional therapies depend on location of disease.
  • Oral lesions: triamcinolone acetonide in benzocaine and carboxymethyl cellulose or topical sucralfate for aphthous ulcers, cheilitis, and/or granulomatous sialadenitis
  • Gastroduodenal CD: no clinical trials, although slow-release mesalamine may be beneficial, as it is partially released in proximal small bowel. Case reports note success of anti-TNF therapies. Symptomatic relief possible from proton pump inhibitors, H2-receptor blockers, and/or sucralfate.
  • Ileitis: supplementation of fat-soluble vitamins, iron, B12, folate, and calcium to prevent bone loss
  • Treatment toxicity: pancreatitis, bone marrow toxicity, lymphoma, nonmelanoma skin cancer, infections (TB, histoplasmosis, others), malignancy
MEDICATION
First Line
  • Asymptomatic patients: observation alone
  • Mild CD
    • 5-Aminosalicylates have minimal role in CD management. They can be used for colonic CD without deep ulcerations or penetration/fibrostenosing disease (2)[C].
    • Antibiotics use is controversial. Controlled trials have not consistently demonstrated efficacy (2)[C].
    • Glucocorticoid therapy: controlled ileal release budesonide (9 mg/day for 8 to 16 weeks, then discontinued over 2- to 4-week taper) for distal ileum and/or right colon involvement (2,3)[A]
    • Consider adjunctive therapy: antidiarrheals (loperamide ); bile acid-binding resin (cholestyramine 4 to 12 g/day); probiotics (either alone or in combination may prevent recurrent inflammation and reduce symptoms in acute CD).
    • Induction/maintenance: 5-ASA is not recommended (3)[C]. Controlled ileal release budesonide, 9 mg/day, is effective for maintenance for up to 6 months (2)[A].
  • Moderate to severe CD
    • Induction: prednisone 40 to 60 mg/day (2)[A] or controlled-release budesonide (for isolated, moderate ileitis) or anti-TNF agents as initial induction agent or for lack of response to corticosteroid or immunomodulator (2,3)[A]
    • Maintenance: no role for mesalamine. If steroids required for induction, use immunomodulator (2,3)[B] or biologic (anti-TNF agent) (2)[A],(3)[B] for maintenance.
    • Except for budesonide, do not use steroids for maintenance (1)[A].
  • Severe disease: immunomodulators, anti-TNF agents ± steroids
    • Azathioprine or 6-mercaptopurine: thiopurine methyltransferase (TPMT) and LFTs prior to initiation. Check CBC/LFTs q2-3mo.
    • Methotrexate: effective for steroid-dependent and steroid-refractory CD (2)[B]
      • Folic acid 1 mg/day; follow LFTs
    • Anti-TNF therapies: active disease, fistulae, steroid sparing, some extraintestinal disease. Infliximab, adalimumab, certolizumab pegol
      • Check for evidence of TB and HBV infection prior to initiation of anti-TNF therapy.
      • Avoid live vaccines.
      • Monitoring: Consider anti-drug Ab levels to assess for immunogenicity. Serum concentrations of anti-TNF agents may also correlate with disease activity.
  • Combination therapy
    • Azathioprine + infliximab is more effective than either alone if no previously treatment with either.
    • Rare complication: hepatosplenic T-cell lymphoma (fatal, mostly seen in young males)
  • Anti-adhesion molecules: prevent inflammatory cells from entering GI tract
    • Vedolizumab: gut-specific, can be used in anti-TNF failures or anti-TNF naive patients as induction and maintenance; given IV, no risk of progressive multifocal leukoencephalopathy (PML); FDA approved May 2014
    • Natalizumab: non-gut-specific, PML risk (1/1,000). Can minimize risk by testing for John Cunningham (JC) virus antibody. However, can avoid risk of PML now with vedolizumab.
ADDITIONAL THERAPIES
Complications
  • Peritonitis: bowel rest and antibiotic therapy (7 to 10 days parenteral antibiotics, followed by 2- to 4-week course of PO ciprofloxacin and metronidazole); surgery, as indicated
    • Consider holding steroids which mask sepsis.
  • Abscess: antibiotics, percutaneous drainage, or surgery with resection of affected segments
  • Small bowel obstruction: IV hydration, nasogastric (NG) suction, total parenteral nutrition (TPN) for malnutrition, resolution typically in 24 to 48 hours. Surgery for nonresponders
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
Vaccinations in CD
  • Check titers; avoid live vaccines (MMR, varicella, zoster) in patients on immunosuppressive therapy (steroids, 6MP, AZA, MTX, or anti-TNF).
  • Regardless of immunosuppression: HPV, influenza, pneumococcal, meningococcal, hepatitis A, B; Tdap
PATIENT EDUCATION
Crohn and Colitis Foundation of America (800) 343-3637; www.ccfa.org
REFERENCES
1. Baumgart DC, Sandborn WJ. Crohn's disease. Lancet. 2012;380(9853):1590-1605.
2. Lichtenstein GR, Hanauer SB, Sandborn WJ, et al. Management of Crohn's disease in adults. Am J Gastroenterol. 2009;104(2):465-483.
3. Talley NJ, Abreu MT, Achkar JP, et al. An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol. 2011;106(Suppl 1):S2-S25.
Additional Reading
&NA;
Bernstein CN. Treatment of IBD: where we are and where we are going. Am J Gastroenterol. 2015; 110(1):114-126.
Codes
&NA;
ICD10
  • K50.919 Crohn's disease, unspecified, with unspecified complications
  • K50.00 Crohn's disease of small intestine without complications
  • K50.10 Crohn's disease of large intestine without complications
Clinical Pearls
&NA;
  • The incidence of CD has risen over the past 4 decades.
  • MRE allows assessment of luminal and extraluminal CD without radiation exposure.
  • Assess for TB and HBV infection prior to initiating anti-TNF therapy.
  • Cigarette smoking doubles the risk of developing CD; tobacco cessation may reduce frequency of flares and need for surgery.
  • Test for C. difficile infection when evaluating diarrhea in all CD patients.
  • Hospitalized CD patients require deep vein thrombosis prophylaxis.