9 Inflammatory Bowel Disease G.R

9 Inflammatory Bowel Disease G.R. Greenberg, R.N. Fedorak and A.B.R. Thomson 1. CROHN’S DISEASE Crohn’s disease, or regional enteritis, is a chronic inflammatory disorder that can affect the small intestine and/or the large intestine. Inflammation, which may or may not be accompanied by noncaseating granulomas, extends through all layers of the gut wall to involve adjacent mesentery and lymph nodes. The inflammatory process is frequently discontinuous, with normal bowel separating portions of diseased bowel. This disease is charac- terized by an indolent variable course, by its diverse clinical manifestations, by its perianal and systemic complications, and by its tendency to recur after surgical resection. 1.1 Pathology Both ulcerative colitis and Crohn’s disease have a characteristic and pathological appearance. However, in any given case the pathological picture may not be specific enough to separate one from the other, or from other diseases such as infectious colitis or ischemic colitis. Therefore, in making the diagnosis the pathological assessment must be correlated with both the clinical and endoscopic assessments. The key pathological feature of Crohn’s disease is an inflammatory process that extends through all layers of the bowel wall. Microscopic examination reveals (1) hyperplasia of perilymphatic histiocytes, (2) diffuse granuloma- tous infiltration, (3) discrete noncaseating granulomas in the submucosa and lamina propria, (4) edema and lymphatic dilation of all layers of the gut, and (5) monocytic infiltration within lymph nodules and Peyer’s patches on the serosal surface of the bowel. 308 FIRST PRINCIPLES OF GASTROENTEROLOGY The mesentery in the vicinity of the diseased bowel is markedly thickened, fatty and edematous. Finger-like projections of thick mesenteric fat characteristically “creep” over the serosal surface of the bowel toward the antimesenteric border. The earliest mucosal lesion of Crohn’s disease is the aphthous ulcer. An aphthous ulcer is a small, superficial mucosal ulceration that endoscopically has the appearance of a white spot, usually less than 1–2 mm in diameter, surrounded by normal mucosa (Figure 1). In the small intestine aphthous ulcers typically occur over Peyer’s patches, and in the colon they occur over lymphoid aggre- gates. However, aphthous ulcers can occur anywhere along the epithelium, even when there is no lymphoid tissue. As the disease progresses these tiny aphthous ulcers enlarge to coalesce and form longitudinal and transverse linear ulcers (Figure 2). These linear ulcers have a characteristic “cobblestone” appearance, resulting from the combination of deep mucosal ulceration and nodular submu- cosal thickening. Ulcers are frequently elongated and tend to lie along the long axis of the bowel, giving the mucosa the appearance of having been clawed. Since the serosa and mesentery are inflamed, a characteristic feature of Crohn’s disease is the tendency for involved bowel loops to be firmly matted together by fibrotic bands. This adhesive process is often associated with the fistula formation characteristic of Crohn’s disease (Figure 3). Fistulas begin as ulcerations and gradually burrow through the serosa into adjacent organs. Such fistulas communicate between the loops of small bowel themselves, as well as between loops of small bowel and colon, skin, perineum, bladder or vagina, or they may end blindly in indolent abscess cavities located within the peritoneal cavity, mesentery or retroperitoneal structures. When the lesions of Crohn’s disease are discontinuous, the intestine that lies adjacent to or between diseased segments (“skip lesions”) shows no gross or histological abnormalities. Skip lesions are characteristic of Crohn’s disease. 1.2 Anatomic Distribution Crohn’s disease can affect the gastrointestinal tract anywhere from mouth to anus. Typically, patients with Crohn’s disease can be divided into those with small bowel disease alone (30%), those with both small and large bowel involvement (50%), and those with disease involving only the colon (20%) (Table 1). When Crohn’s disease involves the small bowel, 80% of the time the terminal ileum is involved (Figure 4). In only 20% of cases are other areas of small bowel also affected. When the colon is involved in Crohn’s disease (Crohn’s colitis), many will have pancolitis with the typical rectal sparing of Crohn’s disease, but approximately 30% will have segmental disease. Much less commonly, Crohn’s disease involves more proximal parts of the gastrointestinal tract such as the mouth, tongue, esophagus, stomach and duodenum. Inflammatory Bowel Disease 309 FIGURE 1. At the endoscopic mucosal level, the earliest visible lesions of Crohn’s disease are often minute aphthous ulcers. Aphthous ulcers are tiny mucosal defects that are appreciated on scanning electron microscopy (left panel). The corresponding light microscopic picture (right panel) demonstrates this mucosal defect with a cleft extending down into the lamina propria. SOURCE: Adapted from the AGA clinical teaching project, copyright 1991. Ulceration Granuloma Sinus Tract FIGURE 2. Aphthous ulcers coalesce into larger ulcers that can extend through all layers of the bowel wall and become transmural. SOURCE: Adapted from the AGA clinical teaching project, copyright 1991. 1.3 Epidemiology Crohn’s disease was first described in 1932, although in retrospect, isolated cases were described throughout the 19th century. Since its first description we have seen a remarkable rise in disease incidence, an increase that reflects 310 FIRST PRINCIPLES OF GASTROENTEROLOGY FIGURE 3. As the inflammatory process of Crohn’s burrows through the entire thickness of the bowel wall, sinus tracts are formed and frequently penetrate the serosal surface and extend into adjacent tissues. Since the serosal surface becomes “sticky,” the fistulizing segments of bowel tend to adhere to surrounding tissues and the fistulous process can tunnel through into contiguous structures. SOURCE: Adapted from the AGA clinical teaching project, copyright 1991. FIGURE 4. Crohn’s disease. Barium contrast x-rays showing (a) ulcerations and narrowing characteristic of terminal ileal involvement and (b) the “string sign” as a consequence of stricturing following ulceration. Inflammatory Bowel Disease 311 TABLE 1. Anatomic distribution of Crohn’s disease Major site of involvement Percentage Small bowel only 30 Small bowel and colon 50 Colon only 20 TABLE 2. Epidemiology of inflammatory bowel disease Factor Ulcerative colitis Crohn’s disease Incidence (per 100,000) 2–10 1–6 Prevalence (per 100,000) 35–100 10–100 Racial incidence High in whites High in whites Ethnic incidence High in Jews High in Jews Sex Slight female preponderance Slight female preponderance much more than enhanced awareness and diagnosis of the disease. Figure 5 demonstrates the changes and incidence over 60 years in selective registries. Although some of the increase in incidence could be due to a shortening in the time interval between symptom onset and disease diagnosis or a better appre- ciation of the disease, it is the general feeling of experts in the field that the increase is real. Given the rapidity of change in disease incidence, it is likely that some environmental factor is responsible, since purely genetic factors do not change as quickly. Crohn’s disease occurs throughout the world, with a prevalence of 10 to 100 cases per 105 people (Table 2). The disorder occurs most frequently among people of European origin, is 3 to 8 times more common among Jews than among non-Jews, and is more common among whites than nonwhites. Interestingly, Crohn’s disease seems to occur in developed countries and is infrequently found in underdeveloped or developing countries. For instance, in contrast to North America and Europe, South America and South East Asia have very few cases of inflammatory bowel disease. This observation provides one of the most compelling arguments for a yet to be determined environmental influence as a cofactor in the etiology of the disease. Although the disorder can begin at any age, its onset most often occurs between 15 and 30 years of age. There is a familial aggregation of patients with Crohn’s disease, representing the polygenetic influence, such that 20–30% of patients with Crohn’s disease have a family history of inflammatory bowel disease. 312 FIRST PRINCIPLES OF GASTROENTEROLOGY FIGURE 5. The incidence of Crohn’s disease has been almost doubling in North America and Europe every decade since the 1940s, while the incidence of ulcerative colitis has remained relatively constant over the past 20 years. 1.4 Etiology The etiology of Crohn’s disease is unknown. The most current hypothesis sug- gests an interaction between predisposing genetic factors and luminal bacte- ria causing over-activation of the mucosal immune system, which in turn leads to chronic uncontrolled intestinal inflammation1-3. A role for genetic factors is supported by findings that mutations of NOD2/CARD15 gene are associated with increased susceptibility to the development of Crohn’s disease4. The NOD2 protein activates the transcription factor NFK␤ in response to microbial products. Clinical manifestations of younger age of onset, ileal involvement and fibrostenotic disease have been described in Crohn’s patients with NOD2 mutations. A role for bacterial antigens from normal commensal flora contributing to the development of intestinal inflammation is supported by findings that gut T-cells in Crohn’s disease react to their own

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