Diagnosis and differential

Table 25.3 Differential diagnosis of colitis

Infectious etiologies




Escherichia coli 0157: H7 and other enterohemorrhagic E. coli

Clostridium difficile



Entamoeba histolytica


Herpes simplex virus



HIV and HIV-related opportunistic infections Other

Ulcerative colitis Crohn's disease Henoch-Schönlein purpura Hemolytic uremic syndrome Intestinal ischemia Intussusception

Allergic colitis (primarily in infancy) Hirschsprung's enterocolitis (primarily in infancy)

Differential diagnosis

The diagnosis of ulcerative colitis is established by the information gathered from a detailed symptom and family history, physical examination, and a combination of laboratory, radiological, endoscopic and histological findings. It is important to exclude other etiologies, such as an infectious process, and to distinguish ulcerative colitis from Crohn's disease. Colonic inflammation is typically characterized by bloody diarrhea with abdominal cramping. The differential diagnosis of colitis depends upon the age of the child at the time of evaluation. In infancy, necrotizing enterocolitis, Hirschsprung's enterocolitis and allergic colitis are common. In contrast, in the older child and adolescent, enteric infection and IBD are the most common diagnoses. Causes of colitis are listed in Table 25.3. In patients with painless rectal bleeding, other conditions (Meckel's diverticulum, polyp) should be considered. In addition to details of the clinical presentation, the history should include family history, recent antibiotic therapy, infectious exposures, growth and sexual development and the presence of extraintestinal manifestations of ulcerative colitis. Physical examination should include assessment of height, weight and body mass index; abdominal distension, tenderness, or mass; extraintestinal manifestations (e.g. aphthous stomatitis, pyoderma gangrenosum, uveitis or arthritis); and fecal blood on rectal examination, perianal abnormalities (e.g. fistulae, fissures or tags). Findings on physical examination may help to distinguish ulcerative colitis from Crohn's disease; for example, pronounced growth failure or a perianal abscess strongly suggests the diagnosis of Crohn's disease. A severely ill child with ulcerative colitis may have tachycardia, orthostatic hypotension, fever, or dehydration.

Such findings in the presence of abdominal distension and a concerning abdominal examination, may herald a fulminant presentation of ulcerative colitis with increased risk of developing toxic megacolon.

Laboratory assessment

Initial laboratory evaluation should include appropriate blood tests, stool for occult blood, Clostridium difficile toxin assay and stool cultures. A complete blood cell count with differential may reveal a leukocytosis with or without left shift, anemia, or thrombocytosis. Thrombocytosis, hyp-oalbuminemia and elevated erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP) may indicate increased disease activity.61-63 The presence of anemia with low mean corpuscular volume (MCV), wide red cell distribution width (RDW) and low iron levels may indicate an iron-deficient anemia secondary to ongoing fecal blood losses or the anemia of chronic disease. Children with significant mucosal inflammation may have normal laboratory test results. In a study of children with ulcerative colitis or Crohn's colitis, 13 of 36 patients with ulcerative colitis (36%) had normal blood test results, including seven of 28 ulcerative colitis patients with macroscopic findings (obvious abnormalities) on colonoscopy, and 12 of 31 ulcerative colitis patients with histological moderate or severe chronic inflammation.63 Stool examination should rule out possible enteric infections (see Table 25.3). In sexually active patients, rectal cultures for gonorrhea should be considered. In ulcerative colitis, Gram stain or methylene blue stain of stools may identify leukocytes.

It has been proposed that certain serum antibodies may be helpful for screening for IBD and discriminating ulcerative colitis from Crohn's disease.64,65 Perinuclear antineutrophil cytoplasmic antibodies (P-ANCA) are seen in 60-80% of adults with ulcerative colitis compared to 10-27% of adults with Crohn's disease.64,66,67 Similarly, anti-Saccharomyces cerevisiae antibodies (ASCA) are commonly found in individuals with Crohn's disease but are rarely seen in ulcerative colitis. In a study of 173 children, ASCA yielded a sensitivity of 55% and specificity of 95% for Crohn's disease, and ANCA had a sensitivity of 57% and specificity of 92% for ulcerative colitis.64 In a study of 128 pediatric patients undergoing evaluation for IBD, Dubinsky et al utilized modified cutoff values to optimize the sensitivity of the ASCA and ANCA assays. For the combination of ASCA and P-ANCA, the sensitivity of detecting IBD increased to 81% with the modified values compared to the 69% with standard cut-off values; however, this was accompanied by an increase in false-positive rates among the children without IBD.65 An overlap of ASCA and P-ANCA positive serology between patients with Crohn's disease or ulcerative colitis remains. In particular, P-ANCA tends to test positive in the serum of patients with Crohn's disease who exhibit ulcerative colitis features.64,68 The value of these tests to supplement the routine diagnostic tests in IBD is a subject under study.

Endoscopic and radiographic evaluation

Evaluation with colonoscopy and ileoscopy with biopsies and a barium upper gastrointestinal series with small-bowel follow-through should be performed to diagnose ulcerative colitis, determine the extent and severity of ulcerative colitis presentation and distinguish ulcerative colitis from Crohn's disease or a non-IBD diagnosis. In patients with severe colitis, a limited flexible sigmoi-doscopy examination with minimal air insufflation may be prudent to avoid increased risk of a full colonoscopy (perforation, hemorrhage, toxic dilatation). In order to establish the extent of disease involvement by colonoscopy, we recommend biopsies from the terminal ileum and each segment of the colon, even if there are no visible findings at a particular level of the colon. In ulcerative colitis, typical findings seen by the endo-scopist include a diffuse, continuous process starting at the rectum and extending more proximally into the colon. However, in children with ulcerative colitis, rectal sparing has been reported.69,70 The colonic mucosa often appears edematous, erythematous and friable, with minute surface erosions and ulcerations (Figure 25.1). Larger, deeper ulcerations with associated exudate may develop in more severe disease. With more chronic (longstanding) ulcerative colitis, pseudopolyps may be present. (Figure 25.2). In contrast, in Crohn's disease, colonoscopy may reveal focal ulcerations (aphthous lesions) with intervening areas of normal-appearing mucosa (skip lesions).

Coliti Plesiomonas
Figure 25.1 Severe colitis at initial presentation of ulcerative colitis. The colonoscopy demonstrates a featureless colon with loss of vascular pattern and hemorrhage.

Figure 25.2 Colonic pseudopolyps present in a 16-year-old girl with an 8-year history of ulcerative colitis. The patient had persistent symptoms of diarrhea and rectal bleeding despite chronic corticosteroid and 6-mercapto-purine therapy, and subsequently underwent colectomy.

In severe or chronic Crohn's disease, linear ulcerations, nodularity (cobblestoning) and strictures or stenoses may be present. In general, the ulcerations in Crohn's disease are deeper and focal versus the diffuse, superficial ulcerations typical of ulcerative colitis (Table 25.4).64-74

An upper gastrointestinal series with small-bowel follow-through should be performed to look for any evidence of abnormality of the terminal ileum or more proximal gastrointestinal tract, and the presence of fistulae, which would suggest Crohn's disease. The only exception is the finding of ulcerative colitis-associated 'backwash ileitis', which should be distinguished from terminal ileal disease of Crohn's disease. With 'backwash ileitis', the ileum appears patulous and inflamed, involves only the distal ileal segment and is associated with pancolitis; there should be no evidence of extensive ulcerations or stricturing, as seen with Crohn's disease.75

Although by definition, the disease of ulcerative colitis is confined to the colon, children with

Crohn's disease or ulcerative colitis can have inflammation of the upper gastrointestinal tract.76-79 In a controlled, blinded study of children with ulcerative colitis or Crohn's disease, biopsies from the esophagus, gastric antrum and duodenum revealed histological evidence of esophagitis, gastritis and duodenitis in patients with either ulcerative colitis or Crohn's disease. Esophagitis occurred in 50%, gastritis in 69% and duodenitis in 23% of patients with ulcerative colitis. In contrast to ulcerative colitis patients, those with Crohn's disease had a higher prevalence of esophagitis, gastritis and duodenitis (72%, 92% and 33%, respectively).76 Granulomas of the upper gastrointestinal tract were seen in 40% of the patients with Crohn's disease and duodenal crypti-tis was noted in 26% of patients with Crohn's disease; none of these lesions was seen in the biopsies of patients with ulcerative colitis.76 In another study, the presence of focally enhanced gastritis in children did not reliably differentiate between Crohn's disease and ulcerative colitis.79 Except for the presence of granulomas of Crohn's disease, it may be difficult to distinguish between ulcerative

Table 25.4 Typical endoscopy and histopathology findings - ulcerative colitis (UC) vs. Crohn's disease (from references 69-74, 84)


Ulcerative colitis

Crohn's disease

Endoscopy findings

diffuse continuous involvement extending from the rectum

focal lesions/disease interspersed with normal-appearing mucosa (skip lesions)

rectum usually involved*

rectal sparing possible

diffuse, superficial, minute ulcerations; deeper ulcerations in severe disease

aphthous lesions often surrounded by normal-appearing mucosa; deep 'collar button' ulcers; linear or serpiginous ulcerations

strictures very rare

strictures, often occurring in terminal ileum


Histopathology findings

no granulomas+

granulomas (36%)

diffuse chronic inflammation limited to the mucosa++; crypt abscesses

focal chronic inflammation, transmural inflammation

with or without architectural distortion**

  • In children, 'rectal sparing' has been seen in UC69,70
  • Giant cell reactions can occur around damaged crypts and spilled mucin. This must be distinguished from 'true'

granulomas, which by definition, are not seen in UC

  • Deeper layers of the colon may be involved in fulminant UC disease
  • In children with UC, initial colonic biopsies at time of diagnosis are less likely to show architectural distortion than biopsies from adults74

colitis and Crohn's disease by the appearance of upper gastrointestinal lesions. Some pediatric centers routinely perform upper endoscopy in addition to colonoscopy under general anesthesia in their initial evaluation of children with suspected IBD, in order to determine the extent and severity of upper gastrointestinal inflammation.

Evaluation of plain abdominal radiographs and abdominal/pelvic computerized tomography (CT) scans may aid in the assessment for complications of ulcerative colitis, including toxic megacolon, perforation or stricture. A plain abdominal radiograph may demonstrate thumbprinting, loss of haustral patterns, colonic dilatation (i.e. toxic megacolon), obstruction, or pneumoperitoneum (i.e. perforation of the bowel).80-82 CT is not typi cally performed in the initial assessment for ulcerative colitis, but may demonstrate diffuse bowel wall thickening, marked rectal wall thickening and perirectal fibrofatty proliferation.75 A barium enema should not be performed during active ulcerative colitis as this predisposes to toxic mega-colon.83 Prior to the routine use of colonoscopy for the diagnosis of ulcerative colitis, published barium enema findings of ulcerative colitis included mucosal granularity, superficial ulcerations, thickened and nodular haustral folds (secondary to inflammation and edema) and colonic shortening.81 With longstanding ulcerative colitis, the colon becomes featureless and markedly shortened81 and strictures may form, which may require colonoscopy for further evaluation for possible cancer.75

Peri Rectal Abcess

Figure 25.3 (a) Low-power view of a colonic biopsy from a patient with active ulcerative colitis. Note the increased lamina propria inflammatory infiltrate, crypt abscesses and crypt architectural distortion. The crypts are irregular in shape and placement and do not descend to the level of the muscularis mucosae. (b) High-power view of colonic crypts in a patient with active ulcerative colitis, demonstrating neutrophilic infiltration in the crypt and a crypt abscess. (Courtesy of Jonathan Glickman, MD, Department of Pathology, Children's Hospital, Boston).

Figure 25.3 (a) Low-power view of a colonic biopsy from a patient with active ulcerative colitis. Note the increased lamina propria inflammatory infiltrate, crypt abscesses and crypt architectural distortion. The crypts are irregular in shape and placement and do not descend to the level of the muscularis mucosae. (b) High-power view of colonic crypts in a patient with active ulcerative colitis, demonstrating neutrophilic infiltration in the crypt and a crypt abscess. (Courtesy of Jonathan Glickman, MD, Department of Pathology, Children's Hospital, Boston).

Pathology of ulcerative colitis

In active ulcerative colitis, typical findings on histopathology include a diffuse inflammatory cell infiltrate of the lamina propria mostly with plasma cells, lymphocytes and neutrophils, but mast cells and eosinophils are also seen73 (Figure 25.3a). Neutrophils invade the epithelium of the crypts, leading to cryptitis, crypt abscess formation and goblet cell mucin depletion (Figure 25.3b). The inflammatory infiltrate is typically confined to the mucosa, but in severe ulcerative colitis, ulceration may extend into the submucosa and deeper layers.73 In quiescent (inactive) ulcerative colitis, the inflammatory infiltrate may diminish, but signs of chronic colitis (architectural distortion, crypt branching and shortening, reduction in the number of crypts and separation of crypts) can persist.73 In children with ulcerative colitis, signs of chronic colitis (e.g. architectural distortion) are not always seen.74

Histological differentiation of ulcerative colitis from Crohn's disease can be difficult. The histo-logical hallmark of Crohn's disease is the non-caseating granuloma, which may be found in up to 36% of children with Crohn's disease.84 However, a giant cell reaction mimicking a granuloma can occur around damaged crypts and spilled mucin. These 'mucin granulomas' must be distinguished from true granulomas, which, by definition, are not seen in ulcerative colitis.73 Histological skip areas, rectal sparing, focal inflammation and transmural inflammation also suggest the diagnosis of Crohn's disease. How-ever, in children, histological skip areas may occur both at initial presentation of ulcerative colitis and as a result of therapy.69,85 In addition, patients with ulcerative colitis can have histological evidence of upper gastrointestinal inflammation similar to that in Crohn's disease.76,77,79 Given the overlap of histopathology findings in ulcerative colitis and Crohn's disease, it may be difficult to distinguish between these two diagnoses if granulomas are not present.

If a clinician cannot reliably distinguish between Crohn's disease and ulcerative colitis based on the available clinical, radiographic and endoscopic data, an interim diagnosis of 'indeterminate colitis' may be given until the patient can be more clearly classified in the future. The prevalence of indeterminate colitis in adults and children with IBD is estimated to be 10-20%.10,86 Approximately one-third of these patients will later be classified as ulcerative colitis or Crohn's disease.87

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