Crohn Disease Workup: Approach Considerations, Routine Laboratory Studies, Serologic Testing (original) (raw)

Approach Considerations

Crohn disease is initially diagnosed on the basis of a combination of clinical, laboratory, histologic, and radiologic findings. Laboratory study results are generally nonspecific but may be helpful in supporting the diagnosis and managing the disease. Serologic studies are sometimes used to facilitate differentiation of Crohn disease from ulcerative colitis or inflammatory bowel disease (IBD) of undetermined type.

Various imaging modalities are available to aid in the diagnosis and management of Crohn disease. Contrast radiologic studies are recommended to determine disease extent, disease severity and complications, and treatment strategy. [12] The choice of modality depends on the clinical question being asked, as follows:

Colonoscopy is the technique of choice to assess disease activity in patients with symptomatic colonic Crohn disease or ulcerative colitis; [59] complementary cross-sectional imaging can be used to assess phenotype and as an alternative to evaluate disease activity [59]
Upper gastrointestinal (GI) endoscopy and/or colonoscopy and histologic examination are recommended in cases of suspected Crohn disease on the basis of clinical findings; [12] upper GI endoscopy is also recommended when lower GI endoscopy is unable to definitely diagnose Crohn disease or in the presence of upper GI symptoms, but not for asymptomatic newly diagnosed patients [59, 12]
Plain radiography or computed tomography (CT) scanning of the abdomen can be used to assess for bowel obstruction; these studies can also be used to assess the pelvis for the presence of any intra-abdominal abscesses
The use of CT enterography or magnetic resonance (MR) enterography is replacing small bowel follow-through (SBFT) studies; the enterographic images can better distinguish between inflammation and fibrosis
Magnetic resonance imaging (MRI) of the pelvis or endoscopic ultrasonography (ie, transrectal ultrasonography) can identify perianal fistulae anatomy and activity and detect the presence or absence of pelvic and perianal abscesses

Capsule endoscopy is sensitive for early mucosal inflammation, but it can only detect mucosal changes, whereas MRI and intestinal ultrasonography are able to reveal transmural inflammation, as well as identify complications. [59, 12] Furthermore, MRI detects fistulae, deep ulcerations, and a thickened bowel wall. [59] Ultrasonography is inexpensive and can be performed at the point of care by the treating gastroenterologist.

Ultrasonography, CT scanning, and MRI can determine pretreatment and posttreatment disease activity or identify disease complications. [12] Cross-sectional imaging should be used to detect strictures in the case of complications. [59] Because of radiation associated with CT scanning, the preferred methods are MRI and intestinal ultrasonography. Cross-sectional imaging is also recommended for the detection of abscesses. For the diagnosis of perianal Crohn disease, clinical and endoscopic rectal examination, as well as MRI, is recommended; ultrasonography in the absence of anal stenosis or transperineal ultrasonography is an alternative to MRI. [59]

A risk-stratification model based on levels of C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), which are significantly associated with complications of Crohn disease, could reduce the use of computed tomography (CT) scans in patients reporting to the emergency department by 43%, while missing only 0.8% of emergencies, according to a retrospective analysis of 613 adult patients. [60] Researchers used logistic regression to model associations between these laboratory values and perforation, abscess, or other serious complications. Further validation studies of the models need to be performed.

Many centers favor judicious use of imaging and employ low-radiation protocols where possible, especially in younger individuals. Patients with complicated Crohn disease who undergo multiple radiologic examinations may be at risk for cumulative exposure to potentially excessive amounts of diagnostic radiation. [61, 62, 63, 64] Ultrasonography and MRI can be used as adjunct studies if radiation exposure is an issue in monitoring disease activity.

Interventional radiology is primarily used in the percutaneous drainages of abscesses that complicate Crohn disease, which may obviate the need for surgical resection. [65]

Endoscopic visualization and biopsy are essential in the diagnosis of Crohn disease. Colonoscopy with intubation of the terminal ileum is used to evaluate the extent of disease, to demonstrate strictures and fistulae, and to obtain biopsy samples to help differentiate the process from other inflammatory, infectious, or acute conditions. Given the increased risk of colorectal cancer in patients with IBD, colonoscopy may have a role in cancer surveillance, although the frequency of this practice remains controversial.

Upper gastrointestinal (GI) endoscopy may be used to diagnose gastroduodenal disease, if suspected. This study is recommended for all children, regardless of the presence or absence of upper GI symptoms.

For more information, see Imaging in Crohn Disease.

Routine Laboratory Studies

Laboratory results for Crohn disease are nonspecific and are of value principally for facilitating disease management. Laboratory values may also be used as surrogate markers for inflammation and nutritional status and to screen for deficiencies of vitamins and minerals.

Complete blood cell count

A complete blood cell (CBC) count is useful in detecting anemia, which may be due to multiple causes, including chronic inflammation, iron malabsorption, chronic blood loss, and malabsorption of vitamin B-12 or folate. Leukocytosis may be due to chronic inflammation, abscess, or steroid treatment.

Chemistry panel

Electrolyte analysis can help determine the patient’s level of hydration and renal function. Hypoalbuminemia is a common laboratory finding in patients with suboptimally treated Crohn disease. Additional common abnormalities include deficiencies in iron and micronutrients (eg, folic acid, vitamin B-12, serum iron, total iron binding capacity, calcium, and magnesium). Liver function test results may be elevated, either transiently (because of inflammation) or chronically (because of sclerosing cholangitis).

Inflammatory markers

Acute inflammatory markers, such as C-reactive protein (CRP) level or erythrocyte sedimentation rate (ESR), may correlate with disease activity in some patients. If Crohn disease activity is suspected, however, a normal ESR or CRP level should not deter further evaluation.

Stool studies

Stool samples should be tested for the presence of white blood cells (WBCs), occult blood, routine pathogens, ova, parasites, and Clostridium difficile toxin. These studies should also be used to rule out infectious etiologies during relapses and before the initiation of immunosuppressive agents. [6]

Fecal calprotectin has been proposed as a noninvasive surrogate marker of intestinal inflammation in IBD. [66] The level of the inflammatory marker calprotectin in feces correlates significantly with endoscopic colonic inflammation in both ulcerative colitis and Crohn disease, and fecal lactoferrin is significantly correlated with histologic inflammation. [67] However, colorectal neoplasia and GI infection also increase fecal calprotectin; therefore, this study should be used with caution.

At present, fecal calprotectin is not in widespread use, except in research protocols. In the future, this marker may be made more available to clinicians for following patients’ disease activity.

Serologic Testing

There are 2 serologic tests that are currently used in efforts to differentiate ulcerative colitis from Crohn disease. Antibodies to the yeast Saccharomyces cerevisiae (ie, anti-S cerevisiae antibodies [ASCA]) are found more commonly in Crohn disease than in ulcerative colitis, whereas perinuclear antineutrophil cytoplasmic antibody (p-ANCA), a myeloperoxidase antigen, is found more commonly in ulcerative colitis than in Crohn disease.

The World Gastroenterology Organization (WGO) indicates that ulcerative colitis is more likely when the test results are positive for pANCA and negative for ASCA antigen; [57] however, the pANCA test may be positive in Crohn disease, and this may complicate obtaining a diagnosis in otherwise uncomplicated colitis. [58]

It should be noted that both tests are recommended only as an adjunct to the clinical diagnosis; the results are not specific and have been found to be positive in other bowel diseases. Patients with Crohn disease whose condition is ASCA-positive have a higher rate of surgery and require surgery earlier in the course of the disease, independent of the area of involvement. [1, 2, 6]

Additional serologic markers, such as Escherichia coli anti-ompC (outer membrane porin C), can be found in more than 50% of Crohn disease cases and in only a small percentage of ulcerative colitis cases. Pseudomonas fluorescens (anti-12) may be found in more than 50% of Crohn disease cases and in only 10% of ulcerative colitis cases. Flagellinlike antigen (anti-Cbir1) is associated independently with small bowel, intestinal penetrating, and fibrostenosing disease. These tests further increase sensitivity and diagnostic value.

Plain Abdominal Radiography

Abdominal radiography is a nonspecific test for evaluation of IBD; however, it can useful if there is concern about obstruction or perforation. If abdominal radiographs are obtained, findings may include mural thickening and dilatation, small bowel and colonic mucosal abnormalities, and abnormal fecal distribution with areas of colonic involvement without fecal material. [65]

In patients with known Crohn disease who present with acute exacerbation, symptoms, or suspected complications, radiographs can be obtained to evaluate for the presence of bowel obstruction, perforation (free air), or toxic colon distention. [65] These conditions necessitate rapid management.

For more information, see Imaging in Crohn’s Disease.

Barium Contrast Studies

Barium enema is noninvasive and usually well tolerated for evaluating features such as pseudodiverticula, fistulization, and the severity and length of colonic strictures. SBFT and enteroclysis may be valuable in demonstrating the distribution of small bowel disease in a patient presenting with suspected IBD. Mucosal fissures, bowel fistulae, strictures, and obstructions can be visualized. The terminal ileum may be narrowed and thickened, with a characteristic pipe appearance.

However, barium studies are contraindicated in patients with known perforation, and water-soluble agents should be used in place of barium. Barium can also cause peritonitis. Although in the past, barium contrast studies were the imaging modalities of choice for Crohn disease, these studies now are less commonly used, with the advent of new and more detailed CT, MRI, and capsule endoscopy techniques to assess for small bowel and pelvic Crohn disease.

For more information, see Imaging in Crohn Disease.

Small bowel follow-through

An upper GI SBFT and spot films of the terminal ileum can be used to assess the small bowel of patients with suspected Crohn disease. SBFT can also detect alteration of the small bowel wall indirectly (through findings such as enteroenteric and enterocolonic fistulization.

Radiographic findings in both the small and the large bowel parallel the clinical pattern. Edema and ulceration of the mucosa in the small bowel may appear as thickening and distortion of valvulae conniventes. Edema of the deep layers of the bowel wall results in separation of the barium-filled bowel loops. Tracking of deep ulcerations, both transversely and longitudinally, results in a cobblestone appearance (see the image below).

Crohn disease. Cobblestoning in Crohn disease. This is a spot view of the terminal ileum from a small bowel follow-through study. It demonstrates linear longitudinal and transverse ulcerations that create a cobblestone appearance. Also, note the relatively greater involvement of the mesenteric side of the terminal ileum and the displacement of the involved loop away from the normal small bowel secondary to mesenteric inflammation and fibrofatty proliferation.

Ileitis can also manifest as a string sign on barium studies secondary to spasm or, rarely, because of fibrotic stricture (see the following images).

Crohn disease. Crohn disease of terminal ileum. The small bowel follow-through study demonstrates the string sign in the terminal ileum. Also, note the pseudodiverticula of the antimesenteric wall of the terminal ileum, secondary to greater distensibility of this less-involved wall segment.

Crohn disease. This spot view of the terminal ileum from a small bowel follow-through study in a patient with Crohn disease demonstrates the string sign, consistent with narrowing and stricturing. Also, note a sinus tract originating from the medial wall of the terminal ileum and the involvement of the medial wall of the cecum.

Enteroclysis

Overall, enteroclysis is reserved for complicated cases. This imaging modality is roughly as accurate as SBFT and has a shorter examination time; however, the peroral SBFT examination uses less total room time, radiologist time, and radiation, and it has greater patient tolerability. [65]

A useful adjunct study to the initial SBFT or enteroclysis is the peroral pneumocolon evaluation, in which air is instilled per rectum after the opacification of the terminal ileum. [65] This double-contrast examination allows assessment of the distal small bowel or ascending colon or both and often yields improved mucosal detail and greater distention of the terminal ileum. [65]

Barium enema

If the patient can tolerate a barium enema, this study may help in the evaluation of colonic lesions (see the following images).

Crohn disease. Aphthous ulcers. A double-contrast barium enema examination in a patient with Crohn colitis demonstrates numerous aphthous ulcers.

Crohn disease. This double-contrast barium enema study demonstrates marked ulceration, inflammatory changes, and narrowing of the right colon in a patient with Crohn colitis.

Fistulae can also be detected by barium studies of the digestive tract or through injection into the opening of the suspected fistulae (see the image below). [68, 69, 70]

Crohn disease. Enterocolic fistula in a patient with Crohn disease. The double-contrast barium enema study demonstrates multiple fistulous tracts between the terminal ileum and the right colon adjacent to the ileocecal valve (so-called double-tracking of the ileocecal valve).

Computed Tomography Scanning

Computed tomography (CT) scanning is helpful in—and considered the imaging technique of choice for—the assessment of extramural complications as well as hepatobiliary and renal complications in adults and children. [65, 68, 69, 70] It may show bowel wall thickening, bowel obstruction, mesenteric edema, abscesses, or fistulae (see the image below).

Crohn disease. Active small bowel inflammation in a patient with Crohn disease. This computed tomography scan demonstrates small bowel wall thickening, mesenteric inflammatory stranding, and mesenteric adenopathy.

CT enterography can be helpful in the assessment of subtle and obvious mucosal damage. VoLumen oral contrast (Bracco Diagnostics, Princeton, NJ) is used as a negative agent to enhance small bowel wall changes, if present. Active disease is demonstrated by bowel wall thickening and mural hyperenhancement that occurs in a stratified enhancement pattern and a hyperemic vasa recta. [65] In the presence of severe inflammation, perienteric inflammatory changes can be seen.

CT enterography is also useful in deciphering whether a stricture is fibrostenotic rather than inflammatory or mixed. The degree and length of narrowing are important in planning for endoscopic examination (eg, by determining whether dilation is possible) and in preoperative staging.

The American College of Radiology (ACR) indicates that CT may be more sensitive than barium studies in detecting Crohn disease, owing to its ability to visualize pelvic small bowel loops, [71, 72] which are often obscured by overlapping bowel in barium studies. This and other evidence partially explain why CT has become the procedure of choice not only for helping diagnose Crohn disease but also for managing abscesses. Moreover, a growing body of literature shows that CT-guided percutaneous abscess drainage may obviate surgery.

For more information, see Imaging in Crohn Disease.

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) has been shown to yield a higher sensitivity and specificity than ileocolonoscopy (the criterion standard) both for diagnosing Crohn disease and for determining its severity. [73, 74] It is especially useful for evaluating pelvic and perianal disease when one is investigating for evidence of perianal fistulae and abscesses (see the image below). Typical changes depicting active disease include thickening of the bowel wall, high T2 signal of the walls with hyperenhancement and stratification, and hyperemic vasa recta. [65]

Crohn disease. This magnetic resonance image demonstrates an inflamed terminal ileum in 10-year-old girl with Crohn disease.

In a prospective study comparing the use of MRI to the standard Crohn Disease Endoscopic Index of Severity (CDEIS), MRI was validated as a modality that accurately assesses intestinal wall thickness, the presence and degree of edema, and ulcers in patients with Crohn disease. [75] This study confirmed that through relative contrast enhancement (RCE), MRI plays an essential role in predicting disease activity and severity in Crohn disease. [75]

MRI is the study of choice for evaluation and management of perianal Crohn disease. It can be superior to CT in demonstrating pelvic lesions. In addition, MRI can be used when ionizing radiation is contraindicated and in children and pregnant women (if done without gadolinium). [65] Compared with CT, MRI of the pelvis can more accurately detect pelvic and perianal abscesses, as well as better categorize fistula anatomy and activity.

MR enterography and CT enterography are increasingly being used for evaluation of the small bowel. Compared with SBFT, both of these studies are as sensitive and specific, and possibly more accurate, in detecting extraenteric complications, including fistulae and abscesses. [76] Because of the lack of radiation exposure, MR enterography is a particularly attractive option.

Owing to the differential water content, MRI can differentiate active inflammation from fibrosis as well as distinguish between inflammatory and (fixed) fibrostenotic lesions in Crohn disease. [68, 69, 70]

Studies have shown that MR enterography may be superior to CT enterography in the depiction of disease activity (eg, mural thickening and enhancement) [77] and in the detection of stricture presence. [78] In particular, the positive impact on medical or surgical management has been noted in evaluation of small bowel Crohn disease [79] ; these conclusions have been gathered by comparing findings on MR enterography to endoscopic evaluations and surgical pathology reports.

For more information, see Imaging in Crohn Disease.

Ultrasonography

Ultrasonography is a quick, inexpensive, and noninvasive screening method used for the diagnosis of IBD or for repeated evaluation for complications. [68, 69, 70] Abdominal ultrasonography can rule out gallbladder and kidney stones as well as detect enlarged lymph nodes and abscesses. However, it has a steep learning curve that yields a range of sensitivity that is operator-dependent. Because of their lack of radiation exposure, ultrasonography and MRI are often preferred to CT, especially in younger patients. [65]

Rectal endoscopic ultrasonography has been used as an alternative to MRI in the assessment of perianal disease. This technique allows differentiation of simple fistulae from complex ones, as well as assessment of fistula tracts in relation to the sphincter muscle. [68, 69, 70] Ultrasonography has been shown to improve the outcomes of fistula healing when used in conjunction with surgical seton (silk string) placement and anti-tumor necrosis factor (TNF) therapy. [80, 81, 82]

For more information, see Imaging in Crohn’s Disease.

Endoscopy and Colonoscopy

Colonoscopy

Ileocolonoscopy is a highly sensitive and specific tool in the diagnosis and management of patients with suspected or already established IBD. This procedure is useful in obtaining biopsy tissue, which helps in the differentiation of other diseases, in the evaluation of mass lesions, and in the performance of cancer surveillance.

Colonoscopy also enables dilation of fibrotic strictures in patients with long-standing disease and has been used in the assessment of mucosal healing. In addition, it may be used in the postoperative period to evaluate surgical anastomoses as a means of predicting the likelihood of clinical relapse as well as the response to postoperative therapy. [1]

Ileocolonoscopy has a sensitivity of 74% and a specificity of 100% in the assessment of Crohn disease, leading to a positive predictive value of 100% as a diagnostic test. [45] When paired with small bowel imaging, the sensitivity of this pair of diagnostic tests is increased to 78%, with a continued positive predictive value of 100%. [45]

For patients with Crohn disease of the colon, magnifying endoscopy allows a more detailed view of the mucosal surface than conventional endoscopy does. In combination with chromoendoscopy (methylene blue), it is possible to analyze the surface staining pattern further to help identify neoplastic changes in situ and take targeted biopsies. [6, 25, 68, 69, 70]

For more information, see Colonoscopy.

Upper GI endoscopy

Upper GI endoscopy (or esophagogastroduodenoscopy [EGD]) with biopsy is helpful in differentiating Crohn disease from peptic ulcer disease induced by nonsteroidal anti-inflammatory drugs (NSAIDs) or Helicobacter pylori or from fungal and viral gastroenteritis in patients with upper GI tract symptoms. A history of ileocolic Crohn disease in a patient with unexplainable upper GI symptoms warrants an EGD.

Endoscopic retrograde cholangiopancreatography

Endoscopic retrograde cholangiopancreatography (ERCP) is helpful as a diagnostic procedure and a therapeutic tool in patients with sclerosing cholangitis and biliary stricture formation. Magnetic resonance cholangiopancreatography (MRCP) may provide equally valuable information without invasive complications. A dominant biliary stricture may benefit from balloon dilation, stent placement, or both, though the latter is controversial in the management of primary sclerosing cholangitis.

Small bowel enteroscopy and capsule endoscopy

Single- and double-balloon enteroscopy allows complete evaluation of the small bowel and makes distal ileal biopsies feasible. Enteroscopy can also be helpful in the detection of complications of Crohn disease, such as stricture and active disease.

Wireless capsule endoscopy helps to identify involvement of the upper GI tract and may be especially useful in cases of jejunal or proximal ileal anastomotic surveillance. Drawbacks of this technique include the inability to take biopsies and the risk of acute obstruction. If an obstruction is suspected, small bowel imaging should be done before capsule endoscopy.

Guidelines on the use of enteroscopy and endoscopy in the diagnosis and management of IBD are available from the American Society for Gastrointestinal Endoscopy. [83]

Nuclear Imaging

Radionucleotide scanning may be helpful in assessing the severity and extent of the disease in patients who are too ill to undergo colonoscopy or barium studies. [68, 69, 70] However, nuclear imaging studies are not the tests of choice: MRI, CT, and endoscopic examination of the mucosa for active disease are preferred.

Leukocytes labeled with either technetium-99m (99m Tc )-HMPAO (hexamethyl propylene amine oxime) or indium-111 (111 In) can be used to assess for active bowel inflammation in IBD. The99m Tc-labeled leukocytes may be able to obtain an exact image of the inflammatory disease distribution and intensity at a moment in time—in a single examination. [65]

Compared with the111 In label, the99m Tc-HMPAO label has better imaging characteristics and can be imaged much sooner after injection. However, imaging must typically be performed within 1 hour after the injection of99m Tc- HMPAO–labeled leukocytes because there is normal excretion into the bowel after this time; in contrast,111 In-labeled leukocytes have no normal bowel excretion.

Fluorine-18-2-fluoro-2-deoxy-D-glucose (FDG) combined with positron emission tomography (PET) or CT helps improve localization of the tracer in areas of active inflammation, but false-positive results can occur with inadequate distention of the bowel. [65] Studies are being conducted to evaluate combining PET/CT with CT enterography/enteroclysis techniques with the aim of further improving localization while reducing the rate of false-positive findings. [65]

For more information, see Imaging in Crohn’s Disease.

Histology

The characteristic pattern of inflammation in Crohn disease is transmural involvement of the bowel wall by lymphoid infiltrates that contain noncaseating granulomas in about 15-30% of cases of biopsy samples and 40-60% of surgical specimens. A granuloma is defined as a collection of monocyte/macrophage cells and other inflammatory cells, with or without giant cells (see the image below).

Crohn disease. The histologic image shows granuloma in the mucosa of a patient with Crohn disease.

Other characteristics include proliferative changes in the muscularis mucosa and in the nerves scattered in the bowel wall and myenteric plexus. In the involved foci of the small and large bowel, Paneth cell hyperplasia is frequent, and areas of pyloric metaplasia may be seen. In severe cases, long and deep fissurelike ulcers form.

Upper GI tract Crohn disease may be more challenging to diagnose. The histologic picture of gastric Crohn disease is typically described as focally enhancing gastritis in the setting of negative H pylori or other infections. Esophageal or duodenal biopsies in Crohn disease may reveal villous architectural changes with moderate inflammation. Granulomas generally are not identified, but when they are present, they provide substantial corroborative evidence for the diagnosis.

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Author

Specialty Editor Board

Chief Editor

Acknowledgements

BS Anand, MD Professor, Department of Internal Medicine, Division of Gastroenterology, Baylor College of Medicine

BS Anand, MD is a member of the following medical societies: American Association for the Study of Liver Diseases, American College of Gastroenterology, American Gastroenterological Association, and American Society for Gastrointestinal Endoscopy