Unlike the findings in UC, the inflammation in CD usually does not involve a continuous segment of bowel and often appears as discrete focal ulcerations (e.g., aphthae) with relatively intact intervening mucosa. As the disease progresses, in the 60% of cases involving the colon, right-sided or proximal colonic inflammation predominates, with relative sparing of the rectum. Anal involvement, in the form of skin tags, anal fissures, abscesses, and fistulas, occurs in approximately 25% of patients, often preceding intestinal symptoms. The inflammation of CD usually is transmural and can be recognized as mesenteric inflammation; fat encroachment on the serosal surface of the intestine; stiffening of the small bowel loops caused by
fibrosis; and adhesions, stricture formation, and fistulas to other loops of bowel, bladder, vagina, or skin.

The histology of the lesions in CD reveals the transmural nature of the acute and chronic inflammation, often showing edema, lymphoid aggregates, and significant fibrosis. Mucosal changes may resemble those of ulcerative or infectious colitis characterized by acute polymorphonuclear leukocyte invasion of crypt epithelium to cause cryptitis or crypt abscesses, as well as chronic features of crypt branching and dropout distorting normal crypt architecture. Some areas of the bowel may be normal or may show only mild chronic inflammation. Noncaseating granulomas may be found in as many as 50% of the patients, and coupled with the transmural inflammation, disease distribution, and clinical presentation, their presence provides strong support for the diagnosis of CD (Fig. 353.1).

As in UC, the cause of CD is unknown, with evidence existing for the collusion of multiple factors, including genetics, luminal agents, altered mucosal integrity, and immunologic response, in the pathogenesis. A current hypothesis suggests that CD is caused by an inappropriate cellular immune response to enteral bacterial products in a genetically susceptible host. The pathogenesis of the chronic inflammation may involve abnormalities in the regulation of the immune response to infectious, toxic, or dietary-derived intestinal antigens or an inappropriate immune response to an unusual antigen or infectious agent. No consistent pathogen has been identified. Altered colonic flora or bacterial products may play a role in the pathogenesis, given the attenuation or absence of disease in germ-free animal models and the therapeutic usefulness of antibiotics. Impaired intestinal mucosal exclusion of luminal antigens may be a causal factor or simply a consequence of inflammation. Inappropriately regulated immune or cytokine responses have been implicated on the basis of the favorable response to corticosteroids, other immunosuppressive agents, and cytokine antagonists. Although evidence for an activated T-lymphocyte population and cytokine production exists, no specific markers of autoimmunity have been demonstrated.

A genetic basis of CD is supported by several observations. First, the prevalence of CD is higher among some subpopulations (e.g., Ashkenazi Jews). Second, concordance of disease among monozygotic twins is approximately 67%. Third, multiple independent genome-wide scans have revealed susceptibility loci in families with several affected members. Finally, mutations in the CARD15/NOD2 gene on chromosome 16 confer an increased risk among both heterozygotes (two- to fourfold) and homozygotes (40-fold). The normal protein product of CARD15/NOD2 is responsible for binding intracellular bacterial products and transducing intracellular inflammatory signals involved in bacterial recognition by monocytes. Not all individuals with CD have mutations in CARD15/NOD2; conversely, not all those with mutations in CARD15/NOD2 develop CD. These features, as well as the several other identified susceptibility loci (e.g., on chromosomes 5 and 7), suggest that CD has a non-Mendelian complex genetic basis.

A recent epidemiologic study of children diagnosed by pediatric gastroenterologists in Wisconsin revealed an incidence of inflammatory bowel disease (IBD) of 7.05 cases per 100,000 per year. The majority of cases, 4.56 per 100,000 population, were CD, more than twice the incidence of UC. In most cases, no family history existed. Unlike previous studies indicating an increased prevalence among whites (especially in the Jewish population) in the developed world, the incidence was not affected by racial or urbanization factors. Male and female representation is approximately equal, as is bimodal age at onset, with peaks occurring in the second and third and again in the sixth decades of life. Approximately 2% of cases, including rare cases in infancy presenting as intractable diarrhea, occur before the patient reaches 10 years of age.

The presentation of CD in children depends on the location and extent of inflammation. In many cases, the onset is insidious with nonspecific features of GI involvement or extraintestinal manifestations leading to delayed or incorrect diagnosis. Diarrhea, abdominal pain (most frequently postprandial periumbilical cramping), fever, and weight loss are the most common presenting features. Rectal bleeding, seen in 30% of CD cases, is seen much less commonly than in UC and signifies colonic involvement. The three general patterns of clinical presentation based on anatomic involvement show considerable overlap: (1) diarrhea and lower abdominal cramping representing colonic inflammation; (2) nausea, vomiting, anorexia, and/or early satiety due to upper gastrointestinal or small intestinal disease; and (3) extraintestinal symptoms and signs, including delayed maturation and growth impairment (Box 353.1).

Colonic involvement may present as diarrhea, often associated with cramps and urgency to defecate after any distention of the inflamed colon by the fecal stream. Other signs of colitis may be indistinguishable from those seen in UC and consist
of an inflammatory exudate of neutrophils into the lumen and occult or overt rectal bleeding. Perianal disease and relative sparing of the rectum occur more frequently in Crohn colitis than in ulcerative colitis and may be the only differentiating features. Perianal skin tags and fissures may be the first physical sign of disease, especially if they are off the sagittal plane. Perianal abscesses and perineal fistulas also should suggest the diagnosis of Crohn colitis. A rare complication, toxic dilation with risk of perforation and sepsis known as toxic megacolon, has been reported in Crohn colitis, though less often than in UC; treatment is the same as that outlined for toxic megacolon complicating severe ulcerative colitis (see Chapter 352).

Another pattern of presentation is produced by upper gastrointestinal inflammation, which probably accounts for much of the postprandial cramping, early satiety, nausea, and anorexia that patients report. Rare involvement of the esophagus or gastroduodenal segments may mimic peptic disease and respond partially to acid control therapy. Gastritis or duodenal ulceration in the absence of Helicobacter pylori infection or use of nonsteroidal antiinflammatory agents should suggest possible CD. Diarrhea may occur in 90% of patients with small bowel involvement and, in the absence of colitis, most likely signifies malabsorption of bile acids by the terminal ileum or nutrients. Estimates of the prevalence of malabsorption in children with CD depend on the nutrient that is malabsorbed but range from 17% for lactose and 29% for fat to 70% for protein. The frequency of lactose malabsorption is normal when adjusted for that expected for the ethnic distribution of patients with CD but in some patients may be a consequence of small bowel inflammation. Deficiencies of iron, zinc, magnesium, folate, and vitamin B₁₂ may be more pronounced in patients with small bowel disease, particularly those with terminal ileum involvement.

Patients may present with nonspecific extraintestinal manifestations and growth retardation (see Box 353.1). Overt clinical signs of involvement of the GI tract may not appear for years, although this inflammation may be extensive enough to cause early satiety, nausea, anorexia, and distention as signs of malabsorption or impaired transit and partial obstruction. Over the course of time, net energy and protein deficits are reflected in decreased weight velocity followed by decreased height velocity and delayed skeletal and sexual maturation. As a consequence of nutritional, growth, and maturational problems, patients may be referred to specialists in endocrinology for assessment of short stature and hypogonadism or to psychiatrists for evaluation of anorexia. Certain extraintestinal features that may be clues indicating the presence of CD include perianal disease, oral aphthae, erythema nodosum, arthritis, uveitis, and digital clubbing. A microcytic anemia with reduced total iron-binding capacity, an elevated leukocyte and platelet count, and an elevated erythrocyte sedimentation rate may be present. Abdominal radiography may show an unusual gas pattern with some small bowel dilation; usually, however, radiography does not establish a diagnosis. Recognizing this insidious mode of presentation leads to timely use of specific tests to confirm the diagnosis.

The major intestinal complications of CD are related to the transmural nature of the inflammation that extends from mucosa to serosa. Contiguous loops of bowel or other organs may become enveloped in inflammation. Adhesions, strictures, and abscesses may develop, with a risk of development of an obstruction or bacterial overgrowth. Fistulas may form to any abdominal or pelvic structure and should be suspected to underlie any chronic draining ulcer or sinus. Enterocutaneous, enteroenteric, perirectal, labial, enterovaginal, and enterovesical fistulas may pose a nutritional hazard because they are conduits for major losses of protein and other nutrients. Perianal disease occurs in 25% of patients with CD, most often in the context of colonic inflammation and fistula formation. Skin tags, anal fissures, and perianal or perirectal abscesses may precede other signs of intestinal CD or develop during an exacerbation of colitis. Although often minor in appearance, these lesions can create severe discomfort and be quite refractory to treatment. Massive hemorrhage and toxic megacolon, which are potential complications of UC, occur only rarely in CD.

The risk of malignancy of all types appears to be increased in patients with CD and is estimated to be 20 times greater than normal for patients with CD diagnosed before the patient is 21 years of age. Nonetheless, the incidence of small bowel
carcinoma is low, and the rates of colonic adenocarcinoma are lower than those in patients with UC. However, rates of colorectal cancer approach those of UC when adjusted for the extent of colonic involvement in Crohn colitis. The association of colonic mucosal dysplasia with carcinoma in CD is not established sufficiently to recommend prophylactic colectomy, although performing surveillance colonoscopy and biopsies as in UC is prudent in patients with long-standing Crohn colitis.

The diagnosis of CD is based on clinical presentation, radiologic findings, and mucosal appearance and histology after exclusion of alternative causes. A complete history should be obtained, with attention given to family history, exposure to infectious agents or antibiotic treatment, extraintestinal manifestations, and retardation in growth rate or in sexual development. Physical examination should include assessment of hydration, nutritional status, signs of peritoneal inflammation, and signs of systemic chronic disease. Features suggesting CD are stomatitis; perianal skin tags, fissures, fistulas, or inflammation; and digital clubbing. Fever, orthostasis, tachycardia, and abdominal tenderness, distention, or mass should be considered indications for admission to the hospital. Disease activity indices have been validated to provide an objective scale for evaluating and measuring the severity or intensity of disease in pediatric patients with CD (Table 353.1).