Crohn disease (CD) is a chronic inflammatory bowel disease (IBD) that can affect any region of the gastrointestinal tract.1 Crohn disease is characterized by remitting and relapsing symptoms such as fatigue, fever, abdominal pain, diarrhea, and weight loss that may lead to hospitalization. The disease often affects patients’ quality of life and causes minimal to severe disability.1 Extraintestinal manifestations of CD include joint disease, ocular inflammation, and dermatologic conditions; potential complications of CD (strictures, fistulas, and abscesses) may require surgery.1 Early diagnosis and initiation of anti-inflammatory and immunologic treatments are important for effective management of this disease.1

An estimated 1.3% of US adults (3 million) reported being diagnosed with IBD (either CD or ulcerative colitis [UC]) in 2015.2 The incidence of CD is increasing in the US, Europe, and Asia for unclear reasons.3 In general, the incidence of IBD peaks at approximately 15 to 29 years with another peak occurring in adults 60 years and older.4

Crohn disease is believed to occur because of an interplay between genetic susceptibility, immunologic factors, environmental influences, and intestinal microflora, resulting in an abnormal mucosal immune response and compromised epithelial barrier function.1

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Risk Factors for Crohn Disease

Approximately 12% of patients with CD have a family history of the disease.5 People of Ashkenazi Jewish descent have a 3- to 4-fold higher risk for the disease than the general population. Crohn disease also is more prevalent among non-Hispanic White persons while those of Hispanic or Asian/Pacific Islander ancestry are at lowest risk for the disease.4 The incidence is also lower among non-Hispanic Black persons than among White persons, however, the highest annual percentage increase in IBD rates occurred among non-Hispanic Black persons between 2001 and 2018.4

Genome-wide association studies have identified more than 200 alleles associated with IBD of which 37 are specific for CD.6,7 Homozygosity for the NOD2 gene is associated with a 20- to 40-fold increased risk of developing CD.5 A slight female predominance has been found in adult-onset CD, which suggests that hormonal factors may play a role in disease expression.8

Environmental aspects that influence CD are widely debated. As low-risk countries such as Japan, China, and India adopt a Western lifestyle, the incidence of CD has increased sharply.5 Cigarette smoking may be an environmental factor as some studies show a 2-fold higher risk for CD in smokers.9 Antibiotic exposure in childhood is also associated with an increased risk for CD.10 Other medications potentially associated with increased risk include oral contraceptives, aspirin, and nonsteroidal anti-inflammatory drugs (NSAIDs).11,12  

Diet may also be contributory. Low dietary fiber and high saturated fat intake have also been associated with increased risk.13 Persons with CD also have been shown to have reduced diversity in gut microbiota when compared with healthy individuals.14

Important lifestyle behaviors that affect CD include sleep, stress, and exercise. Disturbed sleep is associated with active disease in CD.15 Major life stressors, anxiety, and depression are associated with an increased risk for CD.16 Physical activity has been associated with a lower risk for CD.17

Etiology and Pathophysiology of Crohn Disease

Both subtypes of IBD — CD and UC — result from a dysregulated response of the mucosal immune system to the bacterial flora that reside within the intestinal lumen.5,18 In IBD, the intestinal epithelial layer has excessive permeability that allows pathogens to leak through to the underlying mucosal layers.19 It is believed that this triggers an autoimmune reaction with persistent activation of immune cells. Neutrophils, lymphocytes, and lymphoid tissue produce pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukins (ILs) that perpetuate the inflammatory response.20

Approximately one-third of patients with CD have an increased amount of mucosa-associated, adherent-invasive Escherichia coli.21 These bacteria cross the mucosal barrier, adhere to and invade intestinal epithelial cells, and replicate within macrophages, which provokes the secretion of high amounts of TNF-α. The intestinal inflammatory infiltrate in CD contains T cells and antibodies that act against the intestinal bacteria.22,23 The key pathologic findings on intestinal biopsies in CD are granulomatous inflammatory changes characterized by focal collections of macrophages, epithelioid cells, and multinucleated giant cells.24

Clinical Manifestations of Crohn Disease

Persons with CD often have symptoms for several years before a diagnosis is confirmed and many are initially misdiagnosed with irritable bowel syndrome (IBS). However, the cardinal symptoms of chronic fatigue, fever, weight loss, and blood and mucus within the diarrhea are present in IBD and not IBS. Blood in stool and rectal bleeding particularly differentiate IBD from IBS.25 The other clinical challenge is differentiating between the diagnosis of UC and CD, and clinicians must be aware of the distinctive features of each condition (Table 1).26

Table 1. Different Features of Crohn Disease and Ulcerative Colitis26

 Crohn DiseaseUlcerative Colitis
Regional involvement• Any area of the GI tract
• Terminal ileum common
• Most common in colon
Ileocolonoscopy findings• Skipped areas of inflammation • Transmural involvement• Continuous inflammation
• Mucosal and submucosal involvement
Characteristic lesions• Cobblestone appearance of intestinal wall• Pseudopolyps; protrusions of regenerating mucosa
Clinical manifestations• Fever, chronic diarrhea with mucus and blood, weight loss
• Extraintestinal manifestations such as musculoskeletal symptoms, perianal abscess, fissure, fistula more common in CD
• Fever, chronic diarrhea with mucus and blood, weight loss
• Blood in stool more common in UC than CD
Colon cancer risk• Less with CD• Greater with UC
CD, Crohn disease; GI, gastrointestinal; UC, ulcerative colitis

Extraintestinal symptoms are present in 43% of patients with CD and can affect multiple body systems. These include musculoskeletal (arthritis and ankylosing spondylitis), oral (stomatitis), ocular (uveitis, scleritis, and episcleritis), dermatologic (pyoderma gangrenosum, psoriasis, and erythema nodosum), and hepatobiliary (primary sclerosing cholangitis) symptoms.27