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MD Consult: Books: Goldman: Cecil Medicine: Chapter 144 – INFLAMMATORY BOWEL DISEASE

Goldman: Cecil Medicine, 23rd ed.

Copyright © 2007 Saunders, An Imprint of Elsevier


William F. Stenson


Inflammatory bowel diseases (IBDs), including ulcerative colitis and Crohn’s disease, are chronic inflammatory diseases of the gastrointestinal tract. They are diagnosed by a set of clinical, endoscopic, and histologic characteristics, but no single finding is absolutely diagnostic for one disease or the other. Moreover, some patients have a clinical picture that falls between the two diseases and are said to have indeterminate colitis.

The inflammatory response in ulcerative colitis is largely confined to the mucosa and submucosa, but in Crohn’s disease the inflammation extends through the intestinal wall from mucosa to serosa. Ulcerative colitis is confined to the colon, and colectomy is a curative procedure. Crohn’s disease, in contrast, can involve any part of the gastrointestinal tract, although the distal end of the small bowel and the colon are most commonly involved. Resection of the inflamed segment is not curative of Crohn’s disease, and inflammation is likely to recur.


The incidence and prevalence of Crohn’s disease and ulcerative colitis vary with geographic location; the highest rates occur in white populations in northern Europe and North America, where the incidence for each disease is about 5 per 100,000 and the prevalence is approximately 50 per 100,000. Rates in central and southern Europe are lower, and in South America, Asia, and Africa they are lower still. Crohn’s disease and ulcerative colitis are both more common in Jews than non-Jews. In the United States, the incidence of IBD in the black population has been a fifth to half that in the white population, but in recent years that gap has narrowed. In northern Europe and North America the incidence of ulcerative colitis has leveled off, but that of Crohn’s disease is still increasing. For both diseases, the incidence is equal in men and women. The peak age at onset is between 15 and 25 years of age, with a second, lesser peak between 55 and 65 years. Both diseases occur in childhood, although the incidence in children younger than 15 years is low.

The risk for ulcerative colitis is increased in both nonsmokers and former smokers when compared with current smokers. Whether initiation of smoking improves symptoms is unclear, although success has been reported with nicotine patches. In contrast, the incidence of smoking is higher in patients with Crohn’s disease than in the general population, and patients who continue to smoke may be less likely to respond to medical therapy.



The most important risk factor for IBD is a positive family history. Approximately 15% of IBD patients have affected first-degree relatives, and the incidence in first-degree relatives is 30 to 100 times that of the general population. The best estimates of the lifetime risk for the development of IBD in first-degree relatives of affected individuals are 3 to 9%. The increased incidence in first-degree relatives contrasts with the absence of an increased incidence in spouses of patients. Dizygotic twins have the same rate of concordance as would be expected for siblings, whereas monozygotic twins have higher rates of concordance for both diseases. Both Crohn’s disease and ulcerative colitis are polygenic disorders. The first well-characterized mutations associated with Crohn’s disease were in NOD2, a gene that codes for a protein that acts as an intracellular receptor for a bacterial product, muramyl dipeptide. Mutations in NOD2 are seen in about 15% of Crohn’s disease patients but are also seen in a smaller percentage of the general population, so mutations in NOD2 are neither necessary nor sufficient for the development of Crohn’s disease.


In IBD, the lamina propria is infiltrated with lymphocytes, macrophages, and other cells of the immune system. An intensive search for the antigens that trigger the immune response has yet to identify a specific microbial pathogen. Anticolon antibodies of unclear significance have been identified in the sera of ulcerative colitis patients. IBD may also be related to a failure to suppress (or “downregulate”) the normal, finely tuned, low-grade chronic inflammation of the intestinal lamina propria in response to chronic exposure to luminal antigens, particularly commensal bacteria.

Whatever the antigenic trigger, activated lamina propria T cells are involved in the pathogenesis of IBD. In Crohn’s disease, the activated lymphocytes appear to be primarily TH1 lymphocytes that produce interferon-γ (IFN-γ). Pro-inflammatory cytokines, including interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), amplify the immune response. Intravenous infusion of antibody to TNF-α is clinically effective in Crohn’s disease. Large numbers of neutrophils are attracted by chemotactic agents, including IL-8 and leukotriene B4, and enter the inflamed mucosa. Epithelial injury in IBD appears to be due to reactive oxygen species from neutrophils and macrophages, as well as cytokines such as TNF-α and IFN-γ.

In mice, colitis develops when the genes for IL-2, IL-10, or transforming growth factor-β1 are knocked out or when there are certain T-cell receptor mutants, and colitis develops in transgenic rats if the human HLA-B27 gene has been introduced. If the same animals are raised in a germ-free environment, colitis does not develop, thereby suggesting that colitis can be the only manifestation of a variety of abnormalities in systemic immunity and that the colitis is the result of an abnormal immune response to commensal bacteria.


Ulcerative colitis and Crohn’s disease each have a characteristic pathologic appearance, but in any given case the pathologic picture may not be specific enough to distinguish between them or to differentiate them from other diseases such as infectious colitis or ischemic colitis ( Table 144-1 ). In IBD, pathologic assessment of disease activity may not correlate with clinical and endoscopic assessment.

TABLE 144-1   — 

Feature Ulcerative Colitis Crohn’s Disease
Rectal involvement Always Common
Skip lesions Never Common
Transmural involvement Rare Common
Granulomas Occasional Common
Perianal disease Never Common
Cobblestone mucosa Rare Common
“Collar button” ulcers Common Occasional
Small intestinal involvement Never Common
Discontinuous involvement Never Common
Fistulas Never Common
Strictures Occasional Common
Aphthous ulcers Never Common
Discontinuous involvement Never Common
Rectal sparing Never Common
Linear or serpiginous ulcers Never Common
Ulcers in the terminal ileum Never Common

In ulcerative colitis, inflammation begins in the rectum, extends proximally a certain distance, and then abruptly stops, with a clear demarcation between involved and uninvolved mucosa. In mild disease, there are superficial erosions, whereas in more severe disease, ulcers may be large but superficial and penetrate the muscularis mucosa only in very severe disease. Inflammatory polyps or pseudopolyps may be present. Most of the pathologic findings in ulcerative colitis are limited to the mucosa and submucosa; the muscularis propria is affected only in fulminant disease. Active ulcerative colitis is marked by neutrophils in the mucosa and submucosa and clumps of neutrophils in crypt lumens (crypt abscesses), as well as by mucus depletion, mucosal edema, and vascular congestion with focal hemorrhage. In addition to signs of acute activity, there are also signs of chronicity, with lymphoid aggregates, plasma cells, mast cells, and eosinophils in the lamina propria.

In Crohn’s disease, the bowel wall is thickened and stiff. The mesentery, which is thickened, edematous, and contracted, fixes the intestine in one position. Transmural inflammation may cause loops of intestine to be matted together. All layers of the intestine are thickened, and the lumen is narrowed. “Skip lesions” with two involved areas separated by a length of normal intestine suggest Crohn’s disease. Colonic inflammation with rectal sparing is more consistent with Crohn’s disease than with ulcerative colitis. The earliest lesions of Crohn’s disease are aphthous ulcers, which typically occur over Peyer’s patches in the small intestine and over lymphoid aggregates in the colon. As the disease progresses, aphthous ulcers enlarge and become stellate or serpiginous. Eventually, the stellate ulcers coalesce to form longitudinal and transverse linear ulcers. The remaining islands of nonulcerated mucosa give a cobblestone appearance. Fissures develop from the base of ulcers and extend down through the muscularis to the serosa. Lymphoid aggregates are found in the submucosa and external to the muscularis propria. Granulomas are common in Crohn’s disease but not in ulcerative colitis.

Clinical Manifestations

Ulcerative Colitis

The dominant symptom in ulcerative colitis is diarrhea, which is usually associated with blood in the stool ( Table 144-2 ). Bowel movements are frequent but small in volume as a result of irritability of the inflamed rectum. Urgency and fecal incontinence may limit the patient’s ability to function in society. Other symptoms include fever and pain, which may be in either lower quadrant or in the rectum. Systemic features—fever, malaise, and weight loss—are more common if all or most of the colon is involved and may have a greater effect than diarrhea on the patient’s ability to function. Some patients, especially elderly persons, complain of constipation rather than diarrhea because rectal spasm prevents the passage of stool. The initial attack of ulcerative colitis may be fulminant with bloody diarrhea, but more commonly the disease begins indolently, with nonbloody diarrhea progressing to bloody diarrhea. Ulcerative colitis may initially be seen with any extent of anatomic involvement, from disease confined to the rectum to pancolitis. Most commonly, ulcerative colitis follows a chronic intermittent course with long periods of quiescence interspersed with acute attacks lasting weeks to months; however, a significant percentage of patients suffer a chronic continuous course.

TABLE 144-2   — 

Mild Fewer than four bowel movements per day with little or no blood, no fever, and sedimentation rate less than 20 mm/hr
Moderate Between mild and severe
Severe Six or more bowel movements per day with blood, fever, anemia, and sedimentation rate greater than 30 mm/hr

In ulcerative colitis of mild to moderate severity, there may be tenderness over the affected area of the colon, and rectal examination may reveal tenderness or blood on the glove. In severe disease, the patient is more likely to be febrile and tachycardic.

Anemia and an elevated leukocyte count and erythrocyte sedimentation rate are useful in confirming severe disease and in monitoring the clinical course of a severe exacerbation. Electrolyte disorders, particularly hypokalemia, are seen with severe diarrhea.

Crohn’s Disease

Crohn’s disease is marked by one of three major patterns: (1) disease in the ileum and cecum (40% of patients), (2) disease confined to the small intestine (30%), and (3) disease confined to the colon (25%). Much less commonly, Crohn’s disease involves more proximal parts of the gastrointestinal tract—the mouth, tongue, esophagus, stomach, and duodenum.

The predominant symptoms are diarrhea, abdominal pain, and weight loss; any of these three symptoms may be most prominent in a given individual. The initial manifestation may not be dramatic; patients may complain for months or years of vague abdominal pain and intermittent diarrhea before the diagnosis is considered. Diarrhea occurs in almost all those with Crohn’s disease, but the pattern varies with the anatomic location of the disease. In patients with colonic disease, especially with rectal involvement, diarrhea is of small volume and associated with urgency and tenesmus. Inflammation in the rectum causes loss of distensibility; entry of even a small amount of stool into a nondistensible rectum causes an immediate and urgent need to defecate. Prolonged inflammation and scarring in the rectum can leave it so rigid and nondistensible that the patient is incontinent. In disease confined to the small intestine, stools are of larger volume and not associated with urgency or tenesmus. Patients with severe involvement of the terminal ileum and those who have undergone surgical resection of the terminal ileum may have bile salt diarrhea or steatorrhea.

The location and pattern of pain correlate with disease location. In patients with ileal disease, cramping right lower quadrant pain occurs after eating and is related to partial intermittent obstruction of a narrowed intestinal lumen. Abdominal distention, nausea, and vomiting may accompany the pain. Weight loss of some degree, which occurs in most patients with Crohn’s disease regardless of the anatomic location, is a product of malabsorption or diminished intake as a result of pain, diarrhea, or anorexia. Fever and chills often accompany disease activity; a low-grade fever may be the patient’s first warning sign of a flare. Induction of remission by drugs or surgery is invariably associated with increased energy and a sense of well-being. Crohn’s disease, like ulcerative colitis, is a relapsing and remitting disease. About 30% of placebo-treated patients with Crohn’s disease of mild to moderate activity go into remission within 4 months. Conversely, of patients in remission and not receiving therapy, about 30% relapse within 1 year and 50% at 2 years.

Physical findings in Crohn’s disease vary with the distribution and severity of the disease. Aphthous ulcers of the lips, gingiva, or buccal mucosa are common. The abdomen may be tender, typically over the area of disease activity. Thickened bowel loops, thickened mesentery, or an abscess may cause a mass, often in the right lower quadrant. The presence of perianal disease is suggested by fistulous openings, induration, redness, or tenderness near the anus.

Laboratory findings are largely nonspecific. Anemia may result from chronic disease, blood loss, or nutritional deficiencies of iron, folate, or vitamin B12. A modestly elevated leukocyte count is indicative of active disease, but a marked elevation suggests the presence of an abscess or other suppurative complication. The erythrocyte sedimentation rate has been used to monitor disease activity, and it tends to be higher in colonic disease than in ileal disease. Hypoalbuminemia is an indication of malnutrition. Ileal disease or resection of more than 100 cm of distal ileum results in a diminished serum vitamin B12 level because of malabsorption.

Extraintestinal Manifestations

Although IBD primarily involves the bowel, it is also associated with manifestations in other organ systems. The extraintestinal manifestations (e.g., sclerosing cholangitis or ankylosing spondylitis) may be more problematic than the bowel disease. The extraintestinal manifestations can be divided into two major groups: (1) those in which the clinical activity follows the activity of the bowel disease and (2) those in which the clinical activity is unrelated to the activity of the bowel disease.


The most common extraintestinal manifestation of IBD is arthritis, including colitic arthritis and ankylosing spondylitis. Colitic arthritis, a migratory arthritis that affects the knees, hips, ankles, wrists, and elbows, parallels the course of the bowel disease; successful treatment of the intestinal inflammation results in improvement in the arthritis. Ankylosing spondylitis ( Chapter 286 ) is characterized by morning stiffness, low back pain, and a stooped posture; it can be relentlessly progressive and crippling. Patients with ulcerative colitis have a 30-fold increase in the incidence of ankylosing spondylitis in comparison to the general population. Nonsteroidal anti-inflammatory drugs reduce the inflammation and pain but do not halt progression of the disease. Medical treatment of the IBD and colectomy are not helpful in managing ankylosing spondylitis. Sacroiliitis, which is inflammation of the joint between the sacrum and the ilium, occurs in conjunction with ankylosing spondylitis but is more often seen alone. Fifteen percent of patients with ulcerative colitis have radiographs consistent with sacroiliitis, but most patients are asymptomatic.

Hepatic Manifestations

Hepatic complications of IBD include fatty liver, pericholangitis, chronic active hepatitis, and cirrhosis. Biliary tract complications are sclerosing cholangitis (ulcerative colitis) and gallstones (Crohn’s disease). Cholesterol gallstones occur in patients with ileal disease or after ileal resection because of malabsorption of bile salts and the resultant decrease in the size of the bile salt pool. Pericholangitis is the most common hepatic complication of IBD, but patients with pericholangitis are usually asymptomatic. Elevations in alkaline phosphatase are seen frequently; elevations in bilirubin are less common.

Sclerosing cholangitis ( Chapter 159 ) is a chronic cholestatic liver disease marked by fibrosing inflammation of the intrahepatic and extrahepatic bile ducts. Even though it occurs in only 1 to 4% of patients with ulcerative colitis and with lower frequency in Crohn’s disease, the majority of patients with sclerosing cholangitis have IBD. Colectomy and medical treatment of the bowel disease do not ameliorate the course; sclerosing cholangitis is one of the most common indications for liver transplantation ( Chapter 158 ) in adults.

Dermal Manifestations

The two common dermal complications of IBD are pyoderma gangrenosum and erythema nodosum ( Chapter 466 ). The lesions of pyoderma gangrenosum almost always develop during a bout of acute colitis and generally resolve with control of the colitis by oral or intradermal corticosteroids; in rare cases, colectomy is required. The activity of erythema nodosum, which is seen particularly in association with Crohn’s disease in children, follows the activity of the bowel disease.

Ocular Manifestations

Ocular complications of IBD are uveitis and episcleritis ( Chapter 449 ). Local therapy with corticosteroids and agents that dilate the pupil helps prevent scarring and blindness.


Diagnostic Tests


In both ulcerative colitis and Crohn’s disease, the radiographic findings may not correlate well with disease activity. The patient’s clinical response or endoscopic findings are more useful for this purpose.

Ulcerative Colitis

In early ulcerative colitis, findings on barium enema may be normal, or there may be limited distensibility of the involved segment resulting in a narrowed, shortened, and tubular form of the lumen. The haustral markings disappear, and the normally tortuous appearance of the colon is straightened ( Fig. 144-1 ). Air contrast examination reveals a fine granular appearance of the mucosa with a slightly irregular surface. In more severe disease, the granularity becomes coarser and eventually nodular; ulcers penetrate through the mucosa and can be seen in profile as small collar-button collections of barium extending beyond the colonic lumen.

FIGURE 144-1  Ulcerative colitis. An air contrast barium enema demonstrates luminal narrowing and loss of haustral markings in the sigmoid and descending colon in a patient with ulcerative colitis.

Crohn’s Disease

The earliest form of Crohn’s disease detectable by air contrast barium enema is marked by the presence of aphthous ulcers, which appear as small discrete collections of barium surrounded by radiolucent halos of inflammatory infiltrate. These small ulcers are usually multiple, and the intervening mucosa is normal. As Crohn’s disease becomes more severe, the aphthous ulcers enlarge, deepen, and connect with one another to form linear ulcers; the intervening mucosa develops a nodular appearance on radiographs, a process termed cobblestoning. Progressive deepening of ulcers can lead to abscess formation or fistulization. Contrast studies are more likely than endoscopic studies to identify fistulas. Transmural inflammation and fibrosis lead to limited distensibility with decreased luminal diameter and stricture formation. Like fistulas, strictures are more easily appreciated on radiographic studies than by endoscopy. Transmural inflammation and fibrosis result in thickening of the bowel wall with wide gaps between the barium-filled lumens of loops of inflamed small bowel ( Fig. 144-2 ). Small bowel Crohn’s disease can be evaluated by small bowel follow-through or by enteroclysis. Computed tomography and ultrasonography are useful in identifying abscesses and other fluid collections and in assessing the thickness of the bowel wall.

FIGURE 144-2  Small bowel follow-through in a patient with Crohn’s disease of the ileum. Luminal narrowing, mucosal ulceration, and separation of the barium-filled loops because of thickening of the bowel wall are apparent.



Ulcerative Colitis

The earliest endoscopic manifestations of ulcerative colitis are the development of diffuse erythema and loss of the fine vascular pattern seen in the normal rectal mucosa ( Fig. 144-3 ). Erythema is usually accompanied by mucosal edema, which is manifested endoscopically by blunting of the rectal valves, loss of normal vasculature, and the development of granular-appearing mucosa. Inflammation is associated with the presence of yellowish exudate on the mucosa. The inflamed mucosa bleeds easily if touched with the endoscope; this easy bleeding is termed friability. In more severe disease, the mucosa bleeds spontaneously and small ulcerations appear. An important aspect of the endoscopic findings in ulcerative colitis is their distribution: inflammation begins in the rectum, extends proximally a certain distance, and then stops; all the mucosa proximal to that point is normal, and all the mucosa distal to it is abnormal.

FIGURE 144-3  Endoscopic view of the colonic mucosa in a patient with idiopathic ulcerative colitis. Friable mucosa, extensive ulceration, and exudates were detected.

Crohn’s Disease

The earliest endoscopic manifestation of Crohn’s disease is an aphthous ulcer, a small discrete ulcer a few millimeters in diameter surrounded by a thin red halo of edematous tissue ( Fig. 144-4 ). Ulcers may be rounded or long and serpiginous. Longitudinal and transverse ulcers may intersect to form a grid with intervening cobblestone-like areas of nonulcerated mucosa ( Fig. 144-5 ). Large, deep, penetrating ulcers can be surrounded by areas of normal-appearing mucosa. The diffuse mucosal irregularities of erythema, edema, and granularity, which are prominent in ulcerative colitis, occur less commonly and later in the course of Crohn’s disease. The rectum may or may not be involved in Crohn’s disease. Areas of involvement are typically interspersed with normal “skip” areas.

FIGURE 144-4  A single aphthous ulcer, the earliest endoscopic finding in Crohn’s disease.

FIGURE 144-5  Crohn’s disease of the colon. Multiple edematous inflammatory polyps give a “cobblestone” appearance to the mucosa. Similar changes may be seen in ulcerative colitis.  (From Forbes CD, Jackson WD: Color Atlas and Text of Clinical Medicine, 3rd ed. London, Mosby, 2003.)

Differential Diagnosis

For many therapeutic decisions it is not particularly important to know whether the patient has ulcerative colitis or Crohn’s disease. However, when surgery is contemplated, the distinction is important. For example, colectomy and ileoanal anastomosis could be recommended as a curative procedure if the physician were confident that the patient had ulcerative colitis rather than Crohn’s colitis.

Distribution of Inflammation

The anatomic distribution of the inflammatory response may be helpful in distinguishing ulcerative colitis from Crohn’s disease. In ulcerative colitis, inflammation is seen in the rectum and extends proximally for some distance; with extensive disease, inflammation extends to the cecum. Although ulcerative colitis does not involve the small intestine, there may be a few centimeters of inflamed mucosa without ulceration in the terminal ileum. If the rectum is spared or if there are areas of uninflamed mucosa (skip areas) between areas of inflamed mucosa, Crohn’s colitis is more likely. Not only is ulcerative colitis continuous along the longitudinal axis of the colon, but the degree of inflammation is also consistent and symmetrical circumferentially at any level. In contrast, in Crohn’s colitis, deep linear ulcers may be separated by areas of normal mucosa. A major distinguishing mark in favor of Crohn’s disease is the presence of transmural inflammatory changes; in ulcerative colitis, inflammation is confined to the mucosa and submucosa. Extensive perianal involvement with fistulas and abscesses point to Crohn’s disease. The presence of noncaseating granulomas suggests Crohn’s disease, but even in Crohn’s disease, most patients have no granulomas on biopsy. Despite all these differences, there is a small but significant number of patients with IBD who cannot be assigned with confidence to one disease category or the other; these patients are considered to have indeterminate colitis.


Infections with Shigella, Amoeba, Giardia, Escherichia coli O157:H7, and Campylobacter can be accompanied by bloody diarrhea, cramps, and an endoscopic picture identical to ulcerative colitis ( Chapter 305 ). An important distinction between these infectious diseases (except amebiasis) and IBD is that the diarrhea in infectious diseases tends to be limited to a period of days to a few weeks whereas the diarrhea in IBD is typically of longer duration. Stool cultures for bacterial pathogens and serologic tests for amebiasis help distinguish infectious diarrhea from IBD. In patients with prolonged diarrhea, other protozoal diseases such as giardiasis must be considered. Pseudomembranous colitis is manifested as profuse watery diarrhea and may last from a few days to months; the presence of small membranous plaques adherent to the mucosa on sigmoidoscopy is pathognomonic. As part of the initial evaluation of patients with acute exacerbations of IBD, it is appropriate to check the stool for Clostridium difficile toxin, especially if there has been recent antibiotic exposure.

Other Symptoms

Mild ulcerative colitis, in which rectal bleeding is the primary manifestation, can be confused with hemorrhoids or anal fissures ( Chapter 148 ). The presence of urgency or diarrhea is more consistent with ulcerative colitis. Sigmoidoscopy should easily differentiate ulcerative colitis from these perianal problems.

Collagenous colitis is a chronic inflammatory disease marked pathologically by the presence of thick collagen deposition in the subepithelial layer of the colonic mucosa ( Chapter 143 ). The typical clinical manifestation is chronic watery diarrhea in a middle-aged woman. Endoscopically, the mucosa appears mildly inflamed or, more commonly, absolutely normal; biopsy with histology provides the diagnosis. Ischemic colitis is part of the differential diagnosis of the initial bout of IBD and should be considered in elderly persons or others at particular risk for ischemic disease ( Chapter 146 ). Diverticulitis, which may be difficult to separate from acute Crohn’s colitis, tends to be a more acute problem without a chronic inflammatory state ( Chapter 145 ). Intestinal lymphoma can mimic the symptoms of Crohn’s disease; in lymphoma, small bowel radiographs may show diffuse involvement with masses in the bowel wall. If Crohn’s disease has a long, indolent course with relatively mild symptoms, it may be difficult to differentiate from IBS, and some patients may have both ( Chapter 139 ).


Medical Therapy

Drugs Used for Inflammatory Bowel Disease

General Supportive Therapy

Antidiarrheal agents, usually loperamide or diphenoxylate, are useful in patients with mild IBD to reduce the number of bowel movements and to relieve rectal urgency. Anticholinergics (tincture of belladonna, clidinium, propantheline bromide, and dicyclomine hydrochloride) may reduce cramps, pain, and rectal urgency. An especially effective combination of an antidiarrheal and an antispasmodic is powdered opium (25 mg) and belladonna (15 mg). Antidiarrheal agents and antispasmodics are contraindicated in severe colitis because of the risk of precipitating toxic megacolon. The chronic use of narcotics for pain should not be part of the management of IBD. Sometimes antidepressants can be helpful. Nonsteroidal anti-inflammatory drugs can exacerbate the clinical activity of IBD and should be used cautiously.

Nutritional management plays only a small role in ulcerative colitis. Patients should avoid specific foods that worsen their symptoms, typically high-fiber foods. Nutritional management plays a much larger role in Crohn’s disease, in which many patients have diminished caloric intake and vitamin B12, vitamin D, calcium, magnesium, zinc, and iron may be malabsorbed. Both total parenteral nutrition and elemental enteral diets can decrease intestinal inflammation by reducing the antigen load in the lumen.


Agents that contain 5-aminosalicylic acid (5-ASA) are mainstays of therapy for ulcerative colitis and play a small role in the management of Crohn’s disease. 5-ASA appears to act from the luminal surface, so oral formulations are designed to prevent absorption of 5-ASA while making it available in the lumen. In sulfasalazine, olsalazine, and balsalazide, 5-ASA is covalently bound to either another molecule of 5-ASA (olsalazine) or another agent (sulfasalazine and balsalazide); when these covalent bonds are broken by colonic bacteria, 5-ASA is released. In Asacol and Pentasa, the delayed-release or sustained-release 5-ASA is delivered as free 5-ASA to different portions of the gastrointestinal tract ( Table 144-3 ). The efficacy of 5-ASA formulations is highly related to the concentration achieved in the lumen at the site of disease, with this dose-response relationship being seen up to doses of at least 4.8 g of 5-ASA per day, which is 12 tablets of Asacol.

5-ASA is also available as an enema, which reaches the descending colon, and as a suppository, which treats the rectum. The enema and suppository formulations are very effective in treating ulcerative proctitis, both as therapy for active disease and for maintenance of remission, either when used alone or with oral 5-ASA formulations.


Oral corticosteroids are effective in mild to moderate ulcerative colitis and Crohn’s disease. Parenteral therapy is reserved for moderate to severe disease. The typical initial dose of prednisone is 40 mg/day for moderate to severe disease. The patient takes high doses of corticosteroids until symptoms begin to diminish, after which the dose is gradually reduced. If an inadequate initial dose of prednisone is used because of fear of side effects, the likelihood of a positive response diminishes. In some patients, disease activity flares when the dose of prednisone is reduced to less than a certain level (steroid dependence). For most patients, administration of oral prednisone in a single morning dose is as effective as divided doses. Corticosteroids should not be used in patients with undrained abscesses or when symptoms are due to a stricture or fibrotic process. Maintenance therapy with corticosteroids is ineffective in preventing recurrences in ulcerative colitis or Crohn’s disease in remission. The many side effects of corticosteroids ( Chapter 33 ) are the major factor limiting their use in IBD.


Immunomodulator drugs act by blocking lymphocyte proliferation, activation, or effector mechanisms. There is extensive experience with azathioprine and its metabolite 6-mercaptopurine (6-MP) in treating IBD and lesser experience with cyclosporine and methotrexate. Azathioprine and 6-MP are effective in treating active Crohn’s disease and in maintaining remission; their role in ulcerative colitis is less clear. Typical initial doses are 1 to 1.5 mg/kg for 6-MP and 2.0 to 2.5 mg/kg for azathioprine. The delay between initiation of therapy and clinical response is typically 3 to 4 months. These drugs are used in patients who have active disease that is unresponsive to corticosteroids (refractory patients) and in corticosteroid-dependent patients. In these patients, 6-MP or azathioprine is added to corticosteroid therapy; after 3 or 4 months, when the 6-MP and azathioprine are likely to have taken effect, the dose of corticosteroids is gradually tapered. Most clinicians maintain patients on 6-MP or azathioprine for several years if remission is induced by these drugs. Some patients are maintained on these drugs indefinitely. The major limiting factor in the use of 6-MP and azathioprine is their toxicity; both commonly cause leukopenia, may cause pancreatitis, and may increase the risk for lymphoma. Methotrexate, given either orally or parenterally, is effective in active Crohn’s disease. Cyclosporine, given intravenously, is effective in reducing inflammation in patients with severe ulcerative colitis who are facing colectomy.


Except in cases of overt sepsis, there is little role for antibiotics in the management of ulcerative colitis. Antibiotics do not affect the remission rate; moreover, the risk of inducing antibiotic-associated pseudomembranous colitis must be considered. Antibiotics play a larger role in Crohn’s disease; they are used in management of the suppurative complications, especially abscess formation and perianal disease, although surgical drainage is the primary therapy for abscesses. Metronidazole (10 to 15 mg/kg/day) is effective in perianal Crohn’s disease and is as effective as sulfasalazine in Crohn’s colitis. The major side effect of metronidazole is peripheral neuropathy, which is dose dependent and generally resolves when use of the drug is discontinued. Ciprofloxacin at 500 mg twice a day for a few weeks is also effective in some patients.

Anti–Tumor Necrosis Factor Antibody

Infliximab, a chimeric mouse-human antibody against TNF-α, is effective in the management of active, moderate to severe Crohn’s disease and fistulas associated with Crohn’s disease,[1] as well as in patients with refractory ulcerative colitis.[2] The efficacy of infliximab may relate to binding free TNF-α or to lysing lymphocytes and macrophages that have TNF-α bound to their surfaces. Treatment is by intravenous infusion (5 mg/kg), which can be performed every 8 weeks or on an as-needed schedule. About 65% of patients with active Crohn’s disease improve, and about a third achieve remission. Long-term response rates, however, are considerably lower. Infliximab is associated with a substantial risk for infection (sepsis, pneumonia, and activation of tuberculosis) and a small but real risk for lymphoma, so it is generally reserved for patients who have failed to respond to azathioprine. Infliximab appears to have a higher rate of efficacy and a lower rate of side effects when it is given with azathioprine rather than as a single agent because azathioprine modulates the intrinsic reaction to the mouse portion of infliximab.

Medical Management of Ulcerative Colitis ( Fig. 144-6 )


For active ulcerative proctitis, a relatively effective and rapidly acting approach is nightly administration of 5-ASA retention enemas or suppositories, often supplemented with an oral aminosalicylate. Corticosteroid enemas can also be used. Either 5-ASA suppositories or corticosteroid foam is appropriate for disease involving up to 20 cm of distal colon; 5-ASA or corticosteroid retention enemas can be used for active disease involving up to 60 cm of distal colon. Another approach to proctitis or distal colitis is an oral aminosalicylate, although a response may not be evident for 3 to 4 weeks.

Extensive Colitis

In patients with colitis of mild to moderate activity and extension proximal to the sigmoid colon, the initial drug of choice is an oral aminosalicylate; efficacy increases with increasing doses. Even with more extensive disease, supplementation of oral aminosalicylates with aminosalicylate enemas or suppositories may help reduce the symptoms of urgency that result from rectal involvement. In patients with more active disease (more than five or six bowel movements per day), patients in whom a more rapid response is desired, or those who have not responded to 3 to 4 weeks of aminosalicylates, the treatment of choice is oral prednisone. Patients with severe diarrhea, systemic symptoms, or significant amounts of blood in stool should be started on 40 mg/day; most patients respond to oral corticosteroids within a few days. After the symptoms are controlled, prednisone can be gradually tapered by 5 mg every 1 to 2 weeks. Patients who respond to oral prednisone and can be fully withdrawn from it should be maintained on an aminosalicylate.

For patients who do not respond to corticosteroids (steroid refractory) or who do respond but whose disease flares whenever the corticosteroids are withdrawn (steroid dependent), options include indefinite corticosteroid therapy, an immunomodulator (azathioprine or 6-MP), or colectomy. Continuation of high-dose corticosteroid therapy for too long a time is the most common serious error in the management of ulcerative colitis. If the patient is taking a substantial dose (>15 mg/day of prednisone) for more than 6 months, a trial of an immunomodulator or colectomy should be given serious consideration.

The most common reason for hospitalization is intractable diarrhea, although blood loss is also a frequent problem. Patients with severe active ulcerative colitis should be evaluated for toxic megacolon. Anticholinergics and antidiarrheal agents are contraindicated in patients with severe ulcerative colitis because of the risk of precipitating toxic megacolon. The mainstays of therapy for severe ulcerative colitis are bedrest, rehydration with intravenous fluids, and intravenous corticosteroids (hydrocortisone, 300 mg/day; prednisolone, 60 to 80 mg/day; or methylprednisolone, 48 to 60 mg/day). Total parenteral nutrition may be necessary in the event of malnutrition. Patients with peritoneal signs or signs of systemic infection should be treated with parenteral antibiotics. Patients who do not improve in 7 to 10 days should be considered for either colectomy or a trial of intravenous cyclosporine.

Maintenance Therapy

Aminosalicylates reduce the incidence of recurrence in patients with ulcerative colitis; almost all patients should receive maintenance therapy. The efficacy of sulfasalazine at 3 to 4 g/day is greater than its efficacy at 2 g/day, even though 2 g/day is the usual recommended maintenance dose. Corticosteroids are not effective as maintenance therapy and should not be used. Azothioprine is also an effective maintenance therapy in patients who fail aminosalicylate therapy.[3] Most of the experience with 6-MP as maintenance therapy for ulcerative colitis is in patients whose acute disease has been brought under control with 6-MP; withdrawal of 6-MP from these patients results in a high incidence of exacerbation.

Medical Management of Crohn’s Disease ( Fig. 144-7 )

General Approach

It is difficult to develop generally applicable guidelines for the management of Crohn’s disease because of the great variety of anatomic locations, clinical manifestations, and gastrointestinal complications such as fistulas, abscesses, strictures, and perforations. Response to therapy is monitored by empirical clinical assessment directed at the problem that is most troublesome for the patient.

A common problem in the management of Crohn’s disease is a marked discrepancy between the severity of the patient’s symptoms and the objective signs of disease activity. Patients with severe pain and diarrhea may have minimal findings on endoscopy or radiographic studies. Patients who have undergone ileal resection may have significant diarrhea on the basis of their surgery alone.

Active Disease

For colonic Crohn’s disease, either oral corticosteroids (prednisone, 40 mg/day) or antibiotics (metronidazole, 10 to 15 mg/kg/day, and/or ciprofloxacin, 500 mg twice a day) are reasonable first-line therapies. In patients with small bowel Crohn’s disease, corticosteroids, either prednisone or budesonide (6 to 9 mg/day), are appropriate. Before corticosteroids are given to a Crohn’s disease patient with abdominal pain, fever, and a high leukocyte count, an abdominal computed tomography scan should be obtained to exclude an abscess.

In patients who have been brought into clinical remission with corticosteroids, the rate at which the dose is tapered is arbitrary and has not been defined by controlled trials. Usually the prednisone dose can be tapered from 40 to 20 mg/day relatively rapidly (5 mg/wk) without inducing a flare of disease activity. If the patient has not been taking a 5-ASA preparation, one should be added to increase the likelihood of successful corticosteroid withdrawal. Once the dose of prednisone has reached 20 mg/day, the taper is slowed to 5 mg every 10 to 14 days; if symptoms flare, the dose of prednisone is increased. At this point, the best approach for most patients is a trial of an immunomodulator, either 6-MP or azathioprine; corticosteroid therapy is continued for 3 to 4 months and then tapered gradually. Approximately 60% of corticosteroid-dependent patients are able to withdraw from corticosteroids with this approach; the alternative is surgery if there is a stricture or a focal area of involvement.

Infliximab is typically given in combination with azathioprine or 6-MP to patients who have failed therapy with azathioprine or 6-MP. A novel investigational approach to Crohn’s disease is the use of granulocyte-macrophage colony-stimulating factor. The approach to severe Crohn’s disease is similar to the approach to severe ulcerative colitis. The patient is hospitalized, given nothing by mouth, rehydrated with intravenous fluids, and administered parenteral corticosteroids. Patients who respond to parenteral corticosteroids are switched to high-dose oral corticosteroids (prednisone, 40 mg/day), and the dose of prednisone is gradually reduced. Patients with severe Crohn’s disease who do not respond to parenteral corticosteroids within a week should be considered for surgery. A course of total parenteral nutrition may be useful as adjunctive therapy.

Maintenance Therapy

Maintenance therapy with aminosalicylates has been recommended for those brought into remission with corticosteroids or by surgery; however, the efficacy of aminosalicylates as maintenance therapy is much less well established in Crohn’s disease than in ulcerative colitis. Maintenance with 6-MP or azathioprine is recommended for patients brought into remission with these drugs or who were corticosteroid dependent and then converted to these drugs.[4] There is no role for corticosteroids as maintenance therapy.

Surgical Therapy

Ulcerative Colitis

Twenty percent to 25% of patients with extensive ulcerative colitis eventually undergo colectomy, usually because their disease has not responded adequately to medical therapy. In ulcerative colitis, colectomy is a curative procedure. Emergency colectomy may be required in patients with toxic megacolon or a severe fulminant attack without toxic megacolon. The standard operation for ulcerative colitis is proctocolectomy and Brooke’s ileostomy. The most popular alternative operation is proctocolectomy and ileoanal anastomosis; in this procedure a pouch is constructed from the terminal 30 cm of ileum, and the distal end of the pouch is pulled through the anal canal. Ileoanal anastomosis is sometimes complicated by inflammation in the ileal pouch, which can be treated with probiotics.[5] The decision for or against colectomy is influenced by the patient’s age, social circumstances, and duration of disease. The risk for the development of malignancy ( Chapter 203 ) enters into the equation when considering colectomy in those with long-standing ulcerative colitis; if the other indications are equivocal, the risk for malignancy may push the balance in favor of colectomy.

Crohn’s Disease

Within 10 years of diagnosis, approximately 60% of patients with Crohn’s disease undergo surgery for their disease. Because surgical resection is not curative of Crohn’s disease and recurrences are likely, the approach is more conservative in terms of the amount of tissue removed. Failure of medical management is a common cause for resection in patients with Crohn’s disease, as it is in ulcerative colitis, but complications (e.g., obstruction, fistula, abscess) are often indications for resection in Crohn’s disease. Surgery is also performed to allow patients to stop taking medications (usually corticosteroids). For small bowel Crohn’s disease, the most common surgical procedure is segmental resection for obstruction or fistula. The incidence of recurrence severe enough to need repeat surgery after ileal or ileocolic resection is about 50% after 10 years and 75% after 15 years. Endoscopic and histologic surgical approaches to Crohn’s colitis include segmental resection, subtotal colectomy with ileoproctostomy, and total colectomy with ileostomy. For patients with extensive colonic disease that includes the rectum, the procedure of choice is total proctocolectomy with a Brooke ileostomy. Total colectomy with ileoanal anastomosis is not appropriate in Crohn’s colitis because recurrence of Crohn’s disease in the ileal segment forming the new pouch would require a repeat operation and loss of a long segment of ileum.


Ulcerative Colitis

The most severe complication of ulcerative colitis is toxic megacolon, or dilation of the colon to a diameter greater than 6 cm associated with worsening of the patient’s clinical condition and the development of fever, tachycardia, and leukocytosis. Physical examination may reveal postural hypotension, tenderness over the distribution of the colon, and absent or hypoactive bowel sounds. Antispasmodics and antidiarrheal agents are likely to initiate or exacerbate toxic megacolon. Medical therapy is designed to reduce the likelihood of perforation and return the colon to normal motor activity as rapidly as possible. The patient is given nothing by mouth and nasogastric suction is begun. Intravenous fluids should be administered to replete water and electrolytes, broad-spectrum antibiotics are given in anticipation of peritonitis resulting from perforation, and parenteral corticosteroids are administered at a dose equivalent to more than 40 mg of prednisone per day. Signs of improvement include a decrease in abdominal girth and the return of bowel sounds. Deterioration is marked by the development of rebound tenderness, increasing abdominal girth, and cardiovascular collapse. If the patient does not begin to show signs of clinical improvement during the first 24 to 48 hours of medical therapy, the risk for perforation increases markedly, and surgical intervention is indicated.

Crohn’s Disease

Abscesses and Fistulas

Abscesses and fistulas, which are common complications in Crohn’s disease, are products of extension of a mucosal fissure or ulcer through the intestinal wall and into extraintestinal tissue. Leakage of intestinal contents through a fissure into the peritoneal cavity results in an abscess. Extension of the inflammatory process through the wall of adjacent viscera or through the abdominal wall to the exterior results in a fistula. Abscesses occur in 15 to 20% of patients with Crohn’s disease and are especially common in the terminal ileum. The typical clinical manifestation of an intra-abdominal abscess is fever, abdominal pain, tenderness, and leukocytosis. Abdominal abscess is most often diagnosed by computed tomography. Broad-spectrum antibiotic therapy, including anaerobic coverage, is indicated. Percutaneous drainage of abscesses in patients with Crohn’s disease may improve the clinical picture but does not provide adequate therapy because of persistent communication between the abscess cavity and the intestinal lumen. Resection of the portion of involved intestine containing the communication is usually required for definitive therapy. The prevalence of fistulas is 20 to 40% in Crohn’s disease. Most fistulas are enteroenteric or enterocutaneous, with smaller numbers being enterovesical or enterovaginal. Total parenteral nutrition or immunomodulator therapy may induce fistula closure; however, the fistulas often recur after the total parenteral nutrition or immunomodulator therapy is stopped. Surgical treatment includes resection of the segment involved with active disease.


Obstruction is a common complication of Crohn’s disease, particularly in the small intestine, and is a leading indication for surgery. Small bowel obstruction in Crohn’s disease may be caused by mucosal thickening from acute inflammation, by muscular hyperplasia and scarring as a result of previous inflammation, or by adhesions. Obstruction may also occur because of impaction of a bolus of fibrous food in a stable, long-standing stricture. Obstruction is marked by cramping abdominal pain and diarrhea that worsen after meals and resolve with fasting. Strictures may be evaluated by oral contrast studies, barium enema, or colonoscopy, depending on the anatomic location. Corticosteroids are useful if acute inflammation is an important component of the obstructive process, but not if the obstruction is due to fibrosis. A common error in the management of Crohn’s disease is treatment with long courses of corticosteroids in patients who have obstructive symptoms from fixed anatomic lesions. If the obstruction does not resolve with nasogastric suction and corticosteroids, surgery is necessary.

Perianal Disease

Perianal disease is an especially difficult complication of Crohn’s disease. A complex of problems is caused by ulcers in the anal canal and the resulting fistulas. The fistulous openings are most commonly found in the perianal skin but can occur in the groin, the vulva, or the scrotum. Fistulas are accompanied by drainage of serous or mucous material. If the fistula does not drain freely, there is local accumulation of pus (perianal abscess) with redness, pain, and induration. The pain of a perianal abscess is exacerbated by defecation, sitting, or walking. The typical physical manifestation of an abscess is redness with tenderness on digital examination. Adequate evaluation of perianal disease generally requires proctoscopic examination under anesthesia. Computed tomography is useful in defining the presence and extent of perianal abscesses. The goals of therapy for perianal disease are relief of local symptoms and preservation of the sphincter. Limited disease can be approached with sitz baths and metronidazole, but in most cases adequate external drainage is also required. Azathioprine or infliximab may be useful in healing perianal disease, but the disease may reactivate when use of the drug is stopped. Persistent severe perianal Crohn’s disease can result in destruction of the anal sphincter and fecal incontinence.


Colon Cancer, Dysplasia, and Colonoscopic Surveillance

Patients with extensive ulcerative colitis have a markedly increased risk for colon cancer in comparison to the general population beginning 8 to 10 years after diagnosis and increasing with time. The risk for malignancy is also a function of the anatomic extent of the disease; the risk is much greater with pancolitis than with left-sided disease. Patients with long-standing ulcerative colitis are at risk for cancer ( Chapter 203 ) even if their symptoms have been relatively mild; that is, colon cancer is seen in patients whose disease has been quiescent for 10 to 15 years. In ulcerative colitis, colon cancers are frequently submucosal and may be missed at colonoscopy. Colon cancer in patients with ulcerative colitis is associated with dysplastic changes in the mucosa at other sites in the colon. Dysplasia cannot be identified by visual inspection; microscopic examination of biopsy specimens is required. Some practitioners perform surveillance colonoscopy with random biopsies in patients with long-standing ulcerative colitis beginning 8 to 10 years after the onset of disease and repeated every 1 to 2 years. If the specimens show dysplasia, the patient is sent for colectomy. Although it is clear that dysplasia is associated with colon cancer in patients with ulcerative colitis, the utility of surveillance colonoscopy has not been firmly established. The risk for colon cancer in Crohn’s colitis is less than in ulcerative colitis but greater than in the general population. The utility of surveillance in Crohn’s colitis is unproven.


Fertility in women with IBD is normal or only minimally impaired, and the incidence of prematurity, stillbirth, and developmental defects in the offspring of women with IBD is similar to that of the general population. The incidence of fetal complications may be somewhat higher in cases in which the mother’s disease is clinically active, regardless of drug therapy. Previous proctocolectomy or the presence of an ileostomy is not an impediment to successful completion of a pregnancy. Many women have taken sulfasalazine throughout the course of pregnancy, and there is no evidence of it causing harm to the fetus. Pregnant women have an increased requirement for folic acid, and sulfasalazine interferes with folate absorption. Therefore, women taking sulfasalazine who are pregnant or considering pregnancy should receive folate supplementation (1 mg twice daily) to ensure that the fetus receives amounts adequate for normal development. The use of corticosteroids by pregnant women with IBD is not associated with an increased rate of fetal complications. In general, it appears that the risk to the pregnancy of treatment with sulfasalazine or corticosteroids is less than the risk of allowing disease activity to go untreated. Most of the data on azathioprine and 6-MP in pregnancy come from the transplant literature and involve higher doses than are commonly used for IBD. Reported fetal effects in the transplant population include congenital malformations, immunosuppression, prematurity, and growth retardation; risks in the IBD population are not known. The effects of pregnancy on IBD depend on disease activity. If the patient’s disease is inactive at the time of conception, it is likely that it will remain inactive during the course of the pregnancy. If the disease is active at the time of conception, the course is harder to predict. Ulcerative colitis that is active at the time of conception tends to worsen. In two thirds of Crohn’s disease cases that are active at conception, the degree of activity remains the same; in the other third, some improve clinically and others deteriorate.

TABLE 144-3   — 

Preparation Delivery Distribution Dose[*]
Mesalamine suppository Direct Rectum 500 mg once or twice a day
Mesalamine enema Direct Left colon 4 g in 60 mL at bedtime
Sulfasalazine Bacterial azo reductase Colon 4–6 g in divided doses
Dipentum Bacterial azo reductase Colon 1.5–3.0 g in divided doses
Asacol Release at pH >7 Distal ileum, colon 2.4–4.8 g in divided doses
Pentasa Time-release ethyl cellulose microgranules Ileum, colon 3–4 g in divided doses
Balsalazide Bacterial azo reductase Colon 6.75 g in divided doses

* Doses given are for active disease; similar doses can be given for maintenance therapy, although some practitioners use lower doses for maintenance.

FIGURE 144-6  Treatment algorithm for ulcerative colitis. ASA = aminosalicylic acid.

FIGURE 144-7  Treatment algorithm for Crohn’s disease. ASA = aminosalicylic acid; IV = intravenous; TPN = total parenteral nutrition.

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