Video capsule endoscopy (VCE) was introduced into the

CLINICAL GASTROENTEROLOGY AND HEPATOLOGY 2013;11:1224 1231 Use and Misuse of Small Bowel Video Capsule Endoscopy in Clinical Practice LAUREN B. GERSON Division of Gastroenterology, Stanford University School of Medicine, Stanford, California Video capsule endoscopy (VCE) was introduced into the United States in 2000 and has significantly advanced the ability to visualize the small intestinal mucosa by using noninvasive technology. Compared with traditional imaging with small bowel barium imaging, the use of VCE has demonstrated the ability to enhance diagnostic yield in patients with suspected small bowel pathology by approximately 25% 50% in patients with suspected small bowel disorders. 1 3 Although the use of VCE has been recommended as the next step in patients with obscure gastrointestinal hemorrhage after a negative upper and/or lower endoscopic examination, 4 its use in other clinical scenarios such as small bowel inflammatory disorders may not be associated with similar diagnostic yields. The major complication associated with the use of VCE remains small bowel retention. Although the risk of this event is virtually nil in patients with obscure bleeding, it can approach 10% in patients with known inflammatory bowel disease (IBD). 5 A critical appraisement of appropriate use of this technology may help physicians and third-party payers to determine which subset of patients with suspected or known small bowel disorders would benefit the most from undergoing a VCE procedure. To critically examine the use of VCE in clinical practice, an evidence-based approach was performed by using the GRADE system, 6,7 and a critical review of the literature on capsule endoscopy was performed by using PubMed, SCOPUS, and the Cochrane Database from 2000 2012. The quality of evidence could range from high (implying that further research was unlikely to change the authors confidence in the estimate of the effect) to moderate (further research would be likely to have an impact on the confidence in the estimate of effect) or low (further research would be expected to have an important impact on the confidence in the estimate of the effect and would be likely to change the estimate). The strength of a recommendation was graded as strong when the desirable effects of an intervention clearly outweigh the undesirable effects and as conditional when there was uncertainty about the tradeoffs. The evidence-based statements generated from this review are shown in Table 1. Studies including more than 20 patients were included for each topic to increase data quality when metaanalyses or randomized controlled trials were not available. Bleeding from a small bowel source remains uncommon, accounting for approximately 5% of sources in patients presenting with overt or occult gastrointestinal hemorrhage. 4 In patients with suspected small intestinal disorders, the yield of capsule endoscopy has been estimated to be approximately 60%. Capsule endoscopy is preferred as the initial test compared to deep enteroscopy because of its ability to visualize the entire small bowel, a decreased potential for complications, and decreased use of endoscopic resources. 8 On the basis of this information, use of VCE has been recommended as the next step in the evaluation of patients with gastrointestinal hemorrhage after a normal upper and lower endoscopic examination. 9 The caveat of this recommendation is that approximately 20% 30% of patients will have sources of bleeding detected within reach of a standard endoscope or colonoscope on repeat examination that were not detected on initial examination. This finding has been demonstrated in patients undergoing both capsule endoscopy 10 and deep enteroscopy. 11 Use of VCE has been demonstrated to be clearly superior to other imaging modalities for the small bowel in patients with obscure bleeding. Based on the prior literature, VCE offers an increased diagnostic yield of 25% 50% compared to the yield demonstrated by using traditional small bowel radiography 1,2 (yield, 3% 20%), PE (yield, 3% 30%), 12 14 and/or elective angiography (5% 15%). 15,16 In patients with a negative capsule endoscopy, the use of multidetector computed tomographic enterography (CTE) or magnetic resonance enterography (MRE) has been shown to detect pathology in some patients, particularly if bleeding is related to an underlying neoplasm. 17 Timing of the VCE examination has been demonstrated to be associated with diagnostic yield in patients with overt obscure hemorrhage. In a landmark study published by Pennazio et al 14 in 2004, the diagnostic yield in 100 patients undergoing VCE was 92% in patients with ongoing overt hemorrhage, 13% in patients with bleeding that had stopped (intervals ranging between 10 days and 1 year), and 44% in the IDA cohort. Subsequent studies defined higher diagnostic yields when VCE was performed within 2 weeks of an overt bleeding episode (detection rate, 91%) compared with 34% when the VCE occurred more than 2 weeks later. 18 Similarly higher diagnostic Appropriate Use of Capsule Endoscopy Obscure Overt Gastrointestinal Hemorrhage The use of VCE has been demonstrated to be superior compared with use of small bowel radiography, push enteroscopy (PE), or computed or magnetic enterography for visualization of small bowel sources of overt hemorrhage or iron deficiency anemia (IDA). Abbreviations used in this paper: CTE, computed tomographic enterography; FAP, familial adenomatous polyposis; FC, fecal calprotectin; IBD, inflammatory bowel disease; IC, ileocolonoscopy; IDA, iron deficiency anemia; MRE, magnetic resonance enterography; PE, push enteroscopy; PJS, Peutz Jeghers syndrome; SBFT, small bowel followthrough; VCE, video capsule endoscopy. 2013 by the AGA Institute 1542-3565/$36.00 http://dx.doi.org/10.1016/j.cgh.2013.03.010

October 2013 USE AND MISUSE OF SMALL BOWEL VCE 1225 Table 1. Evidence-based Recommendations for Use of VCE Recommendations for use of VCE Obscure gastrointestinal hemorrhage VCE should be performed for evaluation of obscure bleeding as the next diagnostic test after normal upper and lower endoscopic examinations. (Strong recommendation, high level of evidence) For patients with obscure overt bleeding, VCE should be administered as soon as feasible to increase the diagnostic yield. (Strong recommendation, high level of evidence) In patients with IDA, VCE should be performed for further evaluation after negative upper endoscopic and colonoscopic examinations. (Strong recommendation, high level of evidence) IBD VCE is recommended in patients with suspected or known Crohn s disease after negative ileoscopy in patients without signs or symptoms of obstruction. (Strong recommendation, high level of evidence) In patients with suspected obstruction, patency VCE or enterography examination should occur as the next diagnostic test. (Conditional recommendation, moderate level of evidence) VCE should not be routinely performed after a normal IC and MRE/CTE examination because of the low diagnostic yield for Crohn s disease. (Conditional recommendation, moderate level of evidence) Celiac disease VCE can be considered as an alternative test to histology for the diagnosis of celiac disease. (Conditional recommendation, moderate level of evidence) VCE should be performed in patients with nonresponsive celiac disease to assess for disease-associated complications. (Conditional recommendation, moderate level of evidence) Hereditary polyposis In patients with PJS, small bowel surveillance with VCE should occur starting at the age of 8 years and continuing every 3 years. (Conditional recommendation, low level of evidence) Screening for distal polyps by VCE can be considered in patients with FAP who have evidence of duodenal polyps on side-viewing endoscopic examination. (Conditional recommendation, low level evidence) Potential misuse of capsule endoscopy Chronic abdominal pain or isolated diarrhea VCE is not recommended in patients with isolated abdominal pain or diarrhea without the presence of inflammatory markers. (Conditional recommendation, moderate level of evidence) VCE should not be performed to evaluate isolated weight loss. (Conditional recommendation, low level of evidence) Scenarios with high risk of retention VCE should be avoided in clinical scenarios with increased risks of capsule retention including known IBD and radiation enteritis. (Conditional recommendation, moderate level of evidence) rates have been demonstrated when deep enteroscopy is performed within 2 weeks of an overt bleeding episode. 19 For inpatients, the yield of VCE has been shown to exceed 90% when administered within 48 hours of hospital admission. 20 However, although associated with higher diagnostic yields, use of VCE in the inpatient setting carries increased rates of gastric retention and incomplete examinations to the cecum. 10 In patients at higher risk of incomplete examinations, endoscopic placement into the duodenum and/or administration of prokinetic therapy should be considered. Use of Video Capsule Endoscopy in Patients With Obscure Occult Bleeding In patients presenting with chronic IDA, performance of VCE is also recommended as the next diagnostic test after a negative upper and lower endoscopic examination. 4 A recent meta-analysis published in 2012 examined the utility of VCE in 1960 patients from 24 studies with IDA. 21 Although the diagnostic yield overall was 47% (95% confidence interval, 42% 52%), there was significant heterogeneity among studies that influenced the results. When only patients with confirmed IDA by established thresholds for hemoglobin and ferritin values were included, the diagnostic yield increased to 67% (95% confidence interval, 61% 72%). Angioectasias accounted for approximately 45% of the positive findings on VCE examinations. The risk of rebleeding after VCE depends on the type of lesion detected and the associated patient comorbidities. Patients with normal VCE examinations have a very low risk ( 5%) of rebleeding during the course of the subsequent year. 22 Rebleeding rates can be expected to be highest ( 50%) in patients with fresh blood on VCE examination or angiodysplastic lesions. In many patients with small bowel arteriovenous malformations, however, bleeding can subside over time without endoscopic or other therapy. 3,23 Patients with comorbid conditions including cardiovascular, renal, and pulmonary disorders are most likely to demonstrate rebleeding from new or existing vascular lesions. 24 Clinical Impact of Video Capsule Endoscopy Several studies have assessed further change in management after VCE studies performed for obscure gastrointestinal bleeding. In the original 2004 study published by Pennazio et al, 14 all of the 23 patients with overt bleeding were treated (including medical therapy in 9 patients, endoscopic treatment in 11, and surgery in 3 patients), resulting in a cessation rate of 87% during the follow-up period ranging from 12 25 months. Of the 39 patients with obscure-occult bleeding, 25 patients underwent further examinations after VCE. The diagnosis remained unknown in 17 patients, 18 were treated medically, 5 underwent endoscopic therapy, 6 had surgery, and 10 patients were not treated. Complete resolution in this cohort was 69% during the follow-up period. In a subsequent 2007 study published in the Netherlands by van Tuyl et al, 25 questionnaires were sent to the treating phy-

1226 LAUREN B. GERSON CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 10 Table 2. Sensitivity and Specificity of VCE for Small Bowel Disorders a Study, year No. of patients VCE CTE Histology SBFT Obscure gastrointestinal bleeding Hara, 2 2004 43 Gold standard CT: 25% (86%) 5% (100%) Eliakim, 60 2004 20 89% (83%) Gold standard 57% (83%) Crohn s disease Dubcenco, 28 2005 39 90% (100%) b Gold standard 28% (100%) Solem, 29 2008 41 83% (53%) c 82% (89%) 74% (100%) 65% (94%) Jensen, 32 2011 93 100% (91%) 76% (85%), MRE 81% (86%) Gold standard Celiac disease Rondonotti, 38 2007 43 87.5% (91%) Gold standard Hopper, 39 2007 21 85% (100%) Gold standard Rokkas, 40 2012 166 89% (95%) Gold standard Nonresponsive celiac disease Atlas, 42 2011 42 56% (85%) Gold standard a Numbers shown as sensitivity (specificity) in table. b Calculated sensitivity and specificity comparing IC and SBFT with VCE. c Sensitivity and specificity calculated compared with consensus diagnosis. sicians for 150 patients undergoing VCE for evaluation of obscure bleeding (N 97), Crohn s disease (N 36), or other reasons (N 17). Assessments occurred 1 year after VCE to determine the impact of VCE on subsequent patient management. Management alterations were considered to be present if there was a change in medication, performance of an endoscopic procedure, surgery or other procedure, or avoidance of additional testing. VCE established a definite diagnosis in 51 patients (34%), probable diagnosis in 51 (34%), and no diagnosis in 48 of the patients (32%). Fifty-nine percent of the patients with a definite diagnosis had a change in management, compared with the overall rate of 38%. Despite change in management as a result of the VCE study findings, performance of a VCE study may not change longterm patient outcomes such as resolution or recurrence of bleeding. This is particularly true for patients with small bowel angiodysplastic lesions, in whom rebleeding rates have been shown to exceed 50% at 1 year post-vce. 22 Long-term outcome studies after deep enteroscopy have demonstrated that patients with small bowel vascular lesions are more likely to experience recurrent bleeding 1 and 3 years after enteroscopy, 19,26 particularly in the setting of concomitant cardiovascular and/or renal disease. 24 On the other hand, studies have demonstrated that approximately 30% 40% of patients with angiodysplastic lesions may experience spontaneous cessation of bleeding and/or anemia over time. 27 In a 2010 retrospective study, 82 patients with a history of obscure gastrointestinal bleeding (including IDA in 57 and overt bleeding in 25) were followed for a mean of 36 16 months (IDA cohort) or 40 months (obscure bleeding group). 23 Abnormal findings on VCE were detected in 60% of both cohorts, with angiodysplastic lesions accounting for 40% of the findings. During the mean follow-up period, there was no difference in the percentage of patients who remained anemic (23% of the IDA group vs 22% of the overt group). Of the 35 patients in the IDA referral group with significant VCE pathology, 15 underwent therapeutic procedures, and 20 were managed conservatively. The authors found that most of the patients referred for VCE examination to evaluate IDA were no longer anemic at 36 months of follow-up, with or without therapeutic intervention. Inflammatory Bowel Disease The use of VCE for patients with inflammatory disorders of the small bowel has been established. Capsule endoscopy can be used to diagnose IBD in patients with suggestive signs and/or symptoms and can exclude the diagnosis in patients with nonspecific inflammation of the bowel on other imaging modalities. VCE can be used to assess disease activity and/or recurrence in patients with established small bowel Crohn s disease. However, the ability of VCE to distinguish whether ulcerations are a result of IBD compared to other causes such as nonsteroidal anti-inflammatory drugs remains a significant limitation. In a study published in 2005, 39 patients (11 with suspected Crohn s disease and 28 with established disease) underwent VCE, ileocolonoscopy (IC), and either small bowel series (small bowel follow-through [SBFT]) or barium enema examinations to evaluate symptoms. All 3 testing modalities were performed in 11 of 39 patients without a diagnosis of Crohn s disease and in 28 of 39 patients with established disease. A final diagnosis of active Crohn s disease was made in 29 of 39 patients (74%); the diagnosis was made on the basis of endoscopy and histopathology in 25 of 39 patients (64%), VCE in 26 of 39 (67%), and radiographic studies in 8 of 39 (20% with a miss rate of 72%). Overall, VCE had a sensitivity of 90% and specificity of 100% compared with SBFT with a sensitivity of 26% and specificity of 100% for the diagnosis of small bowel Crohn s disease 28 (Table 2). In a subsequent four-way crossover trial published in 2008, 41 patients with suspected or known Crohn s disease underwent testing with CTE (performed in all patients), IC (in 36 patients), SBFT (N 38), and VCE (N 28; 10 patients excluded because of partial small bowel obstructions, and 2 patients dropped out). 29 Active Crohn s disease was present in 51% of the cohort, and 42% were normal. Overall, VCE had a sensitivity of 83%, which was comparable with that of CTE for the diagnosis of small bowel Crohn s disease, but the specificity for VCE was 52%, which was lower compared with CTE, IC, and SBFT because of the presence of nonspecific VCE findings. Suspected Inflammatory Bowel Disease In a meta-analysis comparing the yield of VCE with SBFT and IC for suspected or established Crohn s disease, the

October 2013 USE AND MISUSE OF SMALL BOWEL VCE 1227 number needed to treat was 3 for the use of VCE compared with SBFT and number needed to treat 7 comparing IC with VCE. Although the differences were highly statistically significant for patients with established Crohn s disease, use of VCE did not show a significant advantage compared with the other modalities for patients with suspected Crohn s disease. 30 The authors questioned whether this latter result was due to a lack of adequate sample size because of the small number of patients with suspected Crohn s disease in these studies. A subsequent meta-analysis in 2010 was performed to determine whether the use of VCE was also the preferred modality for patients with suspected Crohn s disease by using a larger sample size. 31 The authors performed an analysis of 12 trials that included more than 428 patients who had undergone testing with PE, VCE, SBFT, IC, CTE, or MRE. The results demonstrated that VCE yield for suspected Crohn s disease patients was superior to those of PE, SBFT, IC, and CTE. The differences between VCE and MRE were not significant, likely because of the small number of studies performed with MRE. In a recent 2011 study not included in the above metaanalysis, 93 patients with suspected or newly diagnosed Crohn s disease underwent initial IC followed by CTE/MRE. 32 VCE was planned if there was no evidence of stenosis on the prior examinations. Crohn s disease of the ileum was diagnosed in 23 patients. The authors found superior sensitivity and specificity for VCE (100% and 91%) compared with MRE (81% and 86%) and CTE (76% and 85%) compared with the gold standard of histology for the diagnosis of Crohn s disease of the terminal ileum. Recommended Diagnostic Algorithm The major barrier for the performance of VCE in patients with suspected or known Crohn s disease is the risk of retention. In patients with suspected Crohn s disease, the risk of retention was 1 of 64 (1.6%), whereas this risk increased to 5 of 38 (13%) in patients with known Crohn s disease. 5 A subsequent meta-analysis showed that retention risks were 1.2% for patients with obscure gastrointestinal bleeding, 2.6% for Crohn s disease, and 2.1% for patients with neoplasms. 33 On the basis of a consensus of experts, IC should remain the first diagnostic test for patients with suspected Crohn s disease. 34 If this examination is normal and there remains a moderate to high suspicion of Crohn s disease, the next test depends on whether there are possible signs of obstruction. In the setting of known or suspected obstruction, the next test should be either CTE/MRE or a patency capsule study because both of these modalities have been shown to have equal sensitivity in the detection of small bowel strictures. 35 In patients without symptoms of obstruction, VCE is recommended as the next step. A cost-effectiveness analysis published in 2010 examined the cost-effectiveness of VCE after 2 prior negative tests for patients with suspected Crohn s disease. 36 Although the incremental cost-effectiveness ratio for CTE was favorable ( $54,000/qualityadjusted life year) compared with SBFT after negative IC examination, performance of a VCE study after either a negative SBFT or CTE study was not cost-effective (incremental cost-effectiveness ratio $500,000/quality-adjusted life year) because of the low likelihood of the disease being present after 2 negative initial tests. Recently, investigators have evaluated the value of fecal calprotectin (FC) as a predictor for positive VCE studies. 37 In 1 study of 70 patients with suspected Crohn s disease after negative esophagogastroduodenoscopy/colonoscopy, 44 patients had FC levels 50 g/g. The authors found that in patients with FC 200 g/g, the yield of VCE was 60%, with Crohn s disease confirmed in 50% of the patients. The authors concluded that VCE should not be performed in patients with FC 100 g/g because of the low diagnostic yield. Future studies combining use of inflammatory markers and VCE are warranted to identify patients with a higher diagnostic yield on VCE studies. Celiac Disease The use of VCE in patients with celiac disease has been evolving and can be considered as an aid in the diagnosis of celiac disease to assess reasons for ongoing or new symptoms, to diagnose disease recurrence, and to screen patients for complications, namely ulcerative jejunitis and adenocarcinoma. Diagnosis of Celiac Disease In a multicenter European study published in 2007, 43 patients with suspected celiac disease and positive antibody levels (antigliadin and/or antiendomysial and/or anti tissue transglutaminase antibodies) were studied with both upper endoscopy with duodenal biopsies and VCE. 38 By using duodenal histology as the gold standard (celiac disease was diagnosed in 32 patients), the sensitivity of VCE for the diagnosis of celiac disease was 87.5% with a specificity of 91%, positive predictive value of 96%, and negative predictive value of 71%. Mucosal disease extended distal to the duodenum in 18 patients (56%). In a subsequent 2007 study of 21 patients with suspected celiac disease and positive antiendomysial antibodies, results from duodenal biopsy and VCE examinations were compared with 23 patients undergoing VCE for other indications. 39 Twenty of 21 patients with positive antibodies demonstrated villous atrophy that was detected by VCE in 17 of 20, rendering a sensitivity of 85% and specificity of 100% for VCE compared with histology. A meta-analysis published in 2012 assessed the accuracy of VCE in the diagnosis of celiac disease. 40 Six studies meeting entry criteria were analyzed. The overall sensitivity of VCE was 89% with a specificity of 95% for the diagnosis of celiac disease compared with histology. Recently, a study was published to assess the use of VCE in cases of equivocal celiac disease. Sixty-two patients with equivocal celiac disease characterized by antibody-negative villous atrophy in 32 patients and Marsh 1 2 changes on histology in 30 cases underwent VCE and were compared with 69 patients with nonresponsive celiac disease. The highest diagnostic yield was in the antibody-negative villous atrophy group, where 28% were diagnosed with celiac disease or Crohn s disease by VCE compared with only 7% in the group with Marsh 1 2 changes (P.04). In the nonresponsive group, VCE was positive in 12% and showed 2 cases of enteropathy-associated lymphoma, 4 cases of type 1 refractory celiac disease, and 1 case of ulcerative jejunitis. Complications Associated With Celiac Disease In a 2005 study of 47 established patients with celiac disease, VCE was used to assess patients with symptoms including abdominal pain, weight loss, diarrhea, and IDA and to screen patients with longstanding disease who were undergoing surveillance for cancer. 41 The studies revealed new findings in

1228 LAUREN B. GERSON CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 10 60% of the cohort including ulcerations in 45%, cancer in 1 patient, and stricture in 1 patient. Eighty-seven percent of the cohort demonstrated mucosal findings consistent with celiac disease. A 2011 study assessed the utility of VCE in patients with nonresponsive celiac disease. 42 Forty-two patients with nonresponsive celiac disease were compared with 84 sex- and agematched controls and 30 patients with uncomplicated celiac disease who had been on a gluten-free diet for 6 months. VCE studies showed villous atrophy in 31% of the nonresponsive celiac disease group, 47% of the uncomplicated patients, and none of the controls. By using histology as the gold standard for villous atrophy, VCE had a sensitivity of 56% and specificity of 85%. Two patients with unresponsive celiac disease had complications found on VCE including ulcerative jejunitis and adenocarcinoma. Video Capsule Endoscopy to Monitor Response to Gluten-free Diet More data are needed to determine the use of VCE to assess mucosal healing after a gluten-free diet is initiated. In a small 2011 study, 12 patients with newly diagnosed celiac disease underwent baseline VCE and symptom assessments. 43 Studies were repeated 12 months after a gluten-free diet. At baseline, 18% of the small bowel demonstrated atrophy by VCE calculated by small bowel transit time; this was reduced to 3% after 12 months and was accompanied by symptomatic improvement and decrease in anti-transglutaminase levels. Mucosal healing appeared to occur in a distal to proximal fashion in the small bowel mucosa. Suspected Neoplasms and Polyposis Syndromes Although the presence of small bowel neoplasms is rare, the introduction of VCE has improved the ability for diagnosis and visualization of small bowel tumors. In a 2006 study in the United States that examined 562 VCE studies performed between 2001 and 2003, 9% of the studies demonstrated tumors, with 48% being malignant; adenocarcinoma, carcinoid, and gastrointestinal stromal tumors were the most common subtype. 44 A subsequent large European multicenter retrospective study published in 2008 examined the diagnostic yield from 5129 VCE studies and demonstrated tumors in 2.4% of the cohort, with gastrointestinal stromal tumors in 32%, adenocarcinomas in 20%, and carcinoids in 15% of the cohort. One hundred twelve were primary and 12 were metastatic, of which 66% were results of metastatic malignant melanoma. Retention occurred in 10% of the studies, and 80% of the tumors were diagnosed solely by VCE. 45 In a subsequent multicenter study in Korea, 1332 VCE studies performed between 2001 and 2008 were reviewed and showed tumors in 4%, of which only 50% were diagnostic by VCE and missed by radiographic examinations. 46 VCE images are usually not able to distinguish histologic tumor type. In approximately 70% 80% of cases the lesions appear polypoid, whereas there will be an ulcerated appearance in the remaining 20% 30% of lesions. Hereditary Polyposis Syndromes The use of capsule endoscopy has been recommended for surveillance in some patients with hereditary polyposis syndromes. In patients with Peutz Jeghers syndrome (PJS), an autosomal dominant condition characterized by the presence of mucocutaneous pigmentation and gastrointestinal tract polyps, small bowel screening with VCE is recommended starting at age of 8 years. The examination is repeated every 3 years if polyps are found at the initial examination or earlier if the patient is symptomatic. If few or no polyps are found at the initial examination, the examination should be repeated at age of 18 years, or sooner if symptoms arise, and then every 3 years. 47 Familial adenomatous polyposis (FAP) is characterized by the presence of multiple colorectal adenomatous polyps (typically more than 100). Duodenal polyps occur in 45% 90% of patients with FAP and are usually adenomatous with a 4% 12% chance of lifetime cancer. Further distal polyps are rare but can extend to the distal ileum. The American Society for Gastrointestinal Endoscopy guidelines in 2006 advocated screening with end-viewing and side-viewing instruments. In the absence of symptoms, upper endoscopic screening should be initiated around age of 25 30 years. Currently there are no formal recommendations for VCE in these patients. However, the currently available VCE in the United States has a high miss rate for detection of the ampulla and associated pathology. 48 The literature has shown that VCE is superior to other imaging modalities for the identification of small bowel polyps. A 2005 study comparing SBFT with VCE for 24 patients (20 with FAP, 4 with PJS) demonstrated a detection rate of 29% (7 of 24 patients) for VCE, whereas the SBFT examination only found polyps in 3 of these 7 patients. 49 In a 2005 study from Germany, 40 patients including 29 with FAP and 11 with PJS underwent VCE, PE, and MRE. Seventy-six percent of the patients with FAP who had duodenal adenomas had jejunal adenomas identified by PE and VCE, and 24% had more distal small bowel lesions only demonstrated by VCE. Patients without duodenal lesions did not have distal small bowel polyps. The detection rate of VCE for polyps in PJS occurred in 10 of 11 patients and was higher than that for PE or MRE. 50 In a 2008 study of 23 FAP patients, 11 of 23 had duodenal polyps by using side-viewing upper endoscopy. VCE detected jejunal or ileal polyps in 7 of 23 of these patients, whereas patients without duodenal polyps had normal VCE examinations. Visualization of the ampulla by using VCE was poor. 51 With the advent of enterography examinations, the diagnostic yield for polyps and neoplasms has improved by using radiographic techniques. In a 2010 study comparing MRE with VCE for 19 PJS patients, which used an end point of detection of polyps 10 mm in size, no differences were found between MRE and VCE detection rates. For polyps 15 mm, MRE performance was superior. 52 Although more data are needed for the performance of MRE, it can be a useful complementary test particularly because the appearance of bulges on VCE can be difficult to interpret. Potential Misuse of Capsule Endoscopy Patients presenting with isolated abdominal pain or diarrhea without other symptoms are unlikely to benefit from VCE. In an expert consensus statement from 2007, patients defined as having suspected Crohn s disease were required to have the presence of gastrointestinal symptoms including abdominal pain, diarrhea, and weight loss (group A) in addition to at least one criterion from the other 3 groups including group B (fevers, arthralgias, arthritis, skin manifestations, pri-

October 2013 USE AND MISUSE OF SMALL BOWEL VCE 1229 mary sclerosing cholangitis, or perianal signs), group C (inflammatory markers including sedimentation rate, C-reactive protein, iron deficiency, leukocytosis, abnormal IBD serologic markers, or stool testing), or group D (abnormal finding on an abdominal imaging test). 34 Currently, the presence of symptoms from group A alone cannot be used to justify a VCE study on the basis of the available evidence. Isolated Symptoms of Abdominal Pain and/or Diarrhea In an initial study published by Bardan et al 53 in 2003, 20 patients with chronic abdominal pain for more than 3 months and negative testing with endoscopy and radiographic studies underwent VCE with a diagnostic yield of 0%. In a subsequent 2006 study conducted at the Mayo Clinic, 64 patients with abdominal pain, diarrhea, or both and negative endoscopic and/or radiologic testing underwent VCE. The diagnostic yields were 6% overall, 6% for isolated abdominal pain, 14% for diarrhea, and 13% when both symptoms were present. Despite the fact that all patients had negative inflammatory markers, 3 patients were found to have Crohn s disease. 54 In 2007, a prospective multicenter European trial was performed to assess the value of VCE in 50 patients with chronic abdominal pain. Patients were allowed to have other symptoms and signs including chronic diarrhea, weight loss, and the presence of inflammatory markers. The 2 blinded VCE readers found significant lesions in 36% and 40% of cases, respectively. The presence of inflammatory serologic markers increased the odds of an abnormal VCE finding by 3.2-fold. 55 In a 2010 assessment of 2921 VCE studies performed between 2001 and 2008, the overall diagnostic yields were 63% for obscure gastrointestinal bleeding, 74% for polyposis syndromes, 55% in patients with known IBD, 27% for chronic diarrhea, and 15% for isolated abdominal pain. 56 The authors did not state whether patients with abdominal pain and/or diarrhea also had positive inflammatory markers present. Scenarios at High Risk of Capsule Retention The major complication associated with VCE is potential capsule retention. If the cause of retention is inflammatory, then capsule passage may occur with treatment of the underlying cause of the inflammation, such as the use of steroids for IBD. Other major treatments for VCE retention include deep enteroscopy and/or surgical removal. The major causes of VCE retention have included small bowel tumors, small bowel diverticula, and inflammation from Crohn s disease, nonsteroidal anti-inflammatory drugs, and/or radiation enteritis. 57,58 In one series of children with Crohn s disease documented by small bowel series, the risk of retention increased to 38%. 59 Although the event of VCE retention is diagnostic when a small bowel tumor is the cause, it can be regarded as a preventable complication when patients have known Crohn s disease or radiation enteritis. Because of the equivalent sensitivity and specificity for current small bowel enterography examinations compared with the patency capsule for the diagnosis of stricturing disease, 35 VCE should be potentially avoided in these clinical scenarios with higher risk of retention. A careful medical history is of key importance in patients at high risk of VCE retention. Conclusions In summary, VCE should be used as the third line test after a normal upper endoscopy and colonoscopy in patients with obscure overt or occult hemorrhage. VCE has been associated with a higher diagnostic yield for suspected or known Crohn s disease. However, the yield of VCE is very low after a normal ileoscopy and enterography examination. VCE should be preceded by a patency capsule test or an enterography examination in cases of suspected obstruction or small bowel stricture. VCE has demonstrated excellent sensitivity and specificity compared with histology for the diagnosis of celiac disease. It can be used to screen nonresponsive or refractory patients for complications associated with celiac disease. VCE is useful in the screening and surveillance of patients with hereditary polyposis syndromes. Currently, VCE is not recommended in patients with isolated abdominal pain, diarrhea, or weight loss unless these symptoms are associated with the presence of abnormal inflammatory markers. References 1. Costamagna G, Shah SK, Riccioni ME, et al. A prospective trial comparing small bowel radiographs and video capsule endoscopy for suspected small bowel disease. Gastroenterology 2002;123: 999 1005. 2. Hara AK, Leighton JA, Sharma VK, et al. Small bowel: preliminary comparison of capsule endoscopy with barium study and CT. Radiology 2004;230:260 265. 3. Laine L, Sahota A, Shah A. Does capsule endoscopy improve outcomes in obscure gastrointestinal bleeding? Randomized trial versus dedicated small bowel radiography. Gastroenterology 2010;138:1673 1680. 4. Raju GS, Gerson L, Das A, et al. American Gastroenterological Association (AGA) Institute technical review on obscure gastrointestinal bleeding. Gastroenterology 2007;133:1697 1717. 5. Cheifetz AS, Kornbluth AA, Legnani P, et al. The risk of retention of the capsule endoscope in patients with known or suspected Crohn s disease. Am J Gastroenterol 2006;101:2218 2222. 6. Atkins D, Best D, Briss PA, et al. Grading quality of evidence and strength of recommendations. BMJ 2004;328:1490 1494. 7. Atkins D, Briss PA, Eccles M, et al. Systems for grading the quality of evidence and the strength of recommendations II: pilot study of a new system. BMC Health Serv Res 2005;5:25 36. 8. Gerson L, Kamal A. Cost-effectiveness analysis of management strategies for obscure GI bleeding. Gastrointest Endosc 2008; 68:920 936. 9. Pennazio M, Eisen G, Goldfarb N. ICCE consensus for obscure gastrointestinal bleeding. Endoscopy 2005;37:1046 1050. 10. Robinson CA, Jackson C, Condon D, et al. Impact of inpatient status and gender on small-bowel capsule endoscopy findings. Gastrointest Endosc 2011;74:1061 1066. 11. Fry LC, Bellutti M, Neumann H, et al. Incidence of bleeding lesions within reach of conventional upper and lower endoscopes in patients undergoing double-balloon enteroscopy for obscure gastrointestinal bleeding. Aliment Pharmacol Ther 2009;29: 342 349. 12. Lewis BS, Swain P. Capsule endoscopy in the evaluation of patients with suspected small intestinal bleeding: results of a pilot study. Gastrointest Endosc 2002;56:349 353. 13. Mylonaki M, Fritscher-Ravens A, Swain P. Wireless capsule endoscopy: a comparison with push enteroscopy in patients with gastroscopy and colonoscopy negative gastrointestinal bleeding. Gut 2003;52:1122 1126. 14. Pennazio M, Santucci R, Rondonotti E, et al. Outcome of patients with obscure gastrointestinal bleeding after capsule endoscopy:

1230 LAUREN B. GERSON CLINICAL GASTROENTEROLOGY AND HEPATOLOGY Vol. 11, No. 10 report of 100 consecutive cases. Gastroenterology 2004;126: 643 653. 15. Defreyne L, Uder M, Vanlangenhove P, et al. Angiography for acute lower gastrointestinal hemorrhage: efficacy of cut film compared with digital subtraction techniques. J Vasc Interv Radiol 2003;14:313 322. 16. Berjljung L, Hjorth S, Svendler CA, et al. Angiography in acute gastrointestinal bleeding. Surg Gynecol Obstet 1977;145:501 503. 17. Hakim FA, Alexander JA, Huprich JE, et al. CT-enterography may identify small bowel tumors not detected by capsule endoscopy: eight years experience at Mayo Clinic Rochester. Dig Dis Sci 2011;56:2914 2919. 18. Bresci G, Parisi G, Bertoni M, et al. The role of video capsule endoscopy for evaluating obscure gastrointestinal bleeding: usefulness of early use. J Gastroenterol 2005;40:256 259. 19. Shinozaki S, Yamamoto H, Yano T, et al. Long-term outcome of patients with obscure gastrointestinal bleeding investigated by double-balloon endoscopy. Clin Gastroenterol Hepatol 2010;8: 151 158. 20. Apostolopoulos P, Liatsos C, Gralnek IM, et al. Evaluation of capsule endoscopy in active, mild-to-moderate, overt, obscure GI bleeding. Gastrointest Endosc 2007;66:1174 1181. 21. Koulaouzidis A, Rondonotti E, Giannakou A, et al. Diagnostic yield of small-bowel capsule endoscopy in patients with iron-deficiency anemia: a systematic review. Gastrointest Endosc 2012;76: 983 992. 22. Lai LH, Wong GL, Chow DK, et al. Long-term follow-up of patients with obscure gastrointestinal bleeding after negative capsule endoscopy. Am J Gastroenterol 2006;101:1224 1228. 23. Sheibani S, Levesque BG, Friedland S, et al. Long-term impact of capsule endoscopy in patients referred for iron-deficiency anemia. Dig Dis Sci 2010;55:703 708. 24. Arakawa D, Ohmiya N, Nakamura M, et al. Outcome after enteroscopy for patients with obscure GI bleeding: diagnostic comparison between double-balloon endoscopy and videocapsule endoscopy. Gastrointest Endosc 2009;69:866 874. 25. van Tuyl SA, van Noorden JT, Stolk MF, et al. Clinical consequences of videocapsule endoscopy in GI bleeding and Crohn s disease. Gastrointest Endosc 2007;66:1164 1170. 26. Gerson LB, Batenic MA, Newsom SL, et al. Long-term outcomes after double-balloon enteroscopy for obscure gastrointestinal bleeding. Clin Gastroenterol Hepatol 2009;7:664 669. 27. Junquera F, Feu F, Papo M, et al. A multicenter, randomized, clinical trial of hormonal therapy in the prevention of rebleeding from gastrointestinal angiodysplasia. Gastroenterology 2001; 121:1073 1079. 28. Dubcenco E, Jeejeebhoy KN, Petroniene R, et al. Capsule endoscopy findings in patients with established and suspected smallbowel Crohn s disease: correlation with radiologic, endoscopic, and histologic findings. Gastrointest Endosc 2005;62:538 544. 29. Solem CA, Loftus EV Jr, Fletcher JG, et al. Small-bowel imaging in Crohn s disease: a prospective, blinded, 4-way comparison trial. Gastrointest Endosc 2008;68:255 266. 30. Triester SL, Leighton JA, Leontiadis GI, et al. A meta-analysis of the yield of capsule endoscopy compared to other diagnostic modalities in patients with non-stricturing small bowel Crohn s disease. Am J Gastroenterol 2006;101:954 964. 31. Dionisio PM, Gurudu SR, Leighton JA, et al. Capsule endoscopy has a significantly higher diagnostic yield in patients with suspected and established small-bowel Crohn s disease: a metaanalysis. Am J Gastroenterol 2010;105:1240 1248. 32. Jensen MD, Nathan T, Rafaelsen SR, et al. Diagnostic accuracy of capsule endoscopy for small bowel Crohn s disease is superior to that of MR enterography or CT enterography. Clin Gastroenterol Hepatol 2011;9:124 129. 33. Liao Z, Gao R, Xu C, et al. Indications and detection, completion, and retention rates of small-bowel capsule endoscopy: a systematic review. Gastrointest Endosc 2010;71:280 286. 34. Mergener K, Ponchon T, Gralnek I, et al. Literature review and recommendations for clinical application of small-bowel capsule endoscopy, based on a panel discussion by international experts: consensus statements for small-bowel capsule endoscopy, 2006/2007. Endoscopy 2007;39:895 909. 35. Yadav A, Heigh RI, Hara AK, et al. Performance of the patency capsule compared with nonenteroclysis radiologic examinations in patients with known or suspected intestinal strictures. Gastrointest Endosc 2011;74:834 839. 36. Levesque BG, Cipriano LE, Chang SL, et al. Cost effectiveness of alternative imaging strategies for the diagnosis of small-bowel Crohn s disease. Clin Gastroenterol Hepatol 2010;8:261 267. 37. Koulaouzidis A, Douglas S, Rogers MA, et al. Fecal calprotectin: a selection tool for small bowel capsule endoscopy in suspected IBD with prior negative bi-directional endoscopy. Scand J Gastroenterol 2011;46:561 566. 38. Rondonotti E, Spada C, Cave D, et al. Video capsule enteroscopy in the diagnosis of celiac disease: a multicenter study. Am J Gastroenterol 2007;102:1624 1631. 39. Hopper AD, Sidhu R, Hurlstone DP, et al. Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in coeliac disease? Dig Liver Dis 2007;39:140 145. 40. Rokkas T, Niv Y. The role of video capsule endoscopy in the diagnosis of celiac disease: a meta-analysis. Eur J Gastroenterol Hepatol 2012;24:303 308. 41. Culliford A, Daly J, Diamond B, et al. The value of wireless capsule endoscopy in patients with complicated celiac disease. Gastrointest Endosc 2005;62:55 61. 42. Atlas DS, Rubio-Tapia A, Van Dyke CT, et al. Capsule endoscopy in nonresponsive celiac disease. Gastrointest Endosc 2011;74: 1315 1322. 43. Lidums I, Teo E, Field J, et al. Capsule endoscopy: a valuable tool in the follow-up of people with celiac disease on a gluten-free diet. Clinical and Translational Gastroenterology 2011;2:e4. 44. Cobrin GM, Pittman RH, Lewis BS. Increased diagnostic yield of small bowel tumors with capsule endoscopy. Cancer 2006;107: 22 27. 45. Rondonotti E, Pennazio M, Toth E, et al. Small-bowel neoplasms in patients undergoing video capsule endoscopy: a multicenter European study. Endoscopy 2008;40:488 495. 46. Cheung DY, Lee IS, Chang DK, et al. Capsule endoscopy in small bowel tumors: a multicenter Korean study. J Gastroenterol Hepatol 2010;25:1079 1086. 47. Beggs AD, Latchford AR, Vasen HF, et al. Peutz-Jeghers syndrome: a systematic review and recommendations for management. Gut 2010;59:975 986. 48. Clarke JO, Giday SA, Magno P, et al. How good is capsule endoscopy for detection of periampullary lesions? results of a tertiary-referral center. Gastrointest Endosc 2008;68:267 272. 49. Mata A, Llach J, Castells A, et al. A prospective trial comparing wireless capsule endoscopy and barium contrast series for small-bowel surveillance in hereditary GI polyposis syndromes. Gastrointest Endosc 2005;61:721 725. 50. Schulmann K, Hollerbach S, Kraus K, et al. Feasibility and diagnostic utility of video capsule endoscopy for the detection of small bowel polyps in patients with hereditary polyposis syndromes. Am J Gastroenterol 2005;100:27 37. 51. Iaquinto G, Fornasarig M, Quaia M, et al. Capsule endoscopy is useful and safe for small-bowel surveillance in familial adenomatous polyposis. Gastrointest Endosc 2008;67:61 67. 52. Gupta A, Postgate AJ, Burling D, et al. A prospective study of MR enterography versus capsule endoscopy for the surveillance of adult patients with Peutz-Jeghers syndrome. AJR Am J Roentgenol 2010; 195:108 116.

October 2013 USE AND MISUSE OF SMALL BOWEL VCE 1231 53. Bardan E, Nadler M, Chowers Y, et al. Capsule endoscopy for the evaluation of patients with chronic abdominal pain. Endoscopy 2003;35:688 689. 54. Fry LC, Carey EJ, Shiff AD, et al. The yield of capsule endoscopy in patients with abdominal pain or diarrhea. Endoscopy 2006; 38:498 502. 55. May A, Manner H, Schneider M, et al. Prospective multicenter trial of capsule endoscopy in patients with chronic abdominal pain, diarrhea and other signs and symptoms (CEDAP-Plus Study). Endoscopy 2007;39:606 612. 56. Rondonotti E, Soncini M, Girelli C, et al. Small bowel capsule endoscopy in clinical practice: a multicenter 7-year survey. Eur J Gastroenterol Hepatol 2010;22:1380 1386. 57. Singeap AM, Trifan A, Cojocariu C, et al. Outcomes after symptomatic capsule retention in suspected small bowel obstruction. Eur J Gastroenterol Hepatol 2011;23:886 890. 58. Li F, Gurudu SR, De Petris G, et al. Retention of the capsule endoscope: a single-center experience of 1000 capsule endoscopy procedures. Gastrointest Endosc 2008;68:174 180. 59. Atay O, Mahajan L, Kay M, et al. Risk of capsule endoscope retention in pediatric patients: a large single-center experience and review of the literature. J Pediatr Gastroenterol Nutr 2009; 49:196 201. 60. Eliakim R, Suissa A, Yassin K, et al. Wireless capsule video endoscopy compared to barium follow-through and computerised tomography in patients with suspected Crohn s disease: final report. Dig Liver Dis 2004;36:519 522. Reprint requests Address requests for reprints to: Lauren B. Gerson, MD, MSc, Division of Gastroenterology, 450 Broadway Street, Pavilion C, Mail Code 6341, Redwood City, California 94063. e-mail: lgersonmd@yahoo. com; fax: (650) 649-1808. Conflicts of interest The author discloses no conflicts.