INFLAMMATORY BOWEL SYNDROME

Inflammatory bowel disease (IBD) is an idiopathic and chronic intestinal inflammation. Ulcerative colitis (UC) and Crohn's disease (CD) are the two major types of IBD.

EPIDEMIOLOGY

The incidence of IBD varies within different geographic areas. Northern countries, such as the United States, United Kingdom, Norway, and Sweden, have the highest rates. The incidence rates of UC and CD in the United States are about 11 per 100,000 and 7 per 100,000, respectively (Table 1). Countries in southern Europe, South Africa, and Australia have lower incidence rates: 2 to 6.3 per 100,000 for UC, and 0.9 to 3.1 per 100,000 for CD. In Asia and South America, IBD is rare; incidence rates of UC and CD are 0.5 and 0.08 per 100,000, respectively. The highest mortality in IBD patients is during the first years of disease and in long-duration disease due to the risk of colon cancer. In a Swedish population study, the standardized mortality ratios for CD and UC were 1.51 and 1.37, respectively.

TABLE 1 Epidemiology of IBD

	Ulcerative Colitis	Crohn's Disease
Incidence (U.S.)	11/100,000	7/100,000
Age of onset	15–30 & 60–80	15–30 & 60–80
Ethnicity	Jewish > Non-Jewish Caucasian > African American > Hispanic > Asian
Male:female ratio	1:1	1.1–1.8:1
Smoking	May prevent disease	May cause disease
Oral contraceptives	No increased risk	Relative risk 1.9
Appendectomy	Protective	Not protective
Monozygotic twins	20% concordance	67% concordance
Dizygotic twins	0% concordance	8% concordance

The peak age of onset of UC and CD is between 15 and 30 years. A second peak occurs between the ages of 60 and 80. The male to female ratio for UC is 1:1 and for CD is 1.1 to 1.8:1. A two- to fourfold increased frequency of UC and CD in Jewish populations has been described in the United States, Europe, and South Africa. Furthermore, disease frequency differs within the Jewish populations. The prevalence of IBD in Ashkenazi Jews is about twice that of Israeli-born, Sephardic, or Oriental Jews. The prevalence decreases progressively in non-Jewish Caucasian, African-American, Hispanic, and Asian populations. Urban areas have a higher prevalence of IBD than rural areas, and high socioeconomic classes have a higher prevalence than lower socioeconomic classes.

The effects of cigarette smoking are different in UC and CD. The risk of UC in smokers is 40% that of nonsmokers. Additionally, former smokers have a 1.7-fold increased risk for UC than people who have never smoked. In contrast, smoking is associated with a twofold increased risk of CD. Oral contraceptives are also linked to CD; the relative risk of CD for oral contraceptive users is about 1.9. Appendectomy appears to be protective against UC, but no studies have applied this as a preventive intervention.

IBD runs in families. If a patient has IBD, the lifetime risk that a first-degree relative will be affected is ~10%. If two parents have IBD, each child has a 36% chance of being affected. In twin studies, 67% of monozygotic twins are concordant for CD and 20% are concordant for UC, whereas 8% of dizygotic twins are concordant for CD and none are concordant for UC. Anatomic site and clinical type of CD is also concordant within families.

Additional evidence for genetic predisposition to IBD comes from its association with certain genetic syndromes. UC and CD are both associated with Turner's syndrome, and Hermansky-Pudlak syndrome is associated with a granulomatous colitis. Glycogen storage disease type 1b can present with Crohn's-like lesions of the large and small bowel. Other immunodeficiency disorders, such as hypogammaglobulinemia, selective IgA deficiency, and hereditary angioedema, also exhibit an increased association with IBD.

ETIOLOGY AND PATHOGENESIS

Although IBD has been described as a clinical entity for over 100 years, its etiology and pathogenesis have not been defined. A consensus hypothesis is that in genetically predisposed individuals, both exogenous factors (e.g., infectious agents, normal lumenal flora) and host factors (e.g., intestinal epithelial cell barrier function, vascular supply, neuronal activity) cause a chronic state of dysregulated mucosal immune function that is further modified by specific environmental factors (e.g., smoking). Although it is possible that the chronic activation of the mucosal immune system may represent an appropriate response to an unidentified infectious agent, a search for such an agent has thus far been unrewarding. As such, IBD is currently considered an inappropriate response to either the endogenous microbial flora within the intestine, with or without some component of autoimmunity. Importantly, the normal intestine contains a large number of immune cells in a chronic state of so-called physiologic inflammation, in which the gut is poised for, but actively restrained from, full immunologic responses. During the course of infections in the normal host, full activation of the gut-associated lymphoid tissue occurs but is rapidly superceded by dampening the immune response and tissue repair. In IBD this process is not regulated normally.

GENETIC CONSIDERATIONS

IBD is a polygenic disorder that gives rise to multiple clinical subgroups within UC and CD. Genome-wide searches have shown potential disease-associated loci on chromosomes 16, 12, 7, 5, 3, and 1, although the specific gene associations are mostly undefined. The disease-related gene on chromosome 16 is NOD-2, an intracellular molecule that senses bacterial peptidoglycan and regulates NF-κB signaling. Homozygosity for mutant alleles confers up to a 40-fold increased risk for fibrostenosing CD, especially in the ileum. HLA alleles may also play a role. UC patients disproportionately express DR2-related alleles, whereas in CD an increased use of the DR5 DQ1 haplotype or the DRB*0301 allele has been described. In UC patients with pancolitis undergoing total proctocolectomy, 14.3% versus 3.2% of non-IBD controls express the HLA DRB1*0103 allele. This allele is associated with extensive disease and extraintestinal manifestations such as mouth ulcers, arthritis, and uveitis. Other associations with immunoregulatory genes include the intercellular adhesion molecule R241 allele in UC and CD and the interleukin (IL) 1 receptor antagonist allele 2 in UC patients that is associated with total colonic inflammation. Patients with IBD and their first-degree relatives may also exhibit diminished intestinal epithelial cell barrier function.

DEFECTIVE IMMUNE REGULATION IN IBD

The normal state of the mucosal immune system is one of inhibited immune responses to lumenal contents due to oral tolerance that occurs in the normal individual. When soluble antigens are administered orally rather than subcutaneously or intramuscularly, antigen-specific non-responsiveness is induced. Multiple mechanisms are involved in the induction of oral tolerance and include deletion or anergy of antigen-reactive T cells or activation of CD4+ T cells that suppress gut inflammation through secretion of inhibitory cytokines, such as IL-10 and transforming growth factor β (TGF-β). Oral tolerance may be responsible for the lack of immune responsiveness to dietary antigens and the commensal flora in the intestinal lumen. In IBD this suppression of inflammation is altered, leading to uncontrolled inflammation. The mechanisms that maintain this regulated immune suppression are unknown.

Gene knockout (-/-) or transgenic (Tg) mouse models of colitis have revealed that deleting specific cytokines (e.g., IL-2, IL-10, TGF-β) or their receptors, deleting molecules associated with T cell antigen recognition (e.g., T cell antigen receptors, MHC class II), or interfering with intestinal epithelial cell barrier function (e.g., blocking N-cadherin, deleting multidrug resistance gene 1a or trefoil factor) leads to colitis. Thus, a variety of specific alterations can lead to autoimmunity directed at the colon in mice.

In both UC and CD, activated CD4+ T cells in the lamina propria and peripheral blood secrete inflammatory cytokines. Some activate other inflammatory cells (macrophages and B cells) and others act indirectly to recruit other lymphocytes, inflammatory leukocytes, and mononuclear cells from the peripheral vasculature into the gut through interactions between homing receptors on leukocytes (e.g., α4β7 integrin) and addressins on vascular endothelium (e.g., MadCAM1). CD4+ T cells are of two major types, both of which may be associated with colitis in animal models and humans: T_H1 cells [interferon (IFN) γ, tumor necrosis factor (TNF)] and T_H2 cells (IL-4, IL-5, IL-13). T_H1 cells appear to induce transmural granulomatous inflammation that resembles CD, and T_H2 cells appear to induce superficial mucosal inflammation resembling UC. The T_H1 cytokine pathway is initiated by IL-12, a key cytokine in the pathogenesis of experimental models of mucosal inflammation. Thus, use of antibodies to block proinflammatory cytokines (e.g., anti-TNF-α, anti-IL-12) or molecules associated with leukocyte recruitment (e.g., anti-α4β7) or use of cytokines that inhibit inflammation (e.g., IL-10) or promote intestinal barrier function (e.g., IL-11) may be beneficial to humans with colitis.

THE INFLAMMATORY CASCADE IN IBD

Once initiated in IBD, the immune inflammatory response is perpetuated as a consequence of T cell activation. A sequential cascade of inflammatory mediators acts to extend the response; each step is a potential target for therapy. Inflammatory cytokines, such as IL-1, IL-6, and TNF, have diverse effects on tissue. They promote fibrogenesis, collagen production, activation of tissue metalloproteinases, and the production of other inflammatory mediators; they also activate the coagulation cascade in local blood vessels (e.g., increased production of von Willebrand's factor). These cytokines are normally produced in response to infection, but are usually turned off or inhibited at the appropriate time to limit tissue damage. In IBD their activity is not regulated, resulting in an imbalance between the proinflammatory and anti-inflammatory mediators. Therapies such as the 5-ASA (5-aminosalicylic acid) compounds are potent inhibitors of these inflammatory mediators through inhibition of transcription factors such as NF-κB that regulate their expression.

EXOGENOUS FACTORS

IBD may have an as yet undefined infectious etiology. Three specific agents have received the greatest attention, Mycobacterium paratuberculosis, Paramyxovirus, and Helicobacter species. The immune response to a specific organism could be expressed differently, depending upon the individual's genetic background. M. paratuberculosis does not have a confirmed disease association, and antimycobacterial agents are not effective in treating CD. A role for the measles virus or paramyxoviruses in the development of CD has been suggested based on an increase in the incidence of CD in England that paralleled use of the measles vaccine. However, studies in the United States have not substantiated this finding. In an animal model of IBD, H. hepaticus has been implicated as a trigger for the inflammatory response; evidence in humans is lacking.

Multiple pathogens (e.g., Salmonella, Shigella sp., Campylobacter sp.) may initiate IBD by triggering an inflammatory response that the mucosal immune system may fail to control. However, in an IBD patient the normal flora is likely perceived as if it were a pathogen. Anaerobic organisms, particularly Bacteroides species, may be responsible for the induction of inflammation. Such a notion is supported by the response in patients with CD to agents that alter the intestinal flora, such as metronidazole, ciprofloxacin, and elemental diets. CD also responds to fecal diversion, demonstrating the ability of lumenal contents to exacerbate disease. On the other hand, other bacteria, so-called probiotics (Lactobacillus sp.), inhibit inflammation in animal models and humans.

Psychosocial factors can contribute to worsening of symptoms. Major life events such as illness or death in the family, divorce or separation, interpersonal conflict, or other major loss are associated with an increase in IBD symptoms such as pain, bowel dysfunction, and bleeding. Acute daily stress can worsen bowel symptoms even after controlling for major life events. When the sickness-impact profile, a measurement of overall psychological and physical functioning, is used, IBD patients have functional impairment greater than that of a normal population but less than that of patients with chronic back pain or amyotrophic lateral sclerosis. IBD patients have been hypothesized to have a characteristic personality that renders them susceptible to emotional stresses. However, emotional dysfunction could also be the result of chronic illness rather than a cause.

PATHOLOGY

ULCERATIVE COLITIS: MACROSCOPIC FEATURES

UC is a mucosal disease that usually involves the rectum and extends proximally to involve all or part of the colon. About 40 to 50% of patients have disease limited to the rectum and rectosigmoid, 30 to 40% have disease extending beyond the sigmoid but not involving the whole colon, and 20% have a total colitis. Proximal spread occurs in continuity without areas of uninvolved mucosa. When the whole colon is involved, the inflammation extends 1 to 2 cm into the terminal ileum in 10 to 20% of patients. This is called backwash ileitis and is of little clinical significance. Although variations in macroscopic activity may suggest skip areas, biopsies from normal-appearing mucosa are usually abnormal. Thus, it is important to obtain multiple biopsies from apparently uninvolved mucosa, whether proximal or distal, during endoscopy.

With mild inflammation, the mucosa is erythematous and has a fine granular surface that looks like sandpaper. In more severe disease, the mucosa is hemorrhagic, edematous, and ulcerated (Fig. 1). In long-standing disease, inflammatory polyps (pseudopolyps) may be present as a result of epithelial regeneration. The mucosa may appear normal in remission, but in patients with many years of disease it appears atrophic and featureless and the entire colon becomes narrowed and shortened. Patients with fulminant disease can develop a toxic colitis or megacolon where the bowel wall thins and the mucosa is severely ulcerated; this may lead to perforation.

FIGURE 1 Pan-ulcerative colitis. Mucosa has a lumpy, bumpy appearance because of areas of inflamed but intact mucosa separated by ulcerated areas. (Courtesy of Dr. EK Rosado and Dr. CA Perkos, Division of Gastrointestinal Pathology, Department of Pathology, Emory University, Atlanta, Georgia.)

ULCERATIVE COLITIS: MICROSCOPIC FEATURES

Histologic findings correlate well with the endoscopic appearance and clinical course of UC. The process is limited to the mucosa and superficial submucosa, with deeper layers unaffected except in fulminant disease. In UC, two major histologic features are indicative of chronicity and help distinguish it from infectious or acute self-limited colitis. First, the crypt architecture of the colon is distorted; crypts may be bifid and reduced in number, often with a gap between the crypt bases and the muscularis mucosae. Second, some patients have basal plasma cells and multiple basal lymphoid aggregates. Mucosal vascular congestion with edema and focal hemorrhage, and an inflammatory cell infiltrate of neutrophils, lymphocytes, plasma cells, and macrophages may be present. The neutrophils invade the epithelium, usually in the crypts, and give rise to cryptitis and, ultimately, to crypt abscesses (Fig. 2).

FIGURE 2 Characteristic findings of IBD in a case of ulcerative colitis: crypt distortion, cryptitis, and crypt abscess. (Courtesy of Dr. EK Rosado and Dr. CA Perkos, Division of Gastrointestinal Pathology, Department of Pathology, Emory University, Atlanta, Georgia.)

CROHN'S DISEASE: MACROSCOPIC FEATURES

CD can affect any part of the gastrointestinal tract from the mouth to the anus. Some 30 to 40% of patients have small-bowel disease alone, 40 to 55% have disease involving both the small and large intestines, and 15 to 25% have colitis alone. In the 75% of patients with small-intestinal disease, the terminal ileum is involved in 90%. Unlike UC, which almost always involves the rectum, the rectum is often spared in CD. CD is segmental, with skip areas in the midst of diseased intestine (Fig. 3). Perirectal fistulas, fissures, abscesses, and anal stenosis are present in one-third of patients with CD, particularly those with colonic involvement. CD may also involve the liver and the pancreas.

FIGURE 3 Portion of colon with stricture in patient with CD. (Courtesy of Dr. EK Rosado and Dr. CA Perkos, Division of Gastrointestinal Pathology, Department of Pathology, Emory University, Atlanta, Georgia.)

Unlike UC, CD is a transmural process. Endoscopically, aphthous or small superficial ulcerations characterize mild disease; in more active disease, stellate ulcerations fuse longitudinally and transversely to demarcate islands of mucosa that frequently are histologically normal. This “cobblestone” appearance is characteristic of CD, both endoscopically and by barium radiography. As in UC, pseudopolyps can form in CD.

Active CD is characterized by focal inflammation and formation of fistula tracts, which resolve by fibrosis and stricturing of the bowel. The bowel wall thickens and becomes narrowed and fibrotic, leading to chronic, recurrent bowel obstructions. Projections of thickened mesentery encase the bowel (“creeping fat”), and serosal and mesenteric inflammation promote adhesions and fistula formation.

CROHN'S DISEASE: MICROSCOPIC FEATURES

The earliest lesions are aphthoid ulcerations and focal crypt abscesses with loose aggregations of macrophages, which form noncaseating granulomas in all layers of the bowel wall from mucosa to serosa (Fig. 4). Granulomas can be seen in lymph nodes, mesentery, peritoneum, liver, and pancreas. Although granulomas are a pathognomonic feature of CD, they are rarely found on mucosal biopsies. Surgical resection reveals granulomas in about half of cases. Other histologic features of CD include submucosal or subserosal lymphoid aggregates, particularly away from areas of ulceration, gross and microscopic skip areas, and transmural inflammation that is accompanied by fissures that penetrate deeply into the bowel wall and sometimes form fistulous tracts or local abscesses.

FIGURE 4 Granulomas (arrow) in bowel wall and serosa of colon, CD. (Courtesy of Dr. EK Rosado and Dr. CA Perkos, Division of Gastrointestinal Pathology, Department of Pathology, Emory University, Atlanta, Georgia.)

CLINICAL PRESENTATION

ULCERATIVE COLITIS

Signs and Symptoms

The major symptoms of UC are diarrhea, rectal bleeding, tenesmus, passage of mucus, and crampy abdominal pain. The severity of symptoms correlates with the extent of disease. Although UC can present acutely, symptoms usually have been present for weeks to months. Occasionally, diarrhea and bleeding are so intermittent and mild that the patient does not seek medical attention.

Patients with proctitis usually pass fresh blood or blood-stained mucus, either mixed with stool or streaked onto the surface of a normal or hard stool. They also have tenesmus, or urgency with a feeling of incomplete evacuation. They rarely have abdominal pain. With proctitis or proctosigmoiditis, proximal transit slows, which may account for the constipation that is commonly seen in patients with distal disease.

When the disease extends beyond the rectum, blood is usually mixed with stool or grossly bloody diarrhea may be noted. Colonic motility is altered by inflammation with rapid transit through the inflamed intestine. When the disease is severe, patients pass a liquid stool containing blood, pus, and fecal matter. Diarrhea is often nocturnal and/or postprandial. Although severe pain is not a prominent symptom, some patients with active disease may experience vague lower abdominal discomfort or mild central abdominal cramping. Severe cramping and abdominal pain can occur in association with severe attacks of the disease. Other symptoms in moderate to severe disease include anorexia, nausea, vomiting, fever, and weight loss.

Physical signs of proctitis include a tender anal canal and blood on rectal examination. With more extensive disease, patients have tenderness to palpation directly over the colon. Patients with a toxic colitis have severe pain and bleeding, and those with megacolon have hepatic tympany. Both may have signs of peritonitis if a perforation has occurred. The classification of disease activity is shown in Table 2.

TABLE 2 Ulcerative Colitis: Disease Presentation

	Mild	Moderate	Severe
Bowel movements	<4 per day	4–6 per day	>6 per day
Blood in stool	Small	Moderate	Severe
Fever	None	<37.5°C mean	>37.5°C mean
Tachycardia	None	<90 mean pulse	>90 mean pulse
Anemia	Mild	>75%	≤75%
Sedimentation rate	<30 mm		>30 mm
Endoscopic appearance	Erythema, decreased vascular pattern, fine granularity	Marked erythema, coarse granularity, absent vascular markings, contact bleeding, no ulcerations	Spontaneous bleeding, ulcerations

LABORATORY, ENDOSCOPIC, AND RADIOGRAPHIC FEATURES

Active disease can be associated with a rise in acute-phase reactants (C-reactive protein, orosomucoid levels), platelet count, erythrocyte sedimentation rate (ESR), and a decrease in hemoglobin. In severely ill patients, the serum albumin level will fall rather quickly. Leukocytosis may be present but is not a specific indicator of disease activity. Proctitis or proctosigmoiditis rarely causes a rise in C-reactive protein. Diagnosis relies upon the patient's history; clinical symptoms, negative stool examination for bacteria, Clostridium difficile toxin, and ova and parasites; sigmoidoscopic appearance (see Fig. 18); and histology of rectal or colonic biopsy specimens.

Sigmoidoscopy is used to assess disease activity and is often performed before treatment. If the patient is not having an acute flare, colonoscopy is used to assess disease extent and activity. Histologic features change more slowly than clinical features but can also be used to grade disease activity.

FIGURE 5 Barium enema in a patient with acute ulcerative colitis: inflammation of the entire colon. (Courtesy of Dr. JM Braver, Gastrointestinal Radiology, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.)

Patients with a severe attack of UC should have a plain, supine film of the abdomen. In the presence of severe disease, the margin of the colon becomes edematous and irregular. Colon thickening and toxic dilation can both be seen on a plain radiograph.

The earliest radiologic change of UC seen on single-contrast barium enema is a fine mucosal granularity (Fig. 5). With increasing severity, the mucosa becomes thickened and superficial ulcers are seen. Deep ulcerations can appear as “collar-button” ulcers, which indicate that the ulceration has penetrated the mucosa. Haustral folds may be normal in mild disease, but as activity progresses they become edematous and thickened. Loss of haustration can occur, especially in patients with long-standing disease. In addition, the colon becomes shortened and narrowed. Polyps in the colon may be postinflammatory polyps or pseudopolyps, adenomatous polyps, or carcinoma.

Computed tomography (CT) scanning is not as helpful as endoscopy and barium enema in making the diagnosis of UC, but typical findings include mild mural thickening (<1.5 cm), inhomogeneous, increased perirectal and presacral fat, target appearance of the rectum, and adenopathy.

COMPLICATIONS

Only 15% of patients with UC present initially with catastrophic illness. Massive hemorrhage occurs with severe attacks of disease in 1% of patients, and treatment for the disease usually stops the bleeding. However, if a patient requires 6 to 8 units of blood within 24 to 48 h, colectomy is indicated. Toxic megacolon is defined as a transverse colon with a diameter of >5 to 6 cm, with loss of haustration in patients with severe attacks of UC. It occurs in about 5% of attacks and can be triggered by electrolyte abnormalities and narcotics. About 50% of acute dilations will resolve with medical therapy alone, but urgent colectomy is required for those that do not improve. Perforation is the most dangerous of the local complications, and the physical signs of peritonitis may not be obvious, especially if the patient is receiving glucocorticoids. Although perforation is rare, the mortality rate for perforation complicating a toxic megacolon is about 15%. In addition, patients can develop a toxic colitis and such severe ulcerations that the bowel may perforate without first dilating.

Obstructions caused by benign stricture formation occur in 10% of patients, with one-third of the strictures occurring in the rectum. These should be surveyed endoscopically for carcinoma. UC patients occasionally develop anal fissures, perianal abscesses, or hemorrhoids, but the occurrence of extensive perianal lesions should suggest CD.

CROHN'S DISEASE

Signs and Symptoms

Although CD usually presents as acute or chronic bowel inflammation, the inflammatory process evolves toward one of two patterns of disease: a fibrostenotic-obstructing pattern or a penetrating-fistulous pattern, each with different treatments and prognoses. The site of disease influences the clinical manifestations.

ILEOCOLITIS

Because the most common site of inflammation is the terminal ileum, the usual presentation of ileocolitis is a chronic history of recurrent episodes of right lower quadrant pain and diarrhea. Sometimes the initial presentation mimics acute appendicitis with pronounced right lower quadrant pain, a palpable mass, fever, and leukocytosis. Pain is usually colicky; it precedes and is relieved by defecation. A low-grade fever is usually noted. High-spiking fever suggests intraabdominal abscess formation. Weight loss is common—typically 10 to 20% of body weight—and develops as a consequence of diarrhea, anorexia, and fear of eating.

An inflammatory mass may be palpated in the right lower quadrant of the abdomen. The mass is composed of inflamed bowel, adherent and indurated mesentery, and enlarged abdominal lymph nodes. Extension of the mass can cause obstruction of the right ureter or bladder inflammation, manifested by dysuria and fever. Edema, bowel wall thickening, and fibrosis of the bowel wall within the mass account for the radiographic “string sign” of a narrowed intestinal lumen.

Bowel obstruction may take several forms. In the early stages of disease, bowel wall edema and spasm produce intermittent obstructive manifestations and increasing symptoms of postprandial pain. Over several years, persistent inflammation gradually progresses to fibrostenotic narrowing and stricture. Diarrhea will decrease and be replaced by chronic bowel obstruction. Acute episodes of obstruction occur as well, precipitated by bowel inflammation and spasm or sometimes by impaction of undigested food or medication. These episodes usually resolve with intravenous fluids and gastric decompression.

Severe inflammation of the ileocecal region may lead to localized wall thinning, with microperforation and fistula formation to the adjacent bowel, the skin, the urinary bladder, or to an abscess cavity in the mesentery. Enterovesical fistulas typically present as dysuria or recurrent bladder infections or less commonly as pneumaturia or fecaluria. Enterocutaneous fistulas follow tissue planes of least resistance, usually draining through abdominal surgical scars. Enterovaginal fistulas are rare and present as dyspareunia or as a feculent or foul-smelling, often painful vaginal discharge. They are unlikely to develop without a prior hysterectomy.

JEJUNOILEITIS

Extensive inflammatory disease is associated with a loss of digestive and absorptive surface, resulting in malabsorption and steatorrhea. Nutritional deficiencies can also result from poor intake and enteric losses of protein and other nutrients. Intestinal malabsorption can cause hypoalbuminemia, hypocalcemia, hypomagnesemia, coagulopathy, and hyperoxaluria with nephrolithiasis. Vertebral fractures are caused by a combination of vitamin D deficiency, hypocalcemia, and prolonged glucocorticoid use. Pellagra from niacin deficiency can occur in extensive small-bowel disease, and malabsorption of vitamin B₁₂ can lead to a megaloblastic anemia and neurologic symptoms.

Diarrhea is characteristic of active disease; its causes include: (1) bacterial overgrowth in obstructive stasis or fistulization, (2) bile-acid malabsorption due to a diseased or resected terminal ileum, and (3) intestinal inflammation with decreased water absorption and increased secretion of electrolytes.

COLITIS AND PERIANAL DISEASE

Patients with colitis present with low-grade fevers, malaise, diarrhea, crampy abdominal pain, and sometimes hematochezia. Gross bleeding is not as common as in UC and appears in about half of patients with exclusively colonic disease. Only 1 to 2% bleed massively. Pain is caused by passage of fecal material through narrowed and inflamed segments of large bowel. Decreased rectal compliance is another cause for diarrhea in Crohn's colitis patients. Toxic megacolon is rare but may be seen with severe inflammation and short-duration disease.

Stricturing can occur in the colon and produce symptoms of bowel obstruction. Also, colonic disease may fistulize into the stomach or duodenum, causing feculent vomiting, or to the proximal or mid small bowel, causing malabsorption by “short circuiting” and bacterial overgrowth. Ten percent of women with Crohn's colitis will develop a rectovaginal fistula.

Perianal disease affects about one-third of patients with Crohn's colitis and is manifested by incontinence, large hemorrhoidal tags, anal strictures, anorectal fistulae, and perirectal abscesses. Not all patients with perianal fistula will have endoscopic evidence of colonic inflammation.

GASTRODUODENAL DISEASE

Symptoms and signs of upper gastrointestinal tract disease include nausea, vomiting, and epigastric pain. Patients usually have a H. pylori –negative gastritis. The second portion of the duodenum is more commonly involved than the bulb. Fistulas involving the stomach or duodenum arise from the small or large bowel and do not necessarily signify the presence of upper gastrointestinal tract involvement. Patients with advanced gastroduodenal CD may develop a chronic gastric outlet obstruction.

Laboratory, Endoscopic, and Radiographic Features

Laboratory abnormalities include elevated ESR and C-reactive protein. In more severe disease, findings include hypoalbuminemia, anemia, and leukocytosis.

Endoscopic features of CD include rectal sparing, aphthous ulcerations, fistulas, and skip lesions. Endoscopy is useful for biopsy of mass lesions or strictures, or for visualization of filling defects seen on barium enema. Colonoscopy allows examination and biopsy of the terminal ileum, and upper endoscopy is useful in diagnosing gastroduodenal involvement in patients with upper tract symptoms. Ileal or colonic strictures may be dilated with balloons introduced through the colonoscope. Endoscopic appearance correlates poorly with clinical remission; thus, repeated endoscopy is not used to monitor the inflammation.

In CD early radiographic findings in the small bowel include thickened folds and aphthous ulcerations. “Cobblestoning” from longitudinal and transverse ulcerations most frequently involves the small bowel (Fig. 6). In more advanced disease, strictures, fistulas (Fig. 7), inflammatory masses, and abscesses may be detected. The earliest macroscopic findings of colonic CD are aphthous ulcers. These small ulcers are often multiple and separated by normal intervening mucosa. As disease progresses, aphthous ulcers become enlarged, deeper, and occasionally connected to one another, forming longitudinal stellate, serpiginous, and linear ulcers (see Fig. 17).

FIGURE 6 Crohn's disease: small bowel series demonstrating “cobblestoning” of the terminal ileum (arrows). (Courtesy of Dr. JM Braver, Gastrointestinal Radiology, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.)
FIGURE 7 Small bowel series demonstrating distal ileal inflammation and fistulization (arrows) in a patient with CD. (Courtesy of Dr. JM Braver, Gastrointestinal Radiology, Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts.)

The transmural inflammation of CD leads to decreased luminal diameter and limited distensibility. As ulcers progress deeper, they can lead to fistula formation. The radiographic “string sign” represents long areas of circumferential inflammation and fibrosis, resulting in long segments of luminal narrowing. The segmental nature of CD results in wide gaps of normal or dilated bowel between involved segments.

CT findings include mural thickening >2 cm, homogeneous wall density, mural thickening of small bowel, mesenteric fat stranding, perianal disease, and adenopathy. CT scanning can help identify abscesses, fistulas, and sinus tracts. Magnetic resonance imaging (MRI) may prove superior for demonstrating pelvic lesions such as ischiorectal abscesses.

Complications

Because CD is a transmural process, serosal adhesions develop that provide direct pathways for fistula formation and reduce the incidence of free perforation. Free perforation occurs in 1 to 2% of patients, usually in the ileum but occasionally in the jejunum or as a complication of toxic megacolon. The peritonitis of free perforation, especially colonic, may be fatal. Generalized peritonitis may also result from the rupture of an intraabdominal abscess. Other complications include intestinal obstruction in 40%, massive hemorrhage, malabsorption, and severe perianal disease.

Serologic Markers

Several serologic markers may be used to differentiate between CD and UC and help to predict the course of disease. Two antibodies that can be detected in the serum of IBD patients are perinuclear antineutrophil cytoplasmic antibodies (pANCAs) and anti-Saccharomyces cerevisiae antibodies (ASCAs). A distinct set of antineutrophil cytoplasmic antibodies with perinuclear staining by indirect immunofluorescence is associated with UC. The antigens to which these antibodies are directed have not been identified, but they are distinct from those associated with vasculitis and may be a marker for reactivity to enteric bacteria. pANCA positivity is found in about 60 to 70% of UC patients and 5 to 10% of CD patients; 5 to 15% of first-degree relatives of UC patients are pANCA positive, whereas only 2 to 3% of the general population is pANCA positive. pANCA may also identify specific disease phenotypes. pANCA positivity is more often associated with pancolitis, early surgery, pouchitis, or inflammation of the pouch after ileal pouch–anal anastamosis (IPAA) and primary sclerosing cholangitis. pANCA in CD is associated with colonic disease that resembles UC.

ASCA antibodies recognize mannose sequences in the cell wall mannan of S. cerevisiae; 60 to 70% of CD patients, 10 to 15% of UC patients, and up to 5% of non-IBD controls are ASCA positive. About 55% of CD patients are seroreactive to outer-membrane porin C (OMPC), a bacterial antigen. The combined measurement of pANCA and ASCA has been advocated as a valuable diagnostic approach to IBD. In one report, pANCA+ with ASCA- results showed a 57% sensitivity and 97% specificity for UC, whereas pANCA- with ASCA+ results showed a 49% sensitivity and 97% specificity for CD. ASCA was associated with small-bowel CD. These antibody tests may help decide whether a patient with indeterminate colitis should undergo an IPAA, because patients with predominant features of CD often have a more difficult postoperative course.

Other serologic markers in IBD patients include anti-goblet cell autoantibodies, pancreatic autoantibodies, and an autoantibody against tropomyosin isoform 5 found in colon epithelial cells. Antibodies to red cell membrane antigens that cross-react with enteropathogens such as Campylobacter sp. may be associated with hemolytic anemia in CD. None of these antibodies are useful in the diagnosis and management of patients with IBD.

DIFFERENTIAL DIAGNOSIS OF UC AND CD

UC and CD have similar features to many other diseases. In the absence of a key diagnostic test, a combination of clinical, laboratory, histopathologic, radiographic, and therapeutic observations is required (Table 3). Once a diagnosis of IBD is made, distinguishing between UC and CD is impossible in 10 to 15% of cases. These are termed indeterminate colitis.

TABLE 3 Different Clinical, Endoscopic, and Radiographic Features

	Ulcerative Colitis	Crohn's Disease
CLINICAL
Gross blood in stool	Yes	Occasionally
Mucus	Yes	Occasionally
Systemic symptoms	Occasionally	Frequently
Pain	Occasionally	Frequently
Abdominal mass	Rarely	Yes
Significant perineal disease	No	Frequently
Fistulas	No	Yes
Small-intestinal obstruction	No	Frequently
Colonic obstruction	Rarely	Frequently
Response to antibiotics	No	Yes
Recurrence after surgery	No	Yes
ANCA-positive	Frequently	Rarely
ASCA-positive	Rarely	Frequently
ENDOSCOPIC
Rectal sparing	Rarely	Frequently
Continuous disease	Yes	Occasionally
“Cobblestoning”	No	Yes
Granuloma on biopsy	No	Occasionally
RADIOGRAPHIC
Small bowel significantly abnormal	No	Yes
Abnormal terminal ileum	Occasionally	Yes
Segmental colitis	No	Yes
Asymmetric colitis	No	Yes
Stricture	Occasionally	Frequently
Note: ANCA, antineutrophil cytoplasm antibody; ASCA, anti-Saccharomyces cerevisiae antibody.

INFECTIOUS DISEASE

Infections of the small intestines and colon can mimic CD or UC. They may be bacterial, fungal, viral, or protozoal in origin (Table 4). Campylobacter colitis can mimic the endoscopic appearance of severe UC and can cause a relapse of established UC. Salmonella can cause watery or bloody diarrhea, nausea, and vomiting. Shigellosis causes watery diarrhea, abdominal pain, and fever followed by rectal tenesmus and by the passage of blood and mucus per rectum. All three are usually self-limited, but 1% of patients infected with Salmonella become asymptomatic carriers.        

Yersinia enterocolitica infection occurs mainly in the terminal ileum and causes mucosal ulceration, neutrophil invasion, and thickening of the ileal wall. Other bacterial infections that may mimic IBD include C. difficile, which presents with watery diarrhea, tenesmus, nausea, and vomiting; and Escherichia coli, three categories of which can cause colitis. These are enterohemorrhagic, enteroinvasive, and enteroadherent E. coli, all of which can cause bloody diarrhea and abdominal tenderness. Diagnosis of bacterial colitis is made by sending stool specimens for bacterial culture and C. difficile toxin analysis. Gonorrhea, Chlamydia, and syphilis can also cause proctitis.

Although most of the patients with viral colitis are immunosuppressed, cytomegalovirus (CMV) and herpes simplex proctitis may occur in immunocompetent individuals. CMV occurs most commonly in the esophagus, colon, and rectum but may also involve the small intestine. Symptoms include abdominal pain, bloody diarrhea, fever, and weight loss. With severe disease, necrosis and perforation can occur. Diagnosis is made by identification of intranuclear inclusions in mucosal cells on biopsy. Herpes simplex infection of the gastrointestinal tract is limited to the oropharynx, anorectum, and perianal areas. Symptoms include anorectal pain, tenesmus, constipation, inguinal adenopathy, difficulty with urinary voiding, and sacral paresthesias. Diagnosis is made by rectal biopsy. HIV itself can cause diarrhea, nausea, vomiting, and anorexia. Small-intestinal biopsies show partial villus atrophy; small-bowel bacterial overgrowth and fat malabsorption may also be noted.

TABLE 4 Diseases that Mimic IBD

Infectious Etiologies
Bacterial   Salmonella   Shigella   Toxigenic Escherichia coli   Campylobacter   Yersinia   Clostridium difficile   Gonorrhea   Chlamydia trachomatis	Mycobacterial   Tuberculosis   Mycobacterium avium Parasitic   Amebiasis   Isospora   Trichuris trichura   Hookworm   Strongyloides	Viral   Cytomegalovirus   Herpes simplex   HIV Fungal   Histoplasmosis   Candida   Aspergillus
NONINFECTIOUS ETIOLOGIES
Inflammatory   Appendicitis   Diverticulitis   Diversion colitis   Collagenous/lymphocytic colitis   Ischemic colitis   Radiation colitis/enteritis   Solitary rectal ulcer   Eosinophilc gastroenteritis   Neutropenic colitis   Beçhet's syndrome   Graft-versus-host disease	Neoplastic   Lymphoma   Metastatic carcinoma   Carcinoma of the ileum   Carcinoid   Familial polyposis	Drugs and Chemicals   NSAIDs   Phosphasoda   Cathartic colon   Gold   Oral contraceptives   Cocaine   Chemotherapy
Note: NSAIDs, nonsteroidal anti-inflammatory drugs.

Protozoan parasites include Isospora belli, which can cause a self-limited infection in healthy hosts but causes a chronic profuse, watery diarrhea and weight loss in AIDS patients. Entamoeba histolytica or related species infect about 10% of the world's population; symptoms include abdominal pain, tenesmus, frequent loose stools containing blood and mucus, and abdominal tenderness. Colonoscopy reveals focal punctate ulcers with normal intervening mucosa; diagnosis is made by biopsy or serum amebic antibodies. Fulminant amebic colitis is rare but has a mortality rate of >50%.

Other parasitic infections that may mimic IBD include hookworm (Necator americanus), whipworm (Trichuris trichiura), and Strongyloides stercoralis. In severely immunocompromised patients Candida or Aspergillus can be identified in the submucosa. Disseminated histoplasmosis can involve the ileocecal area.

NONINFECTIOUS DISEASE

Many diseases may mimic IBD (Table 4). Diverticulitis can be confused with CD clinically and radiographically. Both diseases cause fever, abdominal pain, tender abdominal mass, leukocytosis, elevated ESR, partial obstruction, and fistulas. Perianal disease or ileitis on small-bowel series favors the diagnosis of CD. Significant endoscopic mucosal abnormalities are more likely in CD than in diverticulitis. Endoscopic or clinical recurrence following segmental resection favors CD. Diverticular-associated colitis is similar to CD, but mucosal abnormalities are limited to the sigmoid and descending colon.

Ischemic colitis is commonly confused with IBD. The ischemic process can be chronic and diffuse as in UC, or segmental as in CD. Colonic inflammation due to ischemia may resolve quickly or may persist and result in transmural scarring and stricture formation. Ischemic bowel disease should be considered in the elderly following abdominal aortic aneurysm repair or when a patient has a hypercoagulable state or a severe cardiac or peripheral vascular disorder. Patients usually present with sudden onset of left lower quadrant pain, urgency to defecate, and the passage of bright red blood per rectum. Endoscopic examination often demonstrates a normal-appearing rectum and a sharp transition to an area of inflammation in the descending colon and splenic flexure.

The effects of radiation therapy on the gastrointestinal tract can be difficult to distinguish from IBD. Acute symptoms can occur within 1 to 2 weeks of starting radiotherapy. When the rectum and sigmoid are irradiated, patients develop bloody, mucoid diarrhea and tenesmus, as in distal UC. With small-bowel involvement, diarrhea is common. Late symptoms include malabsorption and weight loss. Stricturing with obstruction and bacterial overgrowth may occur. Fistulas can penetrate the bladder, vagina, or abdominal wall. Flexible sigmoidoscopy reveals mucosal granularity, friability, numerous telangiectasias, and occasionally discrete ulcerations. Biopsy can be diagnostic.

Solitary rectal ulcer syndrome is uncommon and can be confused with IBD. It occurs in persons of all ages and may be caused by impaired evacuation and failure of relaxation of the puborectalis muscle. Ulceration may arise from anal sphincter overactivity, higher intrarectal pressures during defecation, and digital removal of stool. Patients complain of constipation with straining and pass blood and mucus per rectum. Other symptoms include abdominal pain, diarrhea, tenesmus, and perineal pain. The ulceration, which can be as large as 5 cm in diameter, is usually seen anteriorly or anteriorlaterally 3 to 15 cm from the anal verge. Biopsies can be diagnostic.

Several types of colitis have been associated with nonsteroidal anti-inflammatory drugs (NSAIDs), including de novo colitis, reactivation of IBD, and proctitis caused by use of suppositories. Most patients with NSAID-related colitis present with diarrhea and abdominal pain and complications include stricture, bleeding, obstruction, perforation, and fistulization. Withdrawal of these agents is crucial, and in cases of reactivated IBD, standard therapies are indicated.

INDETERMINATE COLITIS

Cases of IBD that cannot be categorized as UC or CD are called indeterminate colitis. Long-term follow-up reduces the number of cases labeled indeterminate to about 10%. The disease course of indeterminate colitis is unclear and surgical recommendations are difficult, especially since up to 20% of pouches fail, requiring ileosotomy. A multistage IPAA (the initial stage consisting of a subtotal colectomy with Hartmann pouch) with careful histologic evaluation of the resected specimen to exclude CD is advised. Medical therapy is similar to that for UC and CD; most clinicians use 5-ASA drugs, glucocorticoids, and immunomodulators as necessary.

THE ATYPICAL COLITIDIES

Two atypical colitides—collagenous colitis and lymphocytic colitis—have completely normal endoscopic appearances. Collagenous colitis has two main histologic components: increased subepithelial collagen deposition and colitis with increased intraepithelial lymphocytes. Female to male ratio is 9:1, and most patients present in the sixth or seventh decades of life. The main symptom is chronic watery diarrhea. Treatments range from sulfasalazine or mesalamine and Lomotil to bismuth to glucocorticoids for refractory disease.

Lymphocytic colitis has features similar to collagenous colitis including age at onset and clinical presentation, but it has almost equal incidence in men and women and no subepithelial collagen deposition on pathologic section. However, intraepithelial lymphocytes are increased. Diarrhea stops in most patients treated with 5-ASA or prednisone.

Diversion colitis is an inflammatory process that arises in segments of the large intestine that are excluded from the fecal stream. It usually occurs in patients with ileostomy or colostomy when a mucus fistula or a Hartmann's pouch has been created. Diversion colitis is reversible by surgical reanastamosis. Clinically, patients have mucus or bloody discharge from the rectum. Erythema, granularity, friability, and, in more severe cases, ulceration can be seen on endoscopy. Histopathology shows areas of active inflammation with foci of cryptitis and crypt abscesses. Crypt architecture is normal and this differentiates it from UC. It may be impossible to distinguish it from CD. Short-chain fatty acid enemas will help in diversion colitis, but the definitive therapy is surgical reanastamosis.

EXTRAINTESTINAL MANIFESTATIONS

IBD is associated with a variety of extraintestinal manifestations; up to one-third of patients have at least one. Patients with perianal CD are at higher risk for developing extraintestinal manifestations than other IBD patients.

DERMATOLOGIC

Erythema nodosum (EN) occurs in up to 15% of CD patients and 10% of UC patients. Attacks usually correlate with bowel activity; skin lesions develop after the onset of bowel symptoms, and patients frequently have concomitant active peripheral arthritis. The lesions of EN are hot, red, tender nodules measuring 1 to 5 cm in diameter and are found on the anterior surface of the lower legs, ankles, calves, thighs, and arms. Therapy is directed toward the underlying bowel disease.

Pyoderma gangrenosum (PG) is seen in 1 to 12% of UC patients and less commonly in Crohn's colitis. Although it usually presents after the diagnosis of IBD, PG may occur years before the onset of bowel symptoms, run a course independent of the bowel disease, respond poorly to colectomy, and even develop years after proctocolectomy. It is usually associated with severe disease. Lesions are commonly found on the dorsal surface of the feet and legs but may occur on the arms, chest, stoma, and even the face. PG usually begins as a pustule and then spreads concentrically to rapidly undermine healthy skin. Lesions then ulcerate, with violaceous edges surrounded by a margin of erythema. Centrally, they contain necrotic tissue with blood and exudates. Lesions may be single or multiple and grow as large as 30 cm. They are sometimes very difficult to treat and often require intravenous antibiotics, intravenous glucocorticoids, dapsone, azathioprine, thalidomide, intravenous cyclosporine, or infliximab.

Other dermatologic manifestations include pyoderma vegetans that occurs in intertriginous areas, pyostomatitis vegetans that involves the mucous membranes, Sweet's syndrome, a neutrophilic dermatosis, and metastatic CD, a rare disorder defined by cutaneous granuloma formation. Psoriasis affects 5 to 10% of patients with IBD and is unrelated to bowel activity. Perianal skin tags are found in 75 to 80% of patients with CD, especially those with colon involvement. Oral mucosal lesions are seen often in CD and rarely in UC and include aphthous stomatitis and “cobblestone” lesions of the buccal mucosa.

RHEUMATOLOGIC

Peripheral arthritis develops in 15 to 20% of IBD patients, is more common in CD, and worsens with exacerbations of bowel activity. It is asymmetric, polyarticular, and migratory and most often affects large joints of the upper and lower extremities. Treatment is directed at reducing bowel inflammation. In severe UC, colectomy frequently cures the arthritis.

Ankylosing spondylitis (AS) occurs in about 10% of IBD patients and is more common in CD than UC. About two-thirds of IBD patients with AS test positive for the HLA-B27 antigen. The activity of AS is not related to bowel activity and does not remit with glucocorticoids or colectomy. It most often affects the spine and pelvis, producing symptoms of diffuse low-back pain, buttock pain, and morning stiffness. The course is continuous and progressive, leading to permanent skeletal damage and deformity.

Sacroiliitis is symmetric, occurs equally in UC and CD, is often asymptomatic, does not correlate with bowel activity, and does not always progress to AS. Other rheumatic manifestations include hypertrophic osteoarthropathy, pelvic/femoral osteomyelitis, and relapsing polychondritis.

OCULAR

The incidence of ocular complications in IBD patients is 1 to 10%. The most common are conjunctivitis, anterior uveitis/iritis, and episcleritis. Uveitis is associated with both UC and Crohn's colitis, may be found during periods of remission, and may develop in patients following bowel resection. Symptoms include ocular pain, photophobia, blurred vision, and headache. Prompt intervention, sometimes with systemic glucocorticoids, is required to prevent scarring and visual impairment. Episcleritis is a benign disorder that presents with symptoms of mild ocular burning. It occurs in 3 to 4% of IBD patients, more commonly in Crohn's colitis, and is treated with topical glucocorticoids.

HEPATOBILIARY

Hepatic steatosis is detectable in about half of the abnormal liver biopsies from patients with CD and UC; patients usually present with hepatomegaly. Fatty liver usually results from a combination of chronic debilitating illness, malnutrition, and glucocorticoid therapy. Cholelithiasis is more common in CD than UC and occurs in 10 to 35% of patients with ileitis or ileal resection. Gallstone formation is caused by malabsorption of bile acids resulting in depletion of the bile salt pool and the secretion of lithogenic bile.

Primary sclerosing cholangitis (PSC) is characterized by both intrahepatic and extrahepatic bile duct inflammation and fibrosis, frequently leading to biliary cirrhosis and hepatic failure; 1 to 5% of patients with IBD have PSC, but 50 to 75% of patients with PSC have IBD. Although it can be recognized after the diagnosis of IBD, PSC can be detected earlier or even years after proctocolectomy. Most patients have no symptoms at the time of diagnosis; when symptoms are present they consist of fatigue, jaundice, abdominal pain, fever, anorexia, and malaise. Diagnosis is made by endoscopic retrograde cholangiopancreatography (ERCP), which demonstrates multiple bile duct strictures alternating with relatively normal segments. The bile acid ursodeoxycholic acid (ursodiol) may reduce alkaline phosphatase and serum aminotransferase levels, but histologic improvement has been marginal. High doses (25 to 30 mg/kg per day) may have long-term benefit. Endoscopic stenting may be palliative for cholestasis secondary to bile duct obstruction. Patients with symptomatic disease develop cirrhosis and liver failure over 5 to 10 years and eventually require liver transplantation. Ten percent of PSC patients develop cholangiocarcinoma and cannot be transplanted. Pericholangitis is a subset of PSC found in about 30% of IBD patients; it is confined to small bile ducts and is usually benign.

UROLOGIC

The most frequent genitourinary complications are calculi, ureteral obstruction, and fistulas. The highest frequency of nephrolithiasis (10 to 20%) occurs in patients with CD following small-bowel resection. Calcium oxalate stones develop secondary to hyperoxaluria, which results from increased absorption of dietary oxalate. Normally, dietary calcium combines with luminal oxalate to form insoluble calcium oxalate, which is eliminated in the stool. In patients with ileal dysfunction, however, nonabsorbed fatty acids bind calcium and leave oxalate unbound. The unbound oxalate is then delivered to the colon, where it is readily absorbed, especially in the presence of colonic inflammation.

OTHER

The risk of thromboembolic disease increases when IBD becomes active, and patients may present with deep vein thrombosis, pulmonary embolism, cerebrovascular accidents, and arterial emboli. Factors responsible for the hypercoagulable state include reactive thrombocytosis; increased levels of fibrinopeptide A, factor V, factor VIII, and fibrinogen; accelerated thromboplastin generation; antithrombin III deficiency secondary to increased gut losses or increased catabolism; and free protein S deficiency. A spectrum of vasculitidies involving small, medium, and large vessels has also been observed in IBD patients.

Patients with IBD have an increased prevalence of osteoporosis and osteomalacia from vitamin D deficiency, calcium malabsorption, malnutrition, glucocorticoid use, and the intestinal inflammation itself. Deficiencies of vitamin B₁₂ and fat-soluble vitamins may occur after ileal resection or with ileal disease.

More common cardiopulmonary manifestations include endocarditis, myocarditis, pleuropericarditis, and interstitial lung disease. A secondary or reactive amyloidosis can occur in patients with long-standing IBD, especially in patients with CD. Amyloid material is deposited systemically and can cause diarrhea, constipation, and renal failure. The renal disease can be successfully treated with colchicine. Pancreatitis is a rare extraintestinal manifestation of IBD and results from duodenal fistulas, ampullary CD, gallstones, PSC, drugs such as 6-mercaptopurine, azathioprine, or very rarely, 5-ASA agents, autoimmune pancreatitis, and primary CD of the pancreas.

TREATMENT

5-ASA AGENTS

The mainstay of therapy for mild to moderate UC and Crohn's colitis is sulfasalazine and the other 5-ASA agents. These agents are effective at inducing remission in both UC and CD and in maintaining remission in UC; it remains unclear whether they have a role in remission maintenance in CD.

Sulfasalazine was originally developed to deliver both antibacterial (sulfapyridine) and anti-inflammatory (5-ASA) therapy into the connective tissues of joints and the colonic mucosa. The molecular structure provides a convenient delivery system to the colon by allowing the intact molecule to pass through the small intestine after only partial absorption, and to be broken down in the colon by bacterial azo reductases that cleave the azo bond linking the sulfa and 5-ASA moieties. Sulfasalazine is effective treatment for mild to moderate UC and Crohn's ileocolitis and colitis, but its high rate of side effects limits its use. Although sulfasalazine is more effective at higher doses, at 6 or 8 g/d up to 30% of patients experience allergic reactions or intolerable side effects such as headache, anorexia, nausea, and vomiting that are attributable to the sulfapyridine moiety. Hypersensitivity reactions, independent of sulfapyridine levels, include rash, fever, hepatitis, agranulocytosis, hypersensitivity pneumonitis, pancreatitis, worsening of colitis, and reversible sperm abnormalities. Sulfasalazine can also impair folate absorption, and patients should be given folic acid supplements.

Newer sulfa-free aminosalicylate preparations deliver increased amounts of the pharmacologically active ingredient of sulfasalazine (5-ASA, mesalamine) to the site of active bowel disease while limiting systemic toxicity. 5-ASA may function through inhibition of NF-κB activity. Sulfa-free aminosalicylate formulations include alternative azo-bonded carriers, 5-ASA dimers, pH-dependent tablets, and continuous-release preparations. Each has the same efficacy as sulfasalazine when equimolar concentrations are used. Olsalazine is composed of two 5-ASA radicals linked by an azo bond, which is split in the colon by bacterial reduction and two 5-ASA molecules are released. Olsalazine is similar in effectiveness to sulfasalazine in treating CD and UC, but up to 17% of patients experience non-bloody diarrhea caused by increased secretion of fluid in the small bowel. Balsalazide contains an azo bond binding mesalamine to the carrier molecule 4-aminobenzoyl-β-alanine; it is effective in the colon. Claversal is an enteric-coated form of 5-ASA that consists of mesalamine surrounded by an acrylic-based polymer resin and a cellulose coating that releases mesalamine at pH > 6.0, a level that is present from the mid-jejunum continuously to the distal colon.

The most commonly used drugs besides sulfasalazine in the United States are Asacol and Pentasa. Asacol is also an enteric-coated form of mesalamine, but it has a slightly different release pattern, with 5-ASA liberated at pH > 7.0. The disintegration of Asacol is variable, with complete breakup of the tablet occurring in many different parts of the gut ranging from the small intestine to the splenic flexure; it has increased gastric residence when taken with a meal. Asacol is used to induce and maintain remission in UC and to induce remission in CD ileitis, ileocolitis, and colitis. Appropriate doses of Asacol and the other 5-ASA compounds are shown in Table 5. Some 50 to 75% of patients with mild to moderate UC and CD improve when treated with 2 g/d of 5-ASA; the dose response continues up to at least 4.8 g/d. Doses of 1.5 to 4 g/d maintain remission in 50 to 75% of patients with UC.

TABLE 5 Oral 5-ASA Preparations

Preparation	Formulation	Delivery	Dosing, g/d
AZO-BOND
Sulfasalazine (500 mg)	Sulfapyridine-5-ASA	Colon	4–8 (acute) 2–6 (maintenance)
Olsalazine (250 mg)	5-ASA-5-ASA	Colon	1–3
Balsalazide (500–750 mg)	Aminobenzoyl-alanine-5-ASA	Colon	2.25–6.75
DELAYED-RELEASE
Asacol (400 mg)	Eudragit S (pH 7)	Distal ileum-colon	2.4–4.8 (acute) 1.6–4.8 (maintenance)
Claversal (250–500 mg)	Eudragit L (pH 6)	Ileum-colon	1.5–3 (acute) 0.75–3 (maintenance)
SUSTAINED-RELEASE
Pentasa (250 mg)	Ethylcellulose microgranules	Stomach-colon	2–4 (acute) 1.5–4 (maintenance)

Pentasa is another mesalamine formulation that uses an ethylcellulose coating to allow water absorption into small beads containing the mesalamine. Water dissolves the 5-ASA, which then diffuses out of the bead into the lumen. Disintegration of the capsule occurs in the stomach. The microspheres then disperse throughout the entire gastrointestinal tract from the small intestine through the distal colon in both fasted or fed conditions. Controlled trials of Pentasa and Asacol in active CD demonstrate a 40 to 60% clinical improvement or remission, but the data are not conclusive that these agents maintain remission in CD. 5-ASA agents may be effective in postoperative prophylaxis of CD.

Topical mesalamine enemas are effective in mild-to-moderate distal UC and CD. Clinical response occurs in up to 80% of UC patients with colitis distal to the splenic flexure. Mesalamine suppositories are effective in treating proctitis.

Glucocorticoids

The majority of patients with moderate to severe UC benefit from oral or parenteral glucocorticoids. Prednisone is usually started at doses of 40 to 60 mg/d for active UC that is unresponsive to 5-ASA therapy. Parenteral glucocorticoids may be administered as intravenous hydrocortisone, 300 mg/d, or methylprednisolone, 40 to 60 mg/d. Adrenocorticotropic hormone (ACTH) is occasionally preferred for glucocorticoid-naïve patients despite a risk of adrenal hemorrhage. ACTH has equivalent efficacy to intravenous hydrocortisone in both glucocorticoid-naïve and -experienced CD patients.

Topically applied glucocorticoids are also beneficial for distal colitis and may serve as an adjunct in those who have rectal involvement plus more proximal disease. Hydrocortisone enemas or foam may control active disease, although they have no proven role as maintenance therapy. These glucocorticoids are significantly absorbed from the rectum and can lead to adrenal suppression with prolonged administration.

Glucocorticoids are also effective for treatment of moderate-to-severe CD and induce a 60 to 70% remission rate compared to a 30% placebo response. The systemic effects of standard glucocorticoid formulations have led to the development of more potent formulations that are less well absorbed and have increased first-pass metabolism. Controlled ileal-release budesonide has been nearly equal to prednisone for ileocolonic CD with fewer glucocorticoid side effects. Budesonide is used for 2 to 3 months at a dose of 9 mg/d, then tapered.

Glucocorticoids play no role in maintenance therapy in either UC or CD. Once clinical remission has been induced, they should be tapered according to the clinical activity, normally at a rate of no more than 5 mg per week. They can usually be tapered to 20 mg/d within 4 to 5 weeks but often take several months to be discontinued altogether. The side effects are numerous, including fluid retention, abdominal striae, fat redistribution, hyperglycemia, subcapsular cataracts, osteonecrosis, myopathy, emotional disturbances, and withdrawal symptoms. Most of these side effects, aside from osteonecrosis, are related to the dose and duration of therapy.

ANTIBIOTICS

Antibiotics have no role in the treatment of active or quiescent UC. However, pouchitis, which occurs in about a third of UC patients after colectomy and IPAA, usually responds to treatment with metronidazole or ciprofloxacin.

Metronidazole is effective in active inflammatory, fistulous, and perianal CD and may prevent recurrence after ileal resection. The most effective dose is 15 to 20 mg/kg per day in three divided doses; it is usually continued for several months. Common side effects include nausea, metallic taste, and disulfiram-like reaction. Peripheral neuropathy can occur with prolonged administration (several months) and on rare occasions is permanent despite discontinuation. Ciprofloxacin (500 mg bid) is also beneficial for inflammatory, perianal, and fistulous CD. These two antibiotics should be used as second-line drugs in active CD after 5-ASA agents and as first-line drugs in perianal and fistulous CD.

AZATHIOPRINE AND 6-MERCAPTOPURINE

Azathioprine and 6-mercaptopurine (6-MP) are purine analogues commonly employed in the management of glucocorticoid-dependent IBD. Azathioprine is rapidly absorbed and converted to 6-MP, which is then metabolized to the active end product, thioinosinic acid, an inhibitor of purine ribonucleotide synthesis and cell proliferation. These agents also inhibit the immune response. Efficacy is seen at 3 to 4 weeks. Compliance can be monitored by measuring the levels of 6-thioguanine and 6-methyl-mercaptopurine, end products of 6-MP metabolism. Azathioprine (2.0 to 2.5 mg/kg per day) or 6-MP (1.0 to 1.5 mg/kg per day) have been employed successfully as glucocorticoid-sparing agents in up to two-thirds of UC and CD patients previously unable to be weaned from glucocorticoids. The role of these immunomodulators as maintenance therapy in UC and CD and for treating active perianal disease and fistulas in CD appears promising. In addition, 6-MP or azathioprine may be effective for postoperative prophylaxis of CD.

Although azathioprine and 6-MP are usually well tolerated, pancreatitis occurs in 3 to 4% of patients, typically presents within the first few weeks of therapy, and is completely reversible when the drug is stopped. Other side effects include nausea, fever, rash, and hepatitis. Bone marrow suppression (particularly leukopenia) is dose-related and often delayed, necessitating regular monitoring of the complete blood count. Additionally, 1 in 300 individuals lacks thiopurine methyltransferase, the enzyme responsible for drug metabolism; an additional 11% of the population are heterozygotes with intermediate enzyme activity. Both are at increased risk of toxicity because of increased accumulation of thioguanine metabolites. No increased risk of cancer has been documented in IBD patients chronically taking these medications.

METHOTREXATE

Methotrexate (MTX) inhibits dihydrofolate reductase, resulting in impaired DNA synthesis. Additional anti-inflammatory properties may be related to decreased IL-1 production. Intramuscular or subcutaneous MTX (25 mg per week) is effective in inducing remission and reducing glucocorticoid dosage, and 15 mg per week is effective in maintaining remission in active CD. Potential toxicities include leukopenia and hepatic fibrosis, necessitating periodic evaluation of complete blood counts and liver enzymes. The role of liver biopsy in patients on long-term MTX is uncertain. Hypersensitivity pneumonitis is a rare but serious complication of therapy.

CYCLOSPORINE

Cyclosporine (CSA) alters the immune response by acting as a potent inhibitor of T cell–mediated responses. Although CSA acts primarily via inhibition of IL-2 production from T helper cells, it also decreases recruitment of cytotoxic T cells and blocks other cytokines, including IL-3, IL-4, IFN-γ, and TNF. It has a more rapid onset of action than 6-MP and azathioprine.

CSA is most effective given at 2 to 4 mg/kg per day intravenously in severe UC that is refractory to intravenous glucocorticoids, with 82% of patients responding. CSA can be an alternative to colectomy. The long-term success of oral CSA is not as dramatic, but if patients are started on 6-MP or azathioprine at the time of hospital discharge, remission can be maintained. Intravenous CSA is effective in 80% of patients with refractory fistulas, but 6-MP or azathioprine must be used to maintain remission. Oral CSA alone is effective only at a higher dose (7.5 mg/kg per day) in active disease but is not effective in maintaining remission without 6-MP/azathioprine. Serum levels should be monitored and kept in the range of 200 to 400 ng/mL.

CSA may cause significant toxicity; renal function should be monitored frequently. Hypertension, gingival hyperplasia, hypertrichosis, paresthesias, tremors, headaches, and electrolyte abnormalities are common side effects. Creatinine elevation calls for dose reduction or discontinuation. Seizures may also complicate therapy, especially if the patient is hypomagnesemic or if serum cholesterol levels are <3.1 mmol/L (<120 mg/dL). Opportunistic infections, most notably Pneumocystis carinii pneumonia, may occur with combination immunosuppressive treatment; prophylaxis should be given.

NUTRITIONAL THERAPIES

Dietary antigens may stimulate the mucosal immune response. Patients with active CD respond to bowel rest, along with total enteral or total parenteral nutrition (TPN). Bowel rest and TPN are as effective as glucocorticoids at inducing remission of active CD but are not effective as maintenance therapy. Enteral nutrition in the form of elemental or peptide-based preparations are also as effective as glucocorticiods or TPN, but these diets are not palatable. Enteral diets may provide the small intestine with nutrients vital to cell growth and do not have the complications of TPN. In contrast to CD, active UC is not effectively treated with either elemental diets or TPN. Standard medical management of UC and CD is reviewed in Table 6.

TABLE 276-6 Medical Management of IBD

Ulcerative Colitis: Active Disease
	Mild	Moderate	Severe	Fulminant
Distal	5-ASA oral and/or enema	5-ASA oral and/or enema Glucocorticoid enema Oral glucocorticoid	5-ASA oral and/or enema Glucocorticoid enema Oral or IV glucocorticoid	Intravenous glucocorticoid Intravenous CSA
Extensive	5-ASA oral and/or enema	5-ASA oral and/or enema Glucocorticoid enema Oral glucocorticoid	5-ASA oral and/or enema Glucocorticoid enema Oral or IV glucocorticoid	Intravenous glucocorticoid Intravenous CSA
Ulcerative Colitis: Maintenance Therapy Distal 5-ASA oral and/or enema 6-MP or azathioprine Extensive 5-ASA oral and/or enema 6-MP or azathioprine
Crohn's Disease: Maintenance Therapy Inflammatory Perianal or Fistulizing Disease 5-ASA oral and/or enema Metronidazole and/or ciprofloxacin Azathioprine or 6-MP Infliximab Azathioprine or 6-MP Infliximab
Note: CSA, cyclosporine; 6-MP, 6-mercaptopurine; TPN, total parenteral nutrition.

NEWER MEDICAL THERAPIES

Anti-Tumor Necrosis Factor Antibody

TNF is a key inflammatory cytokine and mediator of intestinal inflammation. The expression of TNF is increased in IBD. Infliximab is a chimeric mouse-human monoclonal antibody against TNF that is extremely effective in CD. It blocks TNF in the serum and at the cell surface and likely lyses TNF-producing macrophages and T cells through complement fixation and antibody-dependent cytotoxicity. Of active CD patients refractory to glucocorticoids, 6-MP, or 5-ASA, 65% will respond to intravenous infliximab (5 mg/kg); one-third will enter complete remission. Of the patients who experience an initial response, 40% will maintain remission for at least 1 year with repeated infusions of infliximab every 8 weeks.

Infliximab is also effective in CD patients with refractory perianal and enterocutaneous fistulas, with a 68% response rate (50% reduction in fistula drainage) and a 50% complete remission rate. Reinfusion, typically every 8 weeks, is necessary to continue therapeutic benefits in many patients.

The development of antibodies to infliximab (ATI) is associated with an increased risk of infusion reactions and a decreased response to treatment. Patients who receive on-demand or episodic infusions rather than periodic (every 8 weeks) infusions are more likely to develop ATI. A humanized antibody to TNF also shows some promise in early clinical testing.

Among 120,000 patients treated with infliximab, 8 developed lymphoma: 5 patients with CD and 3 with rheumatoid arthritis. As the risk of lymphoma is already increased in these conditions, it is unclear whether infliximab is the cause. Thus, infliximab is extremely effective in refractory inflammatory and fistulous CD but should be used only when necessary. Results on the efficacy of infliximab in UC are mixed.

Newer Immunosuppressive Agents

Tacrolimus has a mechanism of action similar to cyclosporine. It has shown efficacy in children with refractory IBD and in adults with extensive involvement of the small bowel.

Mycophenolate mofetil is another immunomodulator that may be effective in CD patients resistant to or intolerant of 6-MP azathioprine. Patients with CD who received 15 mg/kg per day have tolerated the drug well and have experienced benefit with reduction of glucocorticoid requirements.

    6-Thioguanine is the active metabolite of 6-MP and has shown activity in patients resistant to or intolerant of 6-MP/azathioprine.

Thalidomide has been shown to inhibit TNF production by monocytes and other cells. Thalidomide is effective in glucocorticoid-refractory and fistulous CD, but randomized controlled trials still need to be performed.

The α4 integrin-specific humanized monoclonal antibody, natalizumab, prevents the migration of leukocytes into the parenchyma and blocks their activation in inflammatory sites. It seems to be effective in CD, but more trials are needed.

SURGICAL THERAPY

Ulcerative Colitis

Nearly half of patients with extensive chronic UC undergo surgery within the first 10 years of their illness. The indications for surgery are listed in Table 7. Morbidity is about 20% in elective, 30% for urgent, and 40% for emergency proctocolectomy. The risks are primarily hemorrhage, contamination and sepsis, and neural injury. Although single-stage total proctocolectomy with ileostomy has been the operation of choice, newer operations maintain continence while surgically removing the involved rectal mucosa.

TABLE 276-7 Indications for Surgery

Ulcerative Colitis   Intractable disease   Fulminant disease   Toxic megacolon   Colonic perforation   Massive colonic hemorrhage   Extracolonic disease   Colonic obstruction   Colon cancer prophylaxis   Colon dysplasia or cancer Crohn's Disease CD of Small Intestine   Stricture and obstruction unresponsive to medical therapy   Massive hemorrhage   Refractory fistula   Abscess CD of Colon and Rectum   Intractable disease   Fulminant disease   Perianal disease unresponsive to medical therapy   Refractory fistula   Colonic obstruction   Cancer prophylaxis   Colon dysplasia or cancer

The IPAA is the most frequent continence-preserving operation performed. Because UC is a mucosal disease, the rectal mucosa can be dissected out and removed down to the dentate line of the anus or about 2 cm proximal to it. The ileum is fashioned into a pouch that serves as a neorectum. This ileal pouch is then sutured circumferentially to the anus in an end-to-end fashion. If performed carefully, this operation preserves the anal sphincter and maintains continence. The overall operative morbidity is 10%, with the major complication being bowel obstruction. Pouch failure necessitating conversion to permanent ileostomy occurs in 5 to 10% of patients. Some inflamed rectal mucosa is usually left behind, and thus endoscopic surveillance is necessary. Primary dysplasia of the ileal mucosa of the pouch has occurred rarely.

Patients with IPAAs usually have about six to eight bowel movements a day. On validated quality-of-life indices, they report better performance in sports and sexual activities than ileostomy patients. The most frequent late complication of IPAA is pouchitis in about one-third of patients with UC. This syndrome consists of increased stool frequency, watery stools, cramping, urgency, nocturnal leakage of stool, arthralgias, malaise, and fever. Pouch biopsies and pANCA/ASCA/OMPC serologies can distinguish true pouchitis from underlying CD. Although it usually responds to antibiotics, in 3 to 5% of patients it is refractory and requires pouch take-down.

Most patients with CD require at least one operation in their lifetime. The need for surgery is related to duration of disease and the site of involvement. Patients with small-bowel disease have an 80% chance of requiring surgery. Those with colitis alone have a 50% chance. The indications for surgery are shown in Table 7.

SMALL INTESTINAL DISEASE

Because CD is chronic and recurrent with no clear surgical cure, as little intestine as possible is resected. Current surgical alternatives for treatment of obstructing CD include resection of the diseased segment and strictureplasty. Surgical resection of the diseased segment is the most frequently performed operation, and in most cases primary anastomosis can be done to restore continuity. If much of the small bowel has already been resected and the strictures are short with intervening areas of normal mucosa, strictureplasties should be done to avoid a functionally insufficient length of bowel. The strictured area of intestine is incised longitudinally and the incision sutured transversely, thus widening the narrowed area. Complications of strictureplasty include prolonged ileus, hemorrhage, fistula, abscess, leak, and restricture.

COLORECTAL DISEASE

A greater percentage of patients with Crohn's colitis require surgery for intractability, fulminant disease, and anorectal disease. Several alternatives are available, ranging from the use of a temporary loop ileostomy to resection of segments of diseased colon or even the entire colon and rectum. For patients with segmental involvement, segmental colon resection with primary anastomosis can be performed. In 20 to 25% of patients with extensive colitis, the rectum is spared sufficiently to consider rectal preservation. Most surgeons believe that an IPAA is contraindicated in CD due to the high incidence of pouch failure. A diverting colostomy may help heal severe perianal disease or rectovaginal fistulas, but disease almost always recurs with reanastomosis. Often, these patients require a total proctocolectomy and ileostomy.

INFLAMMATORY BOWEL DISEASE AND PREGNANCY

Patients with quiescent UC and CD have normal fertility rates; the fallopian tubes can be scarred by the inflammatory process of CD, especially on the right side because of the proximity of the terminal ileum. In addition, perirectal, perineal, and rectovaginal abscesses and fistulae can result in dyspareunia. Infertility in men can be caused by sulfasalazine but reverses when treatment is stopped.

In mild or quiescent UC and CD, fetal outcome is nearly normal. Spontaneous abortions, stillbirths, and developmental defects are increased with increased disease activity, not medications. The courses of CD and UC during pregnancy mostly correlate with disease activity at the time of conception. Patients should be in remission for 6 months before conceiving. Most CD patients can deliver vaginally, but cesarean section may be the preferred route of delivery for patients with anorectal and perirectal abscesses and fistulas to reduce the likelihood of fistulas developing or extending into the episiotomy scar.

Sulfasalazine, mesalamine, and balsalazide are safe for use in pregnancy and nursing, but folate supplementation must be given with sulfasalazine. Topical 5-ASA agents are also safe during pregnancy and nursing. Glucocorticoids are generally safe for use during pregnancy and are indicated for patients with moderate to severe disease activity. The amount of glucocorticoids received by the nursing infant is minimal. The safest antibiotics to use for CD in pregnancy for short periods of time (weeks, not months) are ampicillin, cephalosporin, or flagyl. Ciprofloxacin causes cartilage lesions in immature animals and should be avoided because of the absence of data on its effects on growth and development in humans.

6-MP and azathioprine pose minimal or no risk during pregnancy, but experience is limited. If the patient cannot be weaned from the drug or has an exacerbation that requires 6-MP/azathioprine during pregnancy, she should continue the drug with informed consent. Their effects during nursing are unknown.

Little data exist on cyclosporine in pregnancy. In a small number of patients with severe IBD treated with intravenous cyclosporine during pregnancy, 80% of pregnancies were successfully completed without development of renal toxicity, congenital malformations, or developmental defects. However, because of the lack of data, cyclosporine should probably be avoided unless the patient would otherwise require surgery. Methotrexate is contraindicated in pregnancy and nursing. Based on 35 reported pregnancies, infliximab does not appear to present a risk to the mother or baby.

Surgery in UC should be performed only for emergency indications, including severe hemorrhage, perforation, and megacolon refractory to medical therapy. Total colectomy and ileostomy carry a 60% risk of postoperative spontaneous abortion. Fetal mortality is also high in CD requiring surgery. Patients with IPAAs have increased nighttime stool frequency during pregnancy that resolves post-partum. Transient small-bowel obstruction or ileus has been noted in up to 8% of patients with ileostomies.

INFLAMMATORY BOWEL DISEASE IN THE ELDERLY

The most common presenting symptoms in the elderly are diarrhea, weight loss, and abdominal pain. CD in the elderly mostly affects the colon with a distal distribution and occurs predominantly in women. Proctitis has been documented in 50% of elderly patients, and the diagnosis is often delayed. Diseases that can mimic CD in the elderly are ischemic colitis, diverticular disease, irritable bowel, infectious colitides, and malignancies, including carcinoma, lymphoma, and carcinoid. The incidence of surgery is high in elderly patients, with up to 50% of patients with ileitis, ileocolitis, or extensive colitis requiring urgent or early surgery for first-time disease. In addition, surgery has a much higher morbidity than in younger patients, although the rate of postoperative recurrence is less. Most elderly patients respond as well as younger individuals to medical management.

UC in the elderly is more common in men, presents usually with diarrhea and weight loss, and may have a more distal distribution than in younger patients. Most elderly patients have a favorable response to medical therapy, especially 5-ASA agents, and immunosuppressives used in conjunction with low doses of glucocorticoids. Cyclosporine has been used more frequently in the elderly, but the age-related decreases in renal clearance may affect dosing. Glucocorticoid complications such as osteoporosis and hyperglycemia are also increased in the elderly. 6-MP and azathioprine are well tolerated in the elderly. Surgery also has a higher morbidity and mortality in UC, and elderly patients have a longer hospital stay than younger patients. The risk of colon cancer in UC and Crohn's colitis is no greater than that in the general population since the duration of disease is short and the extent of disease is often distal.

CANCER IN INFLAMMATORY BOWEL DISEASE

ULCERATIVE COLITIS

Patients with long-standing UC are at increased risk for developing colonic epithelial dysplasia and carcinoma (Fig. 8). Several features distinguish sporadic colon cancer (SCC) and colitis-associated colon cancer (CAC). First, SCCs usually arise from an adenomatous polyp; CACs typically arise from either flat dysplasia or a dysplasia-associated lesion or mass (DALM). Second, multiple synchronous colon cancers occur in 3 to 5% of SCC but in 12% of CAC. Third, the mean age of individuals with SCC is in the sixties; the mean age of those with CAC is in the thirties. Fourth, SCC exhibits a left-sided predominance, whereas CAC is distributed more uniformly throughout the colon. Fifth, mucinous and anaplastic cancers are more common in CAC than SCC. At the molecular level, p53 mutations occur much earlier and APC gene mutations much later in CAC than in SCC.

FIGURE 276-8 Low-power transition between dysplasia (D) and nondysplastic (N) mucosa in a case of ulcerative colitis. (Courtesy of Dr. EK Rosado and Dr. CA Perkos, Division of Gastrointestinal Pathology, Department of Pathology, Emory University, Atlanta, Georgia.)

The risk of neoplasia in chronic UC increases with duration and extent of disease. For patients with pancolitis, the risk of cancer rises 0.5 to 1% per year after 8 to 10 years of disease. This observed increase in cancer rates has led to the endorsement of surveillance colonoscopy with biopsies for patients with chronic UC as the standard of care. Annual or biennial colonoscopy with multiple biopsies has been advocated for patients with >8 to 10 years of pancolitis or 12 to 15 years of left-sided colitis and has been widely employed to screen and survey for subsequent dysplasia and carcinoma.

CROHN'S DISEASE

Risk factors for developing colorectal cancer in CD are a history of colonic (or ileocolonic) involvement and long disease duration. The cancer risks in CD and UC are probably equivalent for similar extent and duration of disease. In patients with extensive.

Crohn's colitis, 22% developed dysplasia or cancer by the fourth surveillance exam after a negative screening colonoscopy. Thus, the same endoscopic surveillance strategy used for UC is recommended for patients with chronic Crohn's colitis. A pediatric colonoscope can be used to pass narrow strictures in CD patients, but surgery should be considered in symptomatic patients with impassable strictures.

MANAGEMENT OF DYSPLASIA AND CANCER

Dysplasia can be flat or polypoid. If flat high-grade dysplasia (HGD) is encountered on colonoscopic surveillance, the usual treatment for UC is colectomy and for CD is either colectomy or segmental resection. If flat low-grade dysplasia (LGD) is found, most investigators recommend immediate colectomy. Adenomas may occur coincidently in UC and CD patients with chronic colitis and can be removed endoscopically provided that biopsies of the surrounding mucosa are free of dysplasia.

IBD patients are also at greater risk for other malignancies. Patients with CD may have an increased risk of developing non-Hodgkin's lymphoma and squamous cell carcinoma of the skin. Although CD patients have a twelvefold increased risk of developing small-bowel cancer, this type of carcinoma is extremely rare.

QUALITY OF LIFE IN INFLAMMATORY BOWEL DISEASE

The assessment of health-related quality of life plays an important role in the evaluation and treatment of IBD patients. Although clinical trials have generally relied upon traditional disease activity indices such as the Crohn's Disease Activity Index (CDAI) to measure therapeutic efficacy, these measures do not reflect quality of life. The Inflammatory Bowel Disease Questionnaire (IBDQ) is a validated, disease-specific instrument that has been used to measure quality of life. It is a 32-item questionnaire that measures global function, systemic and bowel symptoms, functional and social impairment, and emotional function. When compared to the general population, IBD patients have an impaired quality of life in all six categories. The most frequent concerns of UC patients are having an ostomy bag, developing cancer, effects of medication, the uncertain nature of the disease, and having surgery. The most frequent concerns of CD patients are the uncertain nature of the disease, energy level, effects of medication, having surgery, and having an ostomy bag.