Pathophysiology Ulcerative Colitis

The inflammatory response in UC is propagated by atypical type 2 helper T cells that produce proinflammatory cytokines such as interleukin-1 (IL-1), IL-6, and tumor necrosis factor (TNF).8 As discussed previously, a genetic predisposition to UC may partially explain the development of excessive colonic and rectal inflammation. The finding of positive perinuclear antineutrophil cytoplasmic antibodies (pANCA) in association with the human leukocyte antigen (HLA)-DR2 allele in a large percentage of patients with UC supports this theory.1

The potential role of environmental factors in development of UC implies that the immune response is directed against an unknown antigen. The findings that development and severity of UC are reduced in patients who smoke, or in those with appendectomies, may support the theory that these factors may somehow modify either the genetic component or phenotypic response to immunologic stimuli.12,14

The inflammatory process within the GI tract is limited to the colon and rectum in patients with UC (Fig. 19-1). Most patients with UC have involvement of the rectum (proctitis) or both the rectum and the sigmoid colon (proctosigmoiditis). Inflammation involving the majority of the colon is referred to as pancolitis. Left-sided disease, defined as inflammation extending from the rectum to the splenic flexure, occurs in

30% to 40% of patients. A small number of cases of UC involve mild inflammation of the terminal ileum, referred to as "backwash ileitis."

The pattern of inflammation in UC is continuous and confluent throughout the affected areas of the GI tract. The inflammation is also superficial and does not typically extend below the submucosal layer of the GI tract (Fig. 19-2). Ulceration or erosion of the GI mucosa may be present and varies with disease severity. The formation of crypt abscesses within the mucosal layers of the GI tract is characteristic of UC and may help to distinguish it from CD. Severe inflammation may also result in areas of hypertrophied GI mucosa, which may manifest as pseudopolyps within the colon.13 The inflammatory response may progress in severity, leading to mucosal friability and significant GI bleeding.

Pathophysiology Ulcerative Colitis

Invofvement of entire colon and /or recium. = Pancolitis

FIGURE 19-1. Major Gl landmarks and disease distribution in inflammatory bowel disease. Crohn's Disease

As with UC, the immune activation seen in CD involves the release of many proinflammatory cytokines. Cytokines thought to play major roles in CD are derived from T-helper type 1 cells and include interferon-y, TNF-a, and IL-1, IL-6, and IL-12. TNF-a is a major contributor to the inflammatory process seen in CD. Its physiologic effects include activation of macrophages, procoagulant effects in the vascular endothe-

13 15

lium, and increases in production of matrix metalloproteinases in mucosal cells. ' Excessive production of both interferon-y and TNF-a may account for the excessive clinical evidence of granulomatous disease in patients with CD.11 TNF-a is also thought to induce production of nuclear factor kP, which stimulates further production of TNF-a and other proinflammatory cytokines.3'16

The role of an immune response directed against endogenous bacteria as the initiating factor is more evident in CD, as evidenced by the apparent strong T-helper 1 activation against bacteria seen in animal models of this disease. The role of dietary antigens in the development of CD compared to UC is also another potential initiating factor. Excess ingestion of refined sugars or margarine may be higher in patients who develop CD.8

The distribution of inflammation in CD differs from that seen in UC, as any part of the entire GI tract may be affected in CD. The small intestine is the site most commonly involved. Within the small intestine, the terminal ileum and cecum are almost always affected. Approximately 20% of patients have isolated colonic involvement, whereas inflammation proximal to the small intestine is almost never seen without the

presence of small or large intestinal disease.

Transmural Crohn

FIGURE 19-2. Depth of disease penetration in ulcerative colitis and Crohn's disease.

Transmural disease may result in penetration or fistula formation

FIGURE 19-2. Depth of disease penetration in ulcerative colitis and Crohn's disease.

In contrast to UC, the pattern of inflammation in CD is described as discontinuous. Areas of inflammation are intermixed with areas of normal GI mucosa, resulting in characteristic "skip lesions." Superficial aphthous ulcers may also develop in the GI mucosa. These ulcers may coalesce into larger linear ulcers, resulting in fissure formation as they increase in depth, giving rise to the characteristic "cobblestone" pattern observed upon examination of the mucosa.

Furthermore, the inflammation may be transmural, penetrating to the muscularis or serosal layers of the GI tract (Fig. 19-2). The propensity for transmural involvement may lead to serious complications of CD, such as strictures, fistulae, abscesses, and perforation. While rectal inflammation is typically less common in CD than UC, several types of perianal lesions may be observed in patients with CD. These include skin tags, hemorrhoids, fissures, anal ulcers, abscesses, and fistulae.15

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