The physical examination in patients with proctitis is significant for a tender anal canal and blood on rectal examination. With more extensive disease, patients have tenderness to palpation directly over the inflamed parts of 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.

Complications

Only 15% of patients with UC present initially with severe disease. Massive hemorrhage occurs in 1% of patients, and treatment for the inflammation usually stops the bleeding. A colectomy is indicated if a patient requires more than 6–8 units of blood within 1–2 days. Toxic megacolon occurs when the transverse colon dilates to more than 5–6 cm and can occur in about 5–6% of attacks. It can be precipitated by electrolyte imbalances, prolonged bed rest, and narcotics. About 50% of acute colonic dilations will resolve with medical therapy alone, but the rest will require surgical intervention. Perforation is the most dangerous of complications, and the symptoms of peritonitis may be masked by high doses of glucocorticoids. The mortality rate for a perforated toxic megacolon is 15%. Rare patients may develop a toxic colitis with severe ulcerations that may perforate without first dilating. Colon strictures that form in patients with UC have a high probability of being malignant, and surgical resection should be performed if a colonoscope cannot be passed through the stricture.

Laboratory Findings

Active disease is associated with a rise in acute-phase reactants (C-reactive protein [CRP]), erythrocyte sedimentation rate (ESR), and platelet count and a decrease in hemoglobin. In severely ill patients, the serum albumin will fall quickly. Leukocytosis may be present but is not an indicator of disease severity. Stool cultures for bacterial pathogens, Clostridium difficile toxin, ova, and parasites should be performed. Diagnosis is based on negative stool examination and a sigmoidoscopy and biopsy, which reveal chronic active inflammation.

Endoscopic and Radiographic Findings

Sigmoidoscopy is used to assess disease activity. If the patient is not acutely flaring, a full colonoscopy is very helpful in assessing extent of disease. Pathology is also very helpful in grading disease activity. Colonoscopy is more useful than barium enema and computed tomography (CT) scanning in assessing extent and activity of UC.

CROHN’S DISEASE

CD usually presents as acute or chronic bowel inflammation and evolves to one of two disease phenotypes: a fibrostenotic-obstructing pattern or a penetrating fistulous pattern (box 71.1). Disease location and disease phenotype dictate treatment and prognosis.

Box 71.1 VIENNA CLASSIFICATION OF CROHN’S DISEASE

Ileocolitis

The most common site of inflammation is the terminal ileum, and the most common presentation is a history of diarrhea, night sweats, gradual weight loss, and right lower quadrant pain. Pain is usually crampy and precedes and is relieved by defecation. It is uncommon to have frankly bloody diarrhea. Sometimes, the presentation will mimic acute appendicitis with significant right lower quadrant pain, a palpable mass, fever, and leukocytosis. Usually the fever is low grade; a high-grade fever suggests that an intra-abdominal abscess might be present. Because Crohn’s disease has a more insidious onset than UC, symptoms may be ignored until they are severe, and 10–20% of body weight is often lost.

    An inflammatory mass may be palpated in the right lower quadrant of the abdomen. This mass is composed of inflamed bowel, adherent and thickened mesentery, and enlarged abdominal lymph nodes. Extension of the mass can cause right ureter or bladder inflammation or obstruction of the right Fallopian tube in women. Edema, bowel wall thickening, and fibrosis of the bowel wall account for the radiographic “string sign” of a narrowed small bowel lumen.

    With inadequate or no treatment, bowel obstruction can occur. Inflammation can cause edema of the bowel wall and intermittent pain and obstructive symptoms. The inflamed bowel wall will eventually scar down and form a stricture. In this scenario, obstruction is caused by impacted food or medication and can be resolved by intravenous fluids, nasogastric decompression, and bowel rest.

    Severe inflammation of the ileocecal area may lead to localized wall thinning with microperforation and fistula formation to the adjacent bowel, skin, bladder, or to an abscess cavity in the mesentery. Enterovesical fistulas usually present as dysuria or recurrent bladder infections or, less commonly, with pneumaturia or fecaluria. Enterocutaneous fistulas typically drain through abdominal surgical scars. Enterovaginal fistulas are rare and only occur in women who have had a hysterectomy. Patients present with dyspareunia or with a foul-smelling, often painful vaginal discharge.

Colitis and Perianal Disease

Patients present with low-grade fevers, abdominal pain, weight loss, crampy abdominal pain, and nonbloody diarrhea. Pain is caused by passage of stool through a narrowed and inflamed colon, and diarrhea can be partially due to rectal inflammation with decreased compliance. Toxic megacolon is rare in Crohn’s colitis, as is gross bleeding. Stricturing in the colon occurs in 4–16% of patients and can cause symptoms of bowel obstruction. If a colonoscope cannot pass through the stricture, surgery is recommended because of the risk of a hidden colon cancer. Colonic disease may fistulize into the stomach or duodenum, causing feculent vomiting, or to the small bowel, causing diarrhea by short-circuiting of intestinal contents. Ten percent of women with Crohn’s colitis will develop a rectovaginal fistula.

    One-third of patients with Crohn’s colitis develop perianal disease manifested by incontinence, large hemorrhoidal skin tags, anorectal fistulas, anal strictures, and perirectal abscesses. Not all patients with perianal disease will have evidence of colonic inflammation.

Jejunoileitis

Extensive Crohn’s disease of the small intestine is associated with a loss of digestive and absorptive surface, resulting in malabsorption and weight loss. Patients will often have nutritional deficiencies including vitamin D, calcium, niacin, and vitamin B₁₂ deficiency and should be checked for these as well as for osteoporosis. Malabsorption can also cause hypoalbuminemia, hypomagnesemia, coagulopathy, and hyperoxaluria with nephrolithiasis in patients with an intact colon. Diarrhea is characteristic of active disease and is due to a combination of active inflammation, bacterial overgrowth from Crohn’s strictures, and bile acid and occasionally fatty acid malabsorption due to extensive ileal disease.

Gastroduodenal Disease

Symptoms and signs of upper-gastrointestinal-tract disease include nausea, vomiting, epigastric pain, and an Helicobacter pylori–negative gastritis. Patients can present with a gastric outlet obstruction due to a stricture at the pylorus or in the duodenum. The second portion of the duodenum is more commonly involved than the duodenal bulb. Fistulas involving the stomach or duodenum can arise from the small or large bowel and do not necessarily signify the presence of upper gastrointestinal tract involvement.

Complications

Because CD is a transmural process, serosal adhesions develop that provide direct pathways for fistula formation. Free perforation is rare and occurs in 1–2% of patients, usually in the ileum or less commonly in the jejunum or as a complication of toxic megacolon. The peritonitis of free perforation may be fatal. Intra-abdominal and pelvic abscesses occur in 10–60% of patients and almost always require intravenous antibiotics and CT-guided drainage. Most patients will need eventual surgery to remove the offending bowel segment. Systemic glucocorticoids increase the risk of intra-abdominal and pelvic abscesses in Crohn’s patients who have never had an operation. Other complications include bowel obstruction in 40%, severe perianal disease, malabsorption, and, rarely, massive hemorrhage.

Laboratory Findings

Laboratory abnormalities include an elevated ESR and CRP. Findings in more severe disease include a hypoalbuminemia, anemia, and leukocytosis. Stool ova and parasites, Giardia antigen, C. difficile toxin, and bacterial cultures should be negative. Fecal calprotectin may also be useful for detecting small-bowel Crohn’s disease activity, and several abstracts have shown it to be as sensitive and specific as ileocolonoscopy and capsule endoscopy.

Endoscopic and Radiographic Findings

Endoscopic features of Crohn’s disease include rectal sparing, aphthous ulcerations, fistulas, and macroscopic and microscopic skip lesions. Colonoscopy allows examination and biopsy of the colon and terminal ileum. Wireless capsule endoscopy (WCE) allows direct visualization of the entire small bowel mucosa but cannot be used in the setting of a small bowel stricture. Capsule retention occurs in 4–6% of patients with established CD but in only <1% of patients with suspected CD. Early radiographic findings in the small bowel include thickened folds, aphthous ulcerations, and longitudinal ulcerations and transverse ulcerations. In more advanced disease, strictures, fistulas, inflammatory masses, and abscesses can be detected. 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 long gaps of normal or dilated bowel between involved segments.

    Both CT and magnetic resonance imaging (MRI) of the small bowel can be performed by enterography (CTE or MRE) using oral and IV contrast, as well as enteroclysis. Though institutional preference guides technique selection, CT and MR enterography tend to be preferred over enteroclysis due to ease and patient preference. Although CTE, MRE, and small bowel follow-through (SBFT) have been shown to be equally accurate in the identification of active small bowel inflammation, CTE and MRE have been shown to be superior to SBFT in the detection of extraluminal complications including fistulas, sinus tracts, and abscesses. Currently the use of CT scans is more common than MRI due to institutional availability and expertise. However, MRI is thought to offer superior soft tissue contrast and has the added advantage of avoiding radiation exposure. The lack of ionizing radiation is particularly appealing in younger patients and when monitoring response to therapy where serial images will be obtained. MRI is superior for visualizing pelvic lesions such as perirectal fistulas and ischiorectal abscesses.

Complications

Because Crohn’s disease is a transmural process, serosal adhesions develop that provide pathways for fistula formation and reduce the influence of free perforation. Free perforation occurs in 1–2% of patients, usually in the ileum but occasionally in the jejunum or as a rare complication of toxic megacolon. The peritonitis of free perforation, especially colonic, may be fatal. Generalized peritonitis may also result from the rupture of an intra-abdominal abscess. Other complications include intestinal obstruction in 40% of patients, massive hemorrhage, which is rare, 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), largely to myeloperoxidase, and anti–Saccharomyces cerevisiae antibodies (ASCAs). pANCA positivity is found in about 60–70% of UC patients and 5–10% of CD patients; 5–15% of first-degree relatives of UC patients are pANCA positive, whereas only 2–3% 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 anastomosis (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 Saccharomyces cerevisiae; 60–70% of CD patients, 10–15% of UC patients, and up to 5% of non-IBD controls are ASCA positive. Fifty-five percent of CD patients in a referral center population are seroreactive to outer membrane porin C (Omp C), and 50–54% of CD patients in a referral center population are positive for the I₂ antibody. The I₂ serologic response recognizes a novel homologue of the bacterial transcription-factor families from a Pseudomonas fluorescens–associated sequence.

    Combining these diagnostic assays further improves their ability to diagnose Crohn’s disease. In a referral population of patients with Crohn’s disease, 85% of patients responded to at least one antigen (pANCA, ASCA, Omp C, and I₂); only 4% responded to all four. In addition, antigen positivity may help predict disease phenotype. ASCA positivity may be associated with an increased rate of early CD complications, Omp C–positive patients are more likely to have internal perforating disease, and I₂-positive patients are more likely to have fibrostenosing disease. Patients positive for I₂, Omp C, and ASCA are the most likely to have undergone small bowel surgery.

    Cbir1 flagellin is an immunodominant antigen of the enteric microbial flora to which strong B-cell and CD4+ T-cell responses occur in colitic mice. Approximately 50% of patients with CD have serum reactivity to Cbir1, whereas UC have little or no reactivity to this flagellin. Anti-Cbir1 expression is associated with small bowel disease, fibrostenosing, and internal penetrating disease. Children with Crohn’s disease positive for all four immune responses (ASCA+, Omp C+, I₂+, and anti-Cbir1+) may have a more aggressive disease phenotype with a shorter time of progression to internal perforating and/or stricturing disease. Recently, it has been shown that incorporating a combination of serological, genetic, and inflammatory markers can improve the accuracy of identifying IBD and differentiating between CD and UC.

DIFFERENTIAL DIAGNOSIS OF UC AND CD

UC and CD have similar features to many other diseases. As there is no key diagnostic test, a combination of clinical, laboratory, histopathologic, radiographic, and therapeutic observations are required. Once a diagnosis of IBD is made, distinguishing between UC and CD is difficult to impossible in 10–15% of cases. These are termed indeterminate colitis. The diseases commonly mistaken for IBD are detailed in box 71.2.

Box 71.2 DISEASES MISTAKEN FOR CROHN’S DISEASE

NEOPLASTIC, DRUGS, AND CHEMICALS

Nonsteroidal anti-inflammatories, phosphosoda, chemotherapy, lymphoma, lymphosarcoma, carcinoma of the ileum, familial polyposis, metastatic carcinoma

INDETERMINATE COLITIS

There are some cases of IBD that cannot be recognized as either UC or CD and are called indeterminate colitis. Long-term follow-up over a period of years reduces the numbers of patients labeled indeterminate to about 10%. The disease course of indeterminate colitis is unclear, and surgical recommendations are difficult because about 20% of pouches in these patients will fail and eventually require an ileostomy. A multistage ileal pouch anal anastomosis (the initial stage consisting of a subtotal colectomy with Hartmann pouch) with careful histological evaluation of the resected specimen to exclude Crohn’s disease is advised. Medical therapy is similar to UC and CD.

THE ATYPICAL COLITIDES

Two atypical colitides, collagenous colitis and lymphocytic colitis, have completely normal endoscopic appearances. Collagenous colitis has two main histological components: increased subepithelial collagen deposition and colitis with increased intraepithelial lymphocytes. Male-to-female ratio is 9:1, and most patients present in the sixth or seventh decade of life. The main symptom is chronic watery diarrhea and sometimes weight loss. Treatments are variable and range from sulfasalazine or Imodium and Lomotil to bismuth or glucocorticoids for refractory disease.

    Lymphocytic colitis has features similar to collagenous colitis including age of 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. Celiac disease should be excluded in all patients with lymphocytic colitis, as the frequency ranges from 9% to 27%. The treatment is the same as in collagenous colitis except for a gluten-free diet in patients with celiac disease.

    Diversion colitis is an inflammatory process that arises in segments of the large intestine that are excluded from the fecal stream. Diversion colitis usually occurs in patients with ileostomies or colostomies when a mucous fistula or a Hartmann pouch has been created. Diversion colitis is reversible by surgical reanastomosis. Clinically, patients have mucous or bloody discharge from the rectum, and erythema, granularity, friability, and, in more severe cases, ulceration can be seen on endoscopy. There are areas of active inflammation with foci of cryptitis and crypt abscesses on histopathology. 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 this treatment is difficult to tolerate, and the definitive therapy is surgical reanastomosis.

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. The extraintestinal manifestations are detailed in table 71.2.

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