• Clinical science

Crohn disease

Abstract

Crohn disease (CD) is an inflammatory bowel disease, the pathogenesis of which is not fully understood. The clinical presentation of CD may be similar to ulcerative colitis (UC), the other most common inflammatory bowel disease. CD mostly affects young adults and adolescents between the ages of 15 and 35. It is typically located in the terminal ileum, but can discontinuously affect the entire gastrointestinal tract and commonly leads to complications such as fistulas, abscesses, and stenosis. Clinical features include diarrhea, weight loss, and abdominal pain in the right lower quadrant (RLQ), as well as extraintestinal manifestations in the eyes, joints, or skin. It is often difficult to diagnose because there is no confirmatory test. Diagnosis is therefore based on the patient's medical history, physical examination, lab tests, imaging (e.g., MRI), endoscopy, and serological testing. Acute episodes are treated with corticosteroids, and in severe cases, immunosuppressants may be indicated. Antibiotics and surgical intervention may be needed to help treat complications. Because the entire gastrointestinal tract may be affected, Crohn disease cannot be cured (in contrast to ulcerative colitis). The goal of treatment is thus to avoid the progression and recurrence of inflammatory episodes.

Epidemiology

  • Prevalence: up to 200 cases per 100,000 adults
  • Incidence: 3–15 cases/100,000 persons per year
  • Sex: =
  • Average age at diagnosis: 15–35 years
    • A second peak is observed around the age of 60, when 10% of cases occur.
  • More common in white populations and people of Jewish descent (especially Ashkenazi Jews, middle European Jews)

References:[1][2][3]

Epidemiological data refers to the US, unless otherwise specified.

Etiology

  • Cause: Unknown factors lead to an imbalance between proinflammatory and anti-inflammatory mediators.
  • Risk factors
    • Nicotine abuse
    • Familial predisposition; (e.g., mutation of the NOD2 gene, HLA-B27 association )

Nicotine consumption is the only (known) controllable risk factor for Crohn disease. Therefore, quitting smoking is especially important for patients with CD!

References:[1][4]

Classification

Crohn Disease Activity Index (CDAI)

The Crohn Disease Activity Index is a validated score that quantifies the severity of an acute episode and evaluates the therapeutic success following recurrence. The CDAI is complex and seldom used in clinical contexts.

The following signs and symptoms are included in the score:

References:[5]

Pathophysiology

  • Unknown mechanisms lead to the activation of lymphatic cells (Th1) in the intestinal walls → inflammation is triggered → local tissue damage (edema, erosions/ulcers, necrosis) → obstruction, fibrotic scarring, stricture, and strangulation of the bowel
    • Mutations in nucleotide oligomerization binding domain 2 (NOD2) protein implicated in the development of Crohn disease but mechanism currently not fully understood
      • Loss of function mutations in NOD2 → likely allow bacteria to enter the intestinal mucosa and cause an unregulated inflammation
      • Dysfunctional NOD2 can cause overactivity of the NF-κB signaling pathway → ↑ production of pro-inflammatory cytokines and antimicrobial peptides → chronic autoinflammation
  • Abscess and fistula formation: intestinal aphthous ulcers → transmural fissures and inflammation of the intestinal walls → adherence to other organs or the skin → penetration of these structures → microperforation and abscess formation → macroperforation into these structures → fistula formation
  • Main locations: terminal ileum and colon but it can be located anywhere between the mouth and the anus (the rectum is spared)

References:[1]

Clinical features

Typically, CD occurs episodically and there is a 30% risk of recurring inflammation over the span of one year. If symptoms persist for six months, the disease is considered chronic.

Intestinal symptoms

Perianal fistulas and abscesses are often the first signs of Crohn disease!

Extraintestinal symptoms

References:[1][6]

Diagnostics

Approach[7]

  • Initially: if a patient has clinical features indicating CD, conduct blood and stool tests
  • Confirm with endoscopy and/or radiographic imaging and/or biopsy
  • Perform contrast radiological studies and/or ultrasonography to assess extent, severity and complications (i.e., abscesses, fistulas or stenoses)

Laboratory tests

Imaging

  • Plain abdominal x-rays: bowel distention, pneumoperitoneum
  • Plain radiography with barium swallow (enteroclysis)
    • Indication: to detect fistulas or stenoses
    • Procedure
      • Water-soluble contrast medium is inserted into the small intestine via a nasopharyngeal tube.
      • Multiple x-rays are taken in a chronological sequence to evaluate each section.
    • Findings
      • String sign
      • Creeping fat
  • Ultrasound findings
    • Gastrointestinal wall thickening caused by inflammation and edema
    • Possible detection of abscesses/fistulas
  • MR enterography with contrast medium (MRI enteroclysis, Hydro-MRI)
    • Indication: identification of the extent and pattern of intestinal inflammation, detection of perianal and pelvic disease, and prediction of activity:

Endoscopy

Endoscopy confirms the diagnosis, assesses the extent of the disease, differentiates CD from other diseases (e.g., ulcerative colitis, peptic ulcers, etc.), and may also be used as a therapeutic tool (e.g., dilatation of ducts, intestinal loops).

  • Ileocolonoscopy
    • Procedure: ileocolonoscopy with biopsies at various locations throughout the terminal ileum, colon, and rectum
    • Typical findings
  • Esophagogastroduodenoscopy
    • Indication: to evaluate the possible involvement of the esophagus, stomach, and duodenum
    • Findings include aphthae on mucosa

References:[10][1][11][12]

Pathology

References:[1][13]

Differential diagnoses

Ulcerative colitis

Differential diagnostic considerations: Crohn disease and ulcerative colitis
Symptoms

Crohn disease

Ulcerative colitis

Frequency/type of defecation
  • Increased (constipation may also result from obstruction)
  • Typically non-bloody, watery diarrhea; may be bloody in some cases
  • Greatly increased
  • Bloody diarrhea with mucus
Nutritional status
  • Poor or malnourished
  • Mostly normal, but weight loss may occur in the case of severe disease
Pain
  • Mostly constant
  • Mainly RLQ
  • Mostly before or during defecation
  • Mainly left lower quadrant
Fistulas
  • Very common
  • Very rare
Endoscopy and imaging
Pattern of involvement
Histology

Other differential diagnoses

References:[14][1]

The differential diagnoses listed here are not exhaustive.

Treatment

General

Pharmacotherapy

  • Treatment of Crohn disease can be approached in two different ways: step‑up therapy and top‑down therapy.
  • Step-up therapy involves treatment with weak medication; if the drug regimen is ineffective, treatment with stronger medication is indicated.
  • Top-down therapy works the other way around, beginning with stronger medications.

Therapy goal Drug Characteristics
Symptomatic
  • Crohn disease generally responds well to antidiarrheal agents.
  • For pain relief in oral lesions
  • Topical 5‑Aminosalicylic acid derivatives (5-ASA derivatives, 5-ASAs) (e.g., suppository, foam, enema)
Acute episode

For mild to moderate disease

  • Consider as initial treatment for patients with no systemic symptoms.
  • May be given in combination with corticosteroids
  • Indication: contraindications to corticosteroids, patients without systemic symptoms
  • Goal: reduction of intestinal bacteria, immune response, and risk of infection
  • Indications: fistulas, perianal abscesses, colonic disease, postoperative recurrence, and/or pouchitis

Moderate to severe disease

  • Start with 30–60 mg prednisone per day, then reduce dose gradually for weeks until a maintenance dose of 10 mg every other day is reached. Afterwards, continue the maintenance dose for 3–6 months.
  • Tapering is important!
  • Effective in gastroduodenal Crohn disease

Steroid-refractory disease, escalation therapy

  • Azathoprine and 6-mercaptopurine: Results may be seen after 3–6 months of treatment ; regular tests to measure toxicity are required.
  • Indications for treatment with alpha 4 integrin inhibitors: ineffective treatment with corticosteroids, TNF-α antibodies, and/or immunomodulators (azathioprine, 6-mercaptopurine, methotrexate)
Maintenance therapy
  • If ineffective, a combination of the previously mentioned drugs may be considered.
  • Methotrexate may be used in children, but not in pregnant women!

Surgical intervention

  • Goal
    • Resect affected and non-functional intestinal loop(s) while preserving intestinal length and function
    • Minimally-invasive surgery if possible
  • Indications
    • Failed medical therapy
    • Severe complications (e.g., abscesses, perforation, toxic megacolon, obstruction, stricture, hemorrhage etc.)
  • Methods
    • Resection of affected bowel (e.g., ileostomy, ileocolostomy, colectomy, proctocolectomy)
    • Intestinal stenosis: balloon dilatation or tissue-sparing end-to-end anastomosis
    • Fistulas, abscesses: percutaneous drainage (prevents retention of secretions and abscessation); if unsuccessful, surgical drainage
    • Obstruction, stricture: conservative resection
    • After multiple resections: strictureplasty (bowel-sparing technique)

Crohn disease is mainly treated with medication, but surgical interventions may be required to treat complications or if medical therapy fails. Surgical intervention alone cannot cure Crohn disease and should therefore be considered as a last resort to avoid complications in which significant amounts of bowel are lost (e.g., short bowel syndrome)!

Prevention

References:[1][15][16][17][18]

Complications

General

  • Intestinal complications (see “Clinical findings” above)
    • Increased risk of carcinoma
    • Growth retardation in children
    • Short bowel syndrome and associated issues after surgeries
  • Amyloidosis
  • Osteoporosis

Intestinal fistulas and abscesses

  • Etiology
  • Pathophysiology
    • In inflammatory conditions: inflammation of the intestinal walls → adherence to other organs or the skin → penetration of these structures → microperforation and possibly abscess formation → macroperforation into these structures → fistula formation
    • After surgery or percutaneous drainage: deficient anastomoses and/or sutures, or improper healing following intervention (e.g., due to reduced organ blood flow) → leakage of intestinal fluids → local infection → abscess formation and/or erosionfistula formation
  • Clinical features: may vary depending on location of fistula
    • Enterocutaneous fistulas: drainage of intestinal content through the skin
    • Enteroenteric fistula: mostly asymptomatic
    • Ileosigmoid fistula: diarrhea, weight loss; , abdominal pain
    • Gastrocolic fistula: abdominal pain; , weight loss, foul‑smelling burps (feculent belching)
    • Enterovesical/colovesical fistula: passing urine together with air (pneumaturia), excrements in urine (fecaluria), recurrent urinary tract infections (UTI)
    • Rectovaginal/anovaginal fistula: passage of stool/gas through the vagina, pain during sex (dyspareunia), perineal pain
    • Aortoenteric fistula: rectal bleeding

References:[17][19]

We list the most important complications. The selection is not exhaustive.

Prognosis

  • Currently not curable
  • Relapses and complications are very common without treatment.
  • 70% of all patients require surgery within 15 years of the onset of complications.
  • Life expectancy is normal with ideal, evidence-based treatment.

References:[1]