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Clinical Focus - Challenges in the Diagnosis of Ulcerative Colitis and Crohn's Disease

  • Authors: Gary Lichtenstein, MD
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Target Audience and Goal Statement

This activity is intended for physicians specializing in the fields of gastroenterology and internal medicine, as well as for other healthcare professionals conducting research and/or providing care for individuals with inflammatory bowel disease.

The goal of this activity is to define the latest issues challenging the physician caring for the patient with ulcerative colitis or Crohn's disease, to enhance the care of patients with these conditions, and to support quality clinical practice of healthcare professionals involved in their care.

Upon completion of this activity, participants will be able to:

  1. Recognize the impact of patient nonadherence to medical therapy in ulcerative colitis and identify potential strategies for meeting the associated challenges.
  2. Review current concepts and approaches in the diagnosis of the patient with suspected inflammatory bowel disease, including serologic testing and endoscopic examination.
  3. Explore issues related to the potential link between colorectal cancer and inflammatory bowel disease, including risk factors, prognosis, and strategies in surveillance.


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Medscape, LLC encourages Authors to identify investigational products or off-label uses of products regulated by the US Food and Drug Administration, at first mention and where appropriate in the content.


  • Gary Lichtenstein, MD

    Professor of Medicine, Director, Center for Inflammatory Bowel Diseases, University of Pennsylvania School of Medicine, Hospital of the University of Pennsylvania, Gastroenterology Division, Department of Internal Medicine, Philadelphia, Pennsylvania


    Disclosure: Gary R. Lichtenstein, MD, has disclosed that he has received grants for research from Abbott, Berlex, Centocor, Human Genome Sciences, InKine, Intesco, Isis, Millennium, Otsuka, Protein Design Labs, Protomed Scientific, and Salix. Dr. Lichtenstein has disclosed that he has served as a consultant to AstraZeneca, Axcan, Bristol-Myers Squibb, Centocor, Elan, Gilead, Human Genome Sciences, Procter & Gamble, Prometheus Laboratories, Protein Design Labs, Protomed Scientific, Salix, Schering-Plough, Serono, Shire, Smith Kline Beecham, Solvay, Synta, UCB, and Wyeth. Dr. Lichtenstein has disclosed that he has served on the speaker's bureau for AstraZeneca, Axcan, Centocor, Procter & Gamble, Salix, Schering-Plough, Shire, and Solvay. Dr. Lichtenstein has also disclosed that he has received honoraria from Falk Pharmaceuticals.

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Clinical Focus - Challenges in the Diagnosis of Ulcerative Colitis and Crohn's Disease

Authors: Gary Lichtenstein, MDFaculty and Disclosures



Crohn's disease and ulcerative colitis constitute 2 idiopathic inflammatory disorders of the gastrointestinal tract that are currently estimated to afflict a half million individuals in the United States and similar numbers of persons in Europe as well. These disorders can be debilitating and significantly impair quality of life for afflicted individuals.

An accurate diagnosis of either ulcerative colitis or Crohn's disease, disease extent, disease severity, and the associated intestinal and extraintestinal complications (abscess, fistula, cancer, extraintestinal manifestations) that may have occurred concurrently is of paramount importance for the appropriate treatment of these disorders. Proper diagnosis is particularly crucial because symptoms may mimic those of other conditions and the effects are chronic, progressing over time.

Diagnostic Tests -- Serologic Testing

To confirm a diagnosis -- and to exclude the presence of other conditions that can cause similar symptoms and mimic inflammatory bowel disease (IBD), such as other inflammatory bowel disorders, colitis, celiac disease, or irritable bowel syndrome -- a number specific clinical maneuvers and tests may be undertaken. These include performing a complete physical examination as well as appropriate diagnostic medical tests, such as stool samples for enteric pathogens, stool samples for ova and parasites, and stool collection for Clostridium difficile toxin assay.

Although a complete blood count cannot establish a diagnosis of Crohn's disease or ulcerative colitis, physicians usually order the test in suspected cases because it may reveal the presence of intestinal bleeding, an infection, or an inflammatory condition.

Recent attention has been paid to 2 serologic markers, anti-Saccharomycescerevisiae antibody (ASCA) and perinuclear anti-neutrophilic cytoplasmic antibody (pANCA), which have been proposed as screening tools for patients who present with signs and symptoms of IBD. The Prometheus IBD First Step Generation II (Prometheus Laboratories; San Diego, California) is a commercially available serologic panel of antibodies, including pANCA/ANCA, ASCA IgA, ASCA IgG, and anti-OmpC (outer membrane porin from Escherichia coli) IgA. This test is intended to exclude the presence of IBD in patients with nonspecific symptoms. (The pANCA and ASCA assays are offered commercially through several other companies as well, but these other serologic panels do not include some of the other antibodies, such as anti-OmpC.) Serologic testing using pANCA and ASCA has also been proposed as a method to reach a definitive diagnosis of Crohn's disease or ulcerative colitis in patients with indeterminate colitis. The Prometheus test panel is intended to aid in confirming the diagnosis of IBD and to help differentiate between ulcerative colitis and Crohn's disease. However, pANCA and ASCA testing does not have the specificity needed to distinguish ulcerative colitis from Crohn's disease in these patients.

It should be stressed that ASCA IgA is present in 50% to 70% of patients with Crohn's disease and in 6% to 14% of patients with ulcerative colitis. The presence of both ASCA IgG and IgA is highly specific for the presence of Crohn's disease. ASCA is the most sensitive serologic marker of Crohn's disease. [1-4]

Anti-OmpC IgA is an autoantibody directed against outer membrane porin C on the cell wall of E coli. This marker is included in the Prometheus test panel to enhance detection of Crohn's disease. The presence of this antibody is associated with a subset of patients who have a more severe form of Crohn's disease. Antibodies to OmpC IgA have been reported in 46% of Crohn's disease patients who were ASCA-negative. This represents 21% of the total Crohn's disease population tested. Additionally, 79% to 84% of the Crohn's disease population seroreacts to the combination of ASCA, pANCA, and OmpC.[5,6]

Utility of Serologic Testing

In the majority of cases, a specific diagnosis can be established with the current diagnostic methods of history and physical exam, barium enema, small-bowel follow-through radiograph, colonoscopy and biopsy, and videocapsule endoscopy. However, despite the availability of our current technology, in approximately 10% of patients with IBD limited to the colon, it is not initially possible to distinguish ulcerative colitis from Crohn's disease. These patients are given a diagnosis of indeterminate colitis.

Hoffenberg and colleagues[7] performed a retrospective cross-sectional study in 120 patients to determine the accuracy of ANCA and ASCA antibodies in distinguishing patients with IBD from patients with other disorders seen in a pediatric gastrointestinal practice and in distinguishing ulcerative colitis from Crohn's disease. Serum samples were taken from children with new or established diagnoses of ulcerative colitis (n = 25) or Crohn's disease (n = 20) and also from controls (n = 74), and were analyzed for the presence of IgG ANCA and IgA and IgG ASCA. Analysis was performed without knowledge of the clinical history or diagnosis of the patient. The highest sensitivity (71%) for detecting IBD was achieved by using both ANCA and ASCA antibodies together. The study authors reported that the best test for ulcerative colitis was ANCA, with a sensitivity of 80% (vs 40% for Crohn's disease patients and 11% for non-IBD controls). However, the ANCA pattern characteristic of ulcerative colitis (pANCA) had a sensitivity of 60%. High titers of ANCA were specific for ulcerative colitis, whereas high titers of ASCA were specific for Crohn's disease. The study authors concluded that while combined ANCA and ASCA testing did not achieve the sensitivity necessary for population screening, it may be helpful in evaluating children suspected of having IBD and in distinguishing ulcerative colitis from Crohn's disease. This study was limited by the small numbers of patients included in each group; the lack of standardization of ANCA testing used; and by different mean ages of subjects in the ulcerative colitis, Crohn's disease, and control groups.

Dubinsky and colleagues[2] conducted a prospective study of pediatric patients to determine whether the accuracy of diagnosing IBD vs functional childhood disorders was improved by the use of modified assays for pANCA and ASCA, with enzyme-linked immunoabsorbent assay (ELISA) test cut-off values maximized to increase sensitivity. ASCA and pANCA serologies were obtained from 128 pediatric patients undergoing diagnostic evaluation for IBD. All investigators were blinded to clinical diagnoses. The sensitivity of the modified assays for diagnosing IBD was 81% compared with 69% for the traditional tests, but specificity in terms of diagnosing IBD was lower, at 72% vs 96%. The study authors concluded that the incorporation of sequential noninvasive testing into a diagnostic strategy may avoid unnecessary and costly evaluations and facilitate clinical decision making when the diagnosis of IBD in children is uncertain. This study was limited by the small numbers of subjects in each group and by a lack of distinction between ulcerative colitis and Crohn's disease.

A case-control study was performed by Vermeire and colleagues,[8] who compared the sensitivity, specificity, and positive predictive value of 4 different ASCA assays in a group of 200 patients with IBD. Given that several companies market ASCA assays, the investigators attempted to determine whether different ASCA assays agree sufficiently for the results to be used interchangeably. A large range of sensitivities and specificities was seen with the different assays. Due to the high degree of variability, caution was suggested in the interpretation of results, and the need for standardization of measurement was stressed.

A subsequent study was performed in 2002 by Joossens and colleagues.[9] This prospective multicenter investigation evaluated the utility of ASCA and pANCA measurement to increase diagnostic accuracy in categorizing indeterminate colitis as either Crohn's disease or ulcerative colitis. The study included 97 patients with indeterminate colitis who were assessed for pANCA and ASCA and followed in a prospective fashion. A definitive diagnosis was reached using conventional techniques (colonoscopy, endoscopy, and standard radiographic studies) for 31 of 97 patients. The study authors reported that positive ASCA/negative pANCA predicted Crohn's disease in 80% of patients with indeterminate colitis who were later confirmed as having Crohn's disease, and negative ASCA/positive pANCA predicted ulcerative colitis in 63.3% of patients with indeterminate colitis who were later confirmed as having ulcerative colitis. Of note, 48.5% of patients did not show antibodies directed against ASCA or pANCA, and most remained diagnosed with indeterminate colitis. Because only 31 patients had a confirmed diagnosis and only 21 of these patients were included in an evaluation of specificity and sensitivity, it is difficult to draw conclusions regarding the accuracy of serologic testing in this study

New Strategies in Serologic Testing

A new marker was recently described -- antibody to CBir1 (anti-CBir1 flagellin). CBir1 is a flagellin-like antigen associated with the presence of IBD. In particular, serum response to anti-CBir1 identifies the presence of Crohn's disease and is associated with a subset of patients with this form of IBD. This marker has been shown to differentiate pANCA-positive results in ulcerative colitis vs ulcerative colitis-like Crohn's disease, and identifies a unique subset of patients with Crohn's disease not previously identified with other serologic markers. Serum responses to CBir1 identifies patients with complicated Crohn's disease (such as small bowel, internal penetrating, and fibrostenosing disease). Levels of anti-CBir1 are increased in 50% to 55% of patients with Crohn's disease.[10]

Along with the discovery of anti-CBir1 flagellin, another technique has been introduced in an attempt to increase diagnostic ability. The Smart Diagnostic Algorithm technology (personal communication with Prometheus Laboratories, 2006) has now been incorporated into the diagnostic armamentarium.[11] This method increases the likelihood of accurate diagnostic prediction. The algorithm uses 2 statistical models to analyze a full range of potential predictors across multiple variables. The Analysis 1 model uses a statistical classifier to make an initial diagnostic prediction and Analysis 2 uses neural network technology to enhance the accuracy of the final diagnostic prediction. This predictive algorithm derives meaning from complicated data by extracting patterns and detecting trends that are too complex to be detected by other statistical methods. Preliminary data have demonstrated a 93% sensitivity and 95% specificity for IBD, 88% sensitivity and 98% specificity for Crohn's disease, and 93% sensitivity and 97% specificity for ulcerative colitis.

Where Are We Now?

At this point in time, patients with negative results would still need to undergo standard diagnostic testing for IBD; patients with a positive result would still need to undergo additional testing to distinguish Crohn's disease from ulcerative colitis and to determine the extent of disease.

Combined serologic testing has also been proposed to help differentiate between ulcerative colitis and Crohn's disease in cases of indeterminate colitis. At this time, there is insufficient evidence to demonstrate that ANCA/pANCA and ASCA testing alone is completely reliable in reaching a definitive diagnosis.

In summary, the presence of ANCA, pANCA, ASCA, anti-OmpC, and anti-CBir1 markers appears to be associated with ulcerative colitis and Crohn's disease. More markers and combined serologic testing represent a promising step forward for diagnosis. With the advent of the new Smart Diagnostic Algorithm technology, it seems possible that there may be improvements in the ability of serology to diagnose IBD and to differentiate Crohn's disease and ulcerative colitis.

Endoscopic Examination


Colonoscopy is more sensitive than radiographic studies in detecting early changes associated with IBD, and represents the primary modality to obtain tissue for histologic evaluation.[12] Clinicians should be cognizant that even if the colonic mucosa appears macroscopically normal, there may be histologic changes diagnostic of IBD. Therefore, it is of paramount importance that biopsies be procured, even from tissue that appears endoscopically normal. Histology represents the most sensitive measure of disease extent and activity.

Colonoscopy with biopsy of involved and endoscopically normal areas is important in determining whether patients with indeterminate colitis have Crohn's colitis or ulcerative colitis. In 10% of all patients, colonoscopy with biopsy is unable to differentiate between Crohn's colitis and ulcerative colitis.[12]

In Crohn's disease, colonoscopy and esophagogastroduodenoscopy (EGD) can confirm the presence (endoscopically and histologically) and distribution of disease and also define the severity of the mucosal disease. Characteristically, there are focal ulcers, skip areas with normal-appearing mucosa, and deep longitudinal ulcers in severe disease. It should be stressed that endoscopic findings do not correlate well with clinical disease activity.[12] Endoscopic evaluation of strictures should include multiple biopsies and brushing cytology. In Crohn's disease, the earliest lesion is focal neutrophilic infiltration of the epithelium by crypt-seeking neutrophils. This occurs primarily over areas of overlying mucosal lymphoid aggregates, with subsequent cryptitis and crypt abscess formation. This lesion may then progress to form an aphthous ulcer. Patients who have significant Crohn's disease have transmural inflammation present. The mucosa demonstrates evidence of chronic inflammatory changes, atrophy, and metaplastic change within the epithelium, ie, Paneth cell metaplasia in the colon. The hallmark of Crohn's disease is the presence of noncaseating granulomas within the bowel wall or in regional lymph nodes. The end result of this disease is transmural inflammation leading to fibrosis and stricturing.

Endoscopy is important for the diagnosis of IBD, whether assessing ulcerative colitis or Crohn's disease. In identifying the presence of IBD, none of the endoscopic features is completely specific, and diagnosis of disease is based on a combination of clinical endoscopic and histologic findings. In early-stage edema, confluent erythema with rectal involvement is typical. As the disease progresses, granularity and contact bleeding is appreciated endoscopically. With progression of disease to the late stages, discrete ulcerations with pus/exudate and loss of haustral folds is characteristic. The presence of aphthoid ulcerations is not seen in patients with ulcerative colitis. Chronic inflammation frequently leads to diffuse mucosal atrophy, leaving behind hypertrophic areas of swollen, edematous tissue and areas of granulation that assume a polypoid configuration. These areas, known as pseudopolyps, have no malignant potential and occur in both ulcerative colitis and Crohn's disease.[13] Histologically, ulcerative colitis has alterations of crypt architecture including crypt architectural distortion (which may be bifid, irregular, with a decreased number, or with a gap between the crypt bases and the muscularis mucosae). Paneth cells are commonly found in normal individuals, proximal to the hepatic flexure; however, in patients with ulcerative colitis, it is not uncommon to discern their presence distal to the hepatic flexure -- suggestive of prior crypt destruction and subsequent regeneration. It is most common to find these features distally. It is also common to find basal plasma cells and many basal lymphoid cells, indicating the presence of chronicity. Basal plasma cells are, however, not specific for ulcerative colitis and may be seen in other chronic disorders, such as collagenous colitis and Crohn's disease and, rarely, in infectious colitis. Other minor features of ulcerative colitis include hyperplasia of argentaffin cells, mucosal vascular congestion with edema, and focal hemorrhage. Depletion of goblet cell mucin is a characteristic and consistent finding in acute ulcerative colitis, and except where dysplasia is present, is another reliable indicator of disease activity.

Radiographic Studies

In patients with Crohn's disease, barium studies, including air-contrast barium enema and a single-contrast small-bowel follow-through examination, can identify the extent of disease and the presence of complications such as fistulas or strictures. These studies, however, may miss subtle luminal disease. In some patients, a small-bowel air-contrast study (enteroclysis) can provide additional information for evaluating jejunal and ileal disease. Enteroclysis is suggested for those individuals who have suspected fistulizing disease not well demonstrated on small-bowel follow-through radiographic study, or for evaluating small intestinal stricturing disease. Enteroclysis is excellent for the detection of Crohn's disease-related fistulas.[14] An upper gastrointestinal radiographic study may have utility in patients with Crohn's disease who have strictures in the gastric and duodenal region. Abdominal or pelvic abscesses or masses can be visualized using ultrasound, either abdominal or transrectal, as well as computed tomography (CT) or magnetic resonance imaging (MRI). MRI is often used to detect perianal disease, such as fistulas or abscesses. In addition to evaluating for potential abdominal abscess, CT is a useful adjunct to barium small-bowel studies for evaluating extraintestinal abnormalities, fistulas, phlegmon, and colorectal cancer. It should be emphasized that colonoscopy is the best modality for the detection of colorectal carcinoma.[13] CT scan can also assess bowel-wall thickening and transmural inflammation, differentiating ulcerative colitis from Crohn's disease, and allowing at least some rudimentary assessment of Crohn's disease activity. Finally, interventional CT can be used to percutaneously drain abdominal abscesses.

The technique of video capsule endoscopy recently has enabled physicians to visualize the terminal ileum with a higher sensitivity as compared with small-bowel radiology.[15] Push enteroscopy frequently has difficulty in reaching the terminal ileum, the most common site of Crohn's disease. However, double-balloon enteroscopy has recently demonstrated success in this setting.[16] Small-bowel radiography may be of adequate sensitivity to detect advanced changes of Crohn's disease in the terminal ileum; however, mild changes confined to the terminal ileum, such as aphthous ulcerations, may be missed unless a peroral pneumocolon or air-contrast enteroclysis is performed. Video capsule endoscopy should be considered in those individuals suspected of having Crohn's disease who have had a negative work-up, including a negative small-bowel radiographic study. Thus, the standard work-up should include colonoscopy with an attempt to intubate the terminal ileum, EGD, and small-bowel radiography. Small-bowel radiographic visualization should be attempted to exclude the presence of any ileal strictures, because capsule retention in the region of a known stricture mandating surgical or endoscopic removal has been described.

It should be emphasized that not all aphthous ulcerations represent Crohn's disease. Caution should be exercised to avoid overinterpretation of the presence of aphthous ulcerations in the small bowel, because individuals with other disorders, such as celiac sprue, as well as normal individuals may also have these lesions. Thus, the presence of these lesions is not specific for the presence of small-bowel Crohn's disease.[17] A more difficult issue involves determining and establishing baseline findings in normal controls who do not have IBD and setting up standards for patients with IBD. This process is now ongoing in an effort to establish a validated capsule endoscopic index. Thus, it appears that currently the most appropriate use of capsule endoscopy is in patients with an unknown diagnosis and a negative work-up (EGD, colonoscopy, and small-bowel radiographic study) for Crohn's disease. In terms of considering this technology as a screening study for abdominal pain or diarrhea in the general population, the prevalence of IBD seems too low to make it an appropriate first test. Capsule endoscopy may also be used in patients who have gastrointestinal bleeding of uncertain etiology.

The utility of radiographic imaging for evaluation of patients with ulcerative colitis also remains a standard and helps to differentiate ulcerative colitis from Crohn's disease. The presence of mucosal granularity is the earliest radiographically detectable evidence of disease in ulcerative colitis. The granular pattern is thought to result from abnormalities associated with edema and hyperemia. Early ulcer formation in ulcerative colitis appears as fine speckled barium collections superimposed on a granular-appearing mucosa. Other associated findings may be present, including haustral fold thickening, colonic shortening, polyps and pseudopolyps, strictures, dysplasia, colorectal cancer, and toxic dilation for various disease stages.

Concluding Remarks

The appropriate diagnosis of ulcerative colitis and Crohn's disease is of paramount importance in order to aid in appropriate patient management. Despite the widespread use of fiber-optic endoscopy, radiologic imaging, and serologic testing, there continues to be a significant need for enhancing the diagnosis and management of these patients. Certain medications are known to be effective only in ulcerative colitis (eg, mesalamine), whereas others are effective only in Crohn's disease (budesonide). Surgery, if needed for patients with refractory disease, may differ if a patient's suspected diagnosis of ulcerative colitis is actually Crohn's disease and vice versa. Future advancements in technology will likely help improve our ability to treat patients more effectively.


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