Crohn disease

Crohn disease (CD) is an inflammatory bowel disease (IBD) of unclear etiology. Unlike ulcerative colitis, CD is not limited to the colon but can manifest anywhere in the gastrointestinal tract. Clinical features commonly include diarrhea, weight loss, and abdominal pain. Extraintestinal manifestations may occur in the eyes, joints, and skin. Diagnosis is based on laboratory studies (e.g., elevated CRP, fecal calprotectin), characteristic endoscopic features (e.g., ulcerations, skip lesions, cobblestone appearance), and evidence of intestinal inflammation on imaging. Medical management aims to induce and maintain remission; it is tailored to the patient and influenced by the location and severity of CD. Acute flares are typically managed with glucocorticoids and biologics (e.g., anti-TNF-α antibodies). Maintenance therapy (using, e.g., biologics, immunomodulators) focuses on limiting the frequency and duration of inflammatory episodes. Surgery is ultimately required in up to half of patients with CD; clinical manifestations commonly recur after surgery. Complications of CD include malabsorption, iron and vitamin deficiency, strictures, bowel obstruction, intraabdominal abscesses, and increased risk of bowel cancer.

• Prevalence: 1 case per 500 population
• Incidence: ∼ 6 cases per 100,000 population per year ^[1]
• Sex: ♂ = ♀
• Typical age of onset: bimodal distribution with one peak at 15–35 years and another one at 55–70 years ^[2][3]
• Populations with higher prevalence ^[4]
  • Individuals of Northern European descent
  • Individuals of Ashkenazi Jewish descent

Epidemiological data refers to the US, unless otherwise specified.

• Cause: Immune dysregulation and dysbiosis, which promotes chronic inflammation, the ultimate cause of which is not fully understood.
• Risk factors ^[4]
  • Familial aggregation
  • Genetic predisposition (e.g., mutation of the NOD2 gene, HLA-B27 association)
  • Tobacco smoke

Smoking tobacco is the primary modifiable risk factor for CD. Therefore, smoking cessation is especially important in patients with CD.

Inflammation

Inflammation is most likely caused by immune dysregulation.

• Dysregulation of IL-23-Th17 signaling → unrestrained Th17 cell function → inflammation → local tissue damage (edema, erosions/ulcers, necrosis) → obstruction, fibrotic scarring, stricture, and strangulation of the bowel ^[5]
• Mutations in the nucleotide oligomerization binding domain 2 (NOD2) protein are likely involved in the development of CD.

Abscess and fistula formation

• Intestinal aphthous ulcers → transmural fissures and inflammation of the intestinal walls → adherence of other organs or the skin → penetration of tissue → microperforation and abscess formation → macroperforation into these structures → fistula formation

CD typically has a chronic intermittent course with episodic acute flares and periods of remission. Clinical features differ according to the severity of CD. Patients with mild CD may be asymptomatic while patients with fulminant CD have severe symptoms.

Constitutional symptoms ^[6]

• Low-grade fever
• Weight loss
• Fatigue

Gastrointestinal symptoms ^[6]

CD most commonly affects the terminal ileum and colon, but involvement of any part of the GI tract (from mouth to anus) is possible. In contrast to ulcerative colitis, rectal involvement is uncommon.

• Chronic diarrhea
• Lower gastrointestinal bleeding (uncommon)
• Abdominal pain, typically in the RLQ
• Palpable abdominal mass in the RLQ
• Features of upper gastrointestinal CD ^[7]
  • Often asymptomatic
  • Epigastric pain
  • Nausea and vomiting
  • Dysphagia, odynophagia, dyspepsia
  • Signs of gastric outlet obstruction (e.g., early satiety, postprandial fullness) ^[8]
• Features of CD complications
  • Malabsorption (e.g., weight loss, anemia, failure to thrive ; )
  • Enterocutaneous or perianal fistulas, often associated with abscess formation ^[9]

Perianal lesions are occasionally the first manifestation of Crohn disease.^[10]

Extraintestinal symptoms ^[11]

Extraintestinal manifestations of CD are present in 20–30% of patients with CD. ^[12]

• Joints
  • Enteropathic arthritis
    • A seronegative spondyloarthropathy that develops in association with inflammatory bowel disease
    • Typically affects joints of the lower extremities but can also involve the spine (e.g., sacroiliitis, spondylitis, inflammation of peripheral joints).
  • Nail clubbing ^[13]
• Eyes
  • Uveitis
  • Iritis
  • Episcleritis
• Liver/bile ducts: cholelithiasis
• Urogenital system: urolithiasis (mostly calcium oxalate stones)
• Oral mucosa
  • Oral aphthae
  • Pyostomatitis vegetans
• Skin
  • Erythema nodosum
  • Acrodermatitis enteropathica
  • Pyoderma gangrenosum

Crohn disease severity

The severity of CD is based on clinical features, laboratory studies, and anatomical findings. ^[10]

Approach ^[10][14]

• Evaluate patients with chronic diarrhea and/or abdominal pain for CD.
• Obtain laboratory studies (blood and stool) to:
  • Rule out differential diagnoses of CD (e.g., infectious gastroenteritis).
  • Assess and monitor disease activity.
• Consult gastroenterology for endoscopy with histological examination to:
  • Definitively diagnose CD.
  • Determine the extent and severity of disease.
  • Assess distribution and monitor disease activity.
• Perform cross-sectional imaging to establish the location and severity of disease and identify complications.

Endoscopy, cross-sectional imaging, and laboratory studies are required for the initial evaluation of suspected CD, evaluation of an acute flare, and monitoring the response to therapy.

Laboratory studies ^[6][10]

Blood tests

• CBC: may show anemia, ↑ platelets (reactive thrombocytosis)
• Inflammatory markers: CRP, ESR
  • CRP has a greater correlation with disease activity than ESR.
  • Both may be normal in patients with mild CD.
• CMP
  • ↑ Creatinine
  • ↓ Albumin (marker of inflammation)
• Iron studies, vitamin B₁₂, folate: to evaluate for micronutrient deficiency ^[15]
• Serology: not routinely recommended due to low sensitivity
  • ↑ Anti-saccharomyces cerevisiae antibodies: more commonly elevated in CD than in ulcerative colitis
  • pANCA: more commonly elevated in ulcerative colitis than in CD ^[10][16]
• Specialized studies
  • Thiopurine methyltransferase (TPMT) activity
  • Genetic testing: considered in selected patients

Stool studies

• Stool analysis ; of diarrhea: to identify bacterial infection (including C. difficile infection), ova, and/or cysts (see also "Diagnostics for infectious gastroenteritis")
• Fecal calprotectin and/or fecal lactoferrin: noninvasive markers of intestinal inflammation
  • Fecal calprotectin: elevated (> 50–100 μg/g)
  • Used to monitor disease activity and response to therapy
  • Helps differentiate IBD from irritable bowel syndrome

Anemia in CD may result from chronic disease, iron deficiency, and/or vitamin B₁₂ deficiency.

Endoscopy

Ileocolonoscopy ^[10]

• Indication: all patients with suspected CD
  • Assesses the distribution and severity of the disease
  • Aids differentiation of CD from other diseases (e.g., ulcerative colitis)
  • Monitors disease activity (e.g., active disease, remission)
  • Can be used therapeutically (e.g., stricture dilatation)
• Supportive findings ^[10][14][17]
  • Skip lesions: segmental and/or discontinuous pattern of involvement (interspersed with normal tissue)
  • Linear and/or serpiginous ulcerations
  • Small aphthous ulcerations
  • Cobblestone sign: inflamed edematous sections interspersed with deep ulcerations that resemble cobblestones
  • Erythema, fissures, strictures, and fistulas
• Biopsy
  • Histopathology: Confirm CD (e.g., chronic inflammation).
  • Exclude CMV colitis in unresponsive CD (e.g., immunohistochemistry for CMV antigens): See "Diagnosis of CMV infection." ^[18]

Discontinuous areas of inflammation, cobblestone appearance of the affected mucosa, and mucosal ulcerations are hallmark endoscopic findings of CD. ^[19]

Other endoscopic techniques ^[10]

• Upper endoscopy: if upper GI involvement is suspected ^[10][20]
• Video capsule endoscopy: Consider in patients with suspected small bowel CD (as an alternative to cross-sectional imaging).

Small bowel evaluation is an essential part of the initial diagnostic workup of CD. Almost one-third of patients with CD have only small bowel disease, which may not be visible on ileocolonoscopy. ^[10]

Imaging ^{[6][10][21][22]}

Cross-sectional imaging is used to evaluate the entire GI tract, and it can identify inflammation and complications (e.g., bowel obstruction, abscess, fistula) that are not visible on endoscopy.

Indications

• Suspected CD (part of initial evaluation)
• Localization of inflammation and assessment of severity ^[10][21]
• Evaluation of suspected acute flare or complications (e.g., abscess)
• Before starting biologics: to ensure there are no pyogenic complications (e.g., abscess)
• Serial imaging to assess response to therapy

Modalities and supportive findings

• Cross-sectional enterography (MR enterography, CT enterography): preferred imaging modality for CD ; ^[10]
  • Edematous thickening of the intestinal wall
  • Mucosal enhancement, mesenteric fat stranding
  • Creeping fat: excessive mesenteric fat around the affected segments of bowel ^[23]
  • Can also identify:
    • Complications (e.g., strictures, fistulas, abscesses)
    • Extraluminal disease (e.g., cholelithiasis, urolithiasis)
    • Response to therapy (e.g., healing of ulcers)
• CT abdomen and pelvis (with IV contrast): preferred in acutely ill patients who cannot tolerate PO contrast
• Additional modalities ^[10][21]
  • Ultrasound abdomen
    • Consider for initial evaluation of suspected CD and for disease monitoring. ^[21]
    • Supportive finding (of active disease): bowel wall thickening (> 4 mm)
  • Plain x-ray abdomen: Consider for expedited assessment of complications.
  • MRI abdomen and pelvis (with IV contrast) or endscopic ultrasound ^[10][21]
    • Preferred modality to evaluate for perianal fistulas and/or abscess
    • Endoscopic ultrasound can be used to monitor treatment response.

• Transmural inflammation: all mucosal layers of the intestinal wall are involved
  • Noncaseating granulomas ^[24]
  • Giant cells
  • Distinct lymphoid aggregates of the lamina propria
• Creeping fat
• Hypertrophic lymph nodes

Monitoring of disease activity ^[10]

• Endoscopic monitoring
  • Schedule an endoscopic exam 6–9 months after treatment is initiated. ^[25]
  • Routine monitoring endoscopy is not recommended in the remission phase.
• Periodic cross-sectional imaging (MR enterography, CTE) : especially in patients with small bowel disease. ^[10]
• Serial CRP and fecal calprotectin: to assess inflammatory status and treatment efficacy (treating-to-target) ^[10][26]

Screening for intestinal cancer ^[10]

• Chronic inflammation increases the risk of intestinal cancer. ^[22]
• Schedule surveillance colonoscopy with biopsies. ^[10]
  • After 8 years after CD onset in patients with ≥ 30% colonic involvement
  • At diagnosis in patients with primary sclerosing cholangitis

Additional preventive care in IBD ^[27]

• Measures to prevent complications of glucocorticoid therapy
• Vaccinations ^[6][27]
  • Administer age-appropriate vaccinations preferably before starting immunosuppressant therapy.
  • Ensure immunizations are up to date at each follow-up.
  • Recommend pneumococcal vaccine, SARS-CoV-2 vaccine, hepatitis B vaccine (if not immune), and yearly influenza vaccine (inactivated).
  • Consider herpes zoster vaccine, RSV vaccine, and varicella vaccine.
  • See “ACIP immunization schedule” for details.
• Annual screening for skin cancer^[27]
• Annual cervical cancer screening: See “Cervical cancer screening for individuals at high risk.” ^[27]
• Screening for anemia and malnutrition (e.g., CBC, iron-binding studies, folate, vitamin B₁₂, LDH, vitamin D, albumin) ^[6]
• Screening for osteoporosis with DXA
  • Recommended in all patients with > 3 months cumulative lifetime exposure to glucocorticoids ^[27]
  • Consider screening the following patients at diagnosis and periodically thereafter:
    • Children at high risk of osteopenia ^[28]
    • Adults with risk factors for osteoporosis ^[29]
• Annual screening for depression and anxiety.^[27]

Crohn disease vs. ulcerative colitis

The crone and the fat granny skipped over the wrecked cobblestones: the most important features of Crohn disease are creeping fat, granuloma, skip lesions, rectal sparing, and cobblestone sign.

Other differential diagnoses

• Acute appendicitis
• Infectious gastroenteritis/colitis ^[28]
• Noninfectious colitis (ischemic colitis, radiation colitis, adverse drug reaction, etc.) ^[28]
• Diverticulitis
• Irritable bowel syndrome
• Gastrointestinal tuberculosis
• Malignant intestinal transformations
• Celiac disease ^[28]
• Indeterminate colitis

The differential diagnoses listed here are not exhaustive.

Fistulizing CD ^[10][32]

• Overview
  • Occurs in one-third of patients with CD
  • Typically involves the perianal region
  • Internal fistulas may involve the bladder, vagina, and/or another portion of the intestine.
  • Recurrences are common
• Clinical features: depend on location of the fistula (see “Fistulas”)
• Diagnosis: MRI of the pelvis and/or endoscopic ultrasound
• Management: Interdisciplinary management including gastroenterology and surgery is required. ^[10]
  • Anal fistula
    • Fistulotomy or seton placement
    • Biologic PLUS antibiotic in addition to surgery
  • Internal fistula
    • Medical therapy (typically a biologic)^[10]
    • Consider surgery when the patient is medically optimized.

Other intestinal complications

• Colorectal cancer (especially in the case of pancolitis)
• Short bowel syndrome and associated issues after surgery
• Stenosis/strictures → bowel obstruction/(sub)ileus
• Intestinal perforation → peritonitis
• Primary sclerosing cholangitis
• Impaired bile acid reabsorption
  • Bile acid diarrhea
  • Bile acid malabsorption → steatorrhea and deficiencies in fat-soluble vitamins
• Abscess formation/phlegmons

Systemic complications

• Signs of malabsorption syndrome
  • Weight loss
  • Failure to thrive and growth failure in children
  • Anemia
    • Iron deficiency anemia
    • Anemia of chronic disease
    • Megaloblastic anemia (vitamin B₁₂ deficiency due to impaired absorption in the chronically inflamed ileum)
  • Osteoporosis
• Amyloidosis

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

Crohn disease in children

See “Inflammatory bowel disease in children.”

Crohn disease in pregnancy

See “Inflammatory bowel disease in pregnancy.”

CD is a chronic disease that is not curable. Patients with any of the following features are at high risk of progression to severe disease; early advanced treatment is recommended to prevent complications of CD. ^[10]

• Ileocolonic involvement at diagnosis
• Upper GI involvement
• Severe disease (e.g., extensive anatomical involvement, deep ulcers)
• Early need for glucocorticoids
• Young age at diagnosis (< 30 years)
• Perianal or rectal disease
• Previous stenosis, fistula, and/or abscess
• Extraintestinal clinical features at diagnosis

Failure to achieve and maintain remission on therapy is associated with worse clinical outcomes, including stricture and fistula formation and the need for surgery. ^[26]