The most common small bowel inflammatory disorders include Crohn disease, nonsteroidal antiinflammatory drug (NSAID) enteropathy, and celiac disease. Capsule endoscopy, computed tomography enterography, and magnetic resonance enterography have a complementary role in the diagnosis of Crohn disease and evaluation of patients with established Crohn disease. The higher risk of capsule retention with known Crohn disease and NSAID enteropathy can be minimized by cross-sectional imaging or the patency capsule. The main role of deep enteroscopy is tissue diagnosis, endoscopic management of small bowel lesions and strictures, and retrieval of retained capsules.
Key points
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Capsule endoscopy, cross-sectional imaging and deep enteroscopy have a complementary role in evaluation of small bowel (SB) inflammatory disorders.
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Capsule endoscopy is recommended as the test of choice after a negative ileocolonoscopy in patients without obstructive symptoms.
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Cross-sectional imaging is preferred to capsule endoscopy for evaluation of established Crohn disease because of the higher risk for capsule retention.
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Capsule endoscopy is useful for the diagnosis of celiac disease in patients unable or unwilling to undergo standard upper endoscopy, and in evaluation of patients with refractory celiac disease.
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Deep enteroscopy is useful to obtain tissue diagnosis and perform endoscopic therapy, including balloon dilation of SB strictures and NSAID-related diaphragms, and capsule retrieval.
Introduction
Inflammatory disorders of the small bowel (SB) are common and can present in many different ways depending on the underlying cause. Many of the inflammatory disorders lead to mucosal ulceration, whereas some only cause superficial mucosal changes. As a result, patients can present with varied symptoms of abdominal pain, diarrhea, bleeding, iron deficiency anemia, malabsorption, weight loss, and/or obstruction. The most common causes of SB inflammation include Crohn disease (CD), nonsteroidal antiinflammatory drug (NSAID) enteropathy, and celiac disease. Less common causes include autoimmune enteropathy, radiation enteritis, infection (tuberculosis, yersinia), lymphoproliferative disorders, ischemia, and Behçet disease. A list of the differential diagnosis can be found in Box 1 . This article focuses on CD, NSAID enteropathy, and celiac disease. It provides updates on the diagnosis of these diseases using capsule endoscopy (CE), deep enteroscopy, and cross-sectional imaging with computed tomography enterography (CTE) or magnetic resonance enterography (MRE).
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CD
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NSAID enteropathy
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Celiac disease
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Radiation enteritis
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Infection
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Ischemia
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Autoimmune enteropathy
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Behçet disease
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Lymphoproliferative disorders
Introduction
Inflammatory disorders of the small bowel (SB) are common and can present in many different ways depending on the underlying cause. Many of the inflammatory disorders lead to mucosal ulceration, whereas some only cause superficial mucosal changes. As a result, patients can present with varied symptoms of abdominal pain, diarrhea, bleeding, iron deficiency anemia, malabsorption, weight loss, and/or obstruction. The most common causes of SB inflammation include Crohn disease (CD), nonsteroidal antiinflammatory drug (NSAID) enteropathy, and celiac disease. Less common causes include autoimmune enteropathy, radiation enteritis, infection (tuberculosis, yersinia), lymphoproliferative disorders, ischemia, and Behçet disease. A list of the differential diagnosis can be found in Box 1 . This article focuses on CD, NSAID enteropathy, and celiac disease. It provides updates on the diagnosis of these diseases using capsule endoscopy (CE), deep enteroscopy, and cross-sectional imaging with computed tomography enterography (CTE) or magnetic resonance enterography (MRE).
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CD
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NSAID enteropathy
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Celiac disease
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Radiation enteritis
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Infection
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Ischemia
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Autoimmune enteropathy
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Behçet disease
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Lymphoproliferative disorders
Small bowel Crohn disease
Inflammatory bowel disease consists of 2 main types: ulcerative colitis and CD. Ulcerative colitis mainly involves the colon, whereas CD can affect the entire gastrointestinal tract. Most commonly, CD involves both the terminal ileum and colon segmentally, but may involve only the SB, especially in young patients. There is no gold standard for diagnosis, which depends on a constellation of findings based on the history and physical examination, laboratory tests, endoscopy, pathology, and radiology.
CD that is isolated to the SB can be challenging to diagnose and manage. It is estimated that one-third of patients have disease confined to the SB. A recent study suggests that SB involvement may occur more often than was previously thought. Endoscopic skipping of the distal terminal ileum may also occur, making diagnosis by ileocolonoscopy challenging. Making this even more challenging is the poor correlation between symptoms and severity of inflammation in the SB. As a result, it is critically important that clinicians have the right technology to completely image the SB when inflammation is suspected. As such, a comprehensive evaluation of the SB may be indicated to make a definitive diagnosis, determine disease extent and severity, and/or evaluate for mucosal healing. The approach to patients with suspected CD is different from the approach to patients with known CD.
Suspected Crohn disease
In most patients with SB CD, the disease is located in the terminal ileum, and thus can be diagnosed with ileocolonoscopy, which also allows direct mucosal examination and biopsy. However, in a subset of patients with isolated SB CD, or in those with sparing of the terminal ileum, it may be more difficult to make a diagnosis. Normal findings on ileocolonoscopy are not sufficient to exclude the diagnosis. Therefore, the indications for a more thorough evaluation of the SB in suspected CD include clinical suspicion in the absence of lesions at ileocolonoscopy, especially if there are alarm symptoms such as anemia, weight loss, abdominal pain, diarrhea, and/or extraintestinal manifestations. There is evidence to suggest that a subgroup of patients have endoscopic skipping of the terminal ileum. In these situations, clinicians must consider complementary SB imaging tests, such as CE, deep enteroscopy, and cross-sectional imaging with CTE or MRE.
Evidence-based studies to date have not determined the ideal test for imaging the SB in suspected CD. Regarding CE, studies have suggested a reasonable sensitivity and specificity in the evaluation of patients with suspected CD. A recent prospective study comparing CE with SB follow-through (SBFT) and ileocolonoscopy showed that CE was better than SBFT, but equivalent to ileocolonoscopy for the diagnosis of ileocecal inflammation. It also showed that CE is safe and can help in diagnosis of CD when ileocolonoscopy is negative. There is also evidence that CE may be more sensitive in detecting inflammatory lesions in the proximal SB compared with CTE or MRE. Cross-sectional imaging can detect transmural inflammation but superficial mucosal disease may be missed. CE offers a comprehensive evaluation of the SB mucosa. In addition, CE has a high negative predictive value for CD. The updated American Society of Gastrointestinal Endoscopy (ASGE) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines on the diagnosis and treatment of SB disorders recommend CE as the initial diagnostic modality after negative ileocolonoscopy in patients without obstructive symptoms.
The main limitation of CE is its low specificity for CD compared with ileocolonoscopy and cross-sectional imaging. NSAIDs should ideally be discontinued for at least 4 weeks before proceeding with CE. An increased fecal calprotectin level may improve specificity and allow a cost-effective selection of patients to undergo CE. It has been shown that a fecal calprotectin level greater than 100 μg/g may be a good predictor of positive SB CE findings, whereas CE may be avoided in patients with a level less than 100 μg/g because of a high negative predictive value (1.0).
Regarding cross-sectional imaging, there is also evidence that CTE and MRE can be useful. The CTE findings most suggestive of CD include mural hyperenhancement and bowel wall thickening greater than 3 mm ( Fig. 1 ). In a retrospective study of 189 patients with CD, terminal ileal intubation was successful in 153 patients. Sixty-seven patients had normal ileoscopy, but 36 had active SB CD. CTE was positive in 34 patients with more proximal disease or intramural disease. MRE has also been shown to correlate with colonoscopy in suspected CD. In addition, there is evidence that the specificity of CTE for CD compared with CE may be better, but more studies are needed to confirm this. In a study comparing CE versus CTE and MRE in patients with suspected or newly diagnosed CD, CE had significantly enhanced detection of CD in the proximal SB compared with CTE and MRE, but the clinical relevance of this is not clear.
Deep enteroscopy has not been extensively studied in suspected CD but there is evidence to suggest it may be of benefit. In a meta-analysis of 11 studies involving 375 patients with suspected SB disease, CE and double balloon enteroscopy (DBE) were complementary with a diagnostic yield of 16% versus 18% respectively for inflammation, most caused by CD. It was concluded that CE is still the preferred initial test because it is noninvasive and can guide the optimal route of DBE. In a study of 30 patients with suspected CD and negative ileocolonoscopy, DBE proved to be useful in making a definitive diagnosis in 24 patients (80%) and suspected findings in 6. A more recent study found that DBE in suspected CD had a diagnostic yield in 33 of 38 patients (79%) and an impact on management in 33 of 43 patients (77%). Of note, it was unsuccessful in 17% and there was 1 complication.
A suggested algorithm for the diagnostic work-up in suspected CD is shown in Fig. 2 .
Established Crohn disease
There has been a paradigm shift in treatment decisions for patients with established CD. In the past, treatment was based predominantly on the symptoms, but it is now known that symptoms are insensitive and nonspecific for bowel inflammation. As such, it is now thought that treatment based on objective markers of inflammation including mucosal healing is a better approach. Mucosal healing at 1 year has been shown to be a predictor of overall disease outcome, including the need for surgery. Cross-sectional imaging, CE, and deep enteroscopy are potential modalities that can help with this assessment of SB inflammation in CD.
Assessing SB inflammation in established CD is an evolving area. There continues to be some controversy about how best to assess the entire SB for inflammation. MRE and CTE have been shown to play an important role in established CD. Wall thickening and abnormal enhancement were sensitive indicators of CD, whereas abnormal T2 signal, mesenteric vascular prominence, and adenopathy were specific. An early retrospective study evaluated 20 patients with known CD who underwent 40 CTEs interpreted by radiologists blinded to their clinical history, and found a reasonable correlation (weighted kappa of 0.57; 95% confidence interval of 0.20–0.94) between symptoms and endoscopic findings. One prospective study showed that MRE and CTE are equally accurate in assessing disease activity compared with ileocolonoscopy. Examples of established CD with CTE and MRE are shown in Fig. 3 . There was a suggestion that MRE may be superior to CTE in detecting strictures and ileal wall enhancement. With regard to MRE, a validated index was developed called the Magnetic Resonance Index of Activity (MaRIA) score based on wall thickness, relative contrast enhancement, edema, and ulcers. A recent prospective multicenter trial of 48 patients with active CD, comparing the MaRIA and Crohn Disease Endoscopy Index of Severity scores, showed that MRE could determine ulcer healing with 90% accuracy and endoscopic remission with 83% accuracy. What is not known and needs to be determined in prospective studies is the significance of transmural inflammation compared with mucosal inflammation in terms of patient outcomes. Recent clinical guidelines recommend the use of cross-sectional imaging for established CD in addition to ileocolonoscopy for SB evaluation.
The potential applications for CE in established CD include assessing for disease extent and severity, postoperative recurrence, and mucosal healing once therapy is initiated. Regarding mucosal healing, symptom assessment is a poor indicator of severity and extent of disease. Multiple studies have shown that CE can detect subtle mucosal abnormalities that may be missed by other modalities. CE can help in identifying CD missed with conventional endoscopy and evaluate extent and severity of SB involvement. Studies have also shown that the high diagnostic yield of CE influences disease management and clinical outcomes, and thus it is thought that CE can play a role in assessing mucosal healing. In one prospective study of 28 patients with persistent symptoms, CE identified active inflammation in 82% compared with only 49% detected by ileocolonoscopy, showing an incremental yield of 33%. A study of 108 patients with established CD who underwent CE and CTE showed that 56% were noted to have jejunal ulcerations not identified on CTE, and this was the only risk factor to predict relapse. Examples of established CD seen with CE are shown in Fig. 4 . A recent study comparing CE with MRE and other biomarkers for SB mucosal healing showed that CE was highly accurate and safe compared with MRE. Capsule endoscopy and MRE were compared in 19 patients with CD involving the proximal SB. MRE and CE showed good correlation for the detection and localization of CD. However, MRE was inferior for the detection of superficial mucosal disease but reliably detected the presence of severe inflammatory changes within the bowel wall and beyond as well as the presence of severe stenoses. An ongoing study evaluating CE for monitoring SB CD activity suggests that the capsule correlates with ileocolonoscopy over time and that the capsule may identify more proximal inflammation. In terms of future applications, a novel CD capsule is being evaluated in CD for the evaluation of the SB and colon. The study showed that the panenteric capsule was equally effective in identifying active CD in the colon and terminal ileum compared with ileocolonoscopy. In addition, the capsule identified more patients with active CD and provides imaging of the entire SB and colon in a single procedure. Another recent prospective study used the colon capsule and compared it with other modalities in the evaluation of the SB and colon in 40 pediatric patients with CD. The sensitivity, specificity, positive predictive value, and negative predictive value of the colon capsule to detect SB inflammation were 90%, 94%, 95%, and 90% respectively; and for colon inflammation, they were 89%, 100%, 100%, and 91% respectively. The accuracy parameters for MRE (sensitivity 85%, specificity 89%) were lower than for the colon capsule. No serious adverse events were reported.
