Small Bowel Exploration by Wireless Capsule Endoscopy: Results from 314 Procedures

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1 The American Journal of Medicine (2006) 119, CLINICAL RESEARCH STUDY Small Bowel Exploration by Wireless Capsule Endoscopy: Results from 314 Procedures Giacomo C. Sturniolo, MD, a Vincenza Di Leo, MD, PhD, a Maria G. Vettorato, RN, a Michele De Boni, MD, b Francesca Lamboglia, MD, a Manuela De Bona, MD, PhD, b Angelo Bellumat, MD, b Diego Martines, MD, a Renata D Inca, MD a a Gastroenterology Section, Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy; b Gastroenterology Unit, Santa Maria del Prato Hospital, Feltre (BL), Italy. ABSTRACT OBJECTIVES: To assess the diagnostic efficiency of capsule endoscopy in a large group of patients with different indications, to weigh the reliability of the procedure for excluding small bowel lesions, and to identify factors associated with the likelihood of obtaining a definitive diagnosis. METHODS: Three hundred four consecutive patients (141 female, mean age 55 years, range years) underwent capsule endoscopy in two different Gastroenterology Units, for a total of 314 procedures, and were followed-up for a median period of 15 months. Referrals were obscure occult/overt gastrointestinal bleeding (203 patients), suspected small bowel disease (74), gastrointestinal polyposis (18), suspected/ previous intestinal or endocrine malignancies (13), previously diagnosed intestinal lymphangectasia (3), and vascular abnormalities (3). RESULTS: Adequate visualization of the small bowel was obtained in 96% of patients, although the capsule did not visualize cecum in 20% of cases. Non-natural excretion of the capsule was observed in 4 patients, all of whom underwent laparotomy for intestinal stenosis. Diagnostic yields were 58% for obscure gastrointestinal bleeding and 31% for patients with suspected small bowel disease. Capsule endoscopy was able to rule out small bowel disease in 14% of patients, and a definitive diagnosis was achieved in 65% of patients. The only parameter associated with the likelihood of reaching a conclusive diagnosis was the indication to the procedure (overall chi-square 13.5, P.004). CONCLUSIONS: Capsule endoscopy represents a reliable tool for verifying the state of the small bowel. Accurate selection of indications and critical evaluation of the results are essential to fully exploit this procedure Elsevier Inc. All rights reserved. KEYWORDS: Small bowel; Capsule endoscopy; Diagnosis After the advent of capsule endoscopy, the small bowel no longer appears a mysterious territory. This tool allows a simple, noninvasive and precise study of this part of the intestine, and it is foreseeable that old diseases will be re-defined, and new pathologic entities will be named. Its clinical impact, for either gastrointestinal (GI) obscure bleeding or other indications, has been recognized in Requests for reprints should be addressed to Giacomo C. Sturniolo, MD, Department of Surgical and Gastroenterological Sciences, Gastroenterology Section, c/o Ospedale Civile, Via Giustiniani 2, Padova, Italy. address: gc.struniolo@unipd.it. prospective studies. 1-6 In particular, its low invasiveness allows one to perform the examination almost simultaneously as an obscure GI bleeding occurs, resulting in a diagnostic yield of up to 92%. 5 Technical improvements, such as the blood indicator and the patency capsule, might accelerate the interpretation of the examination and make the test safer. 7-9 The ability of capsule endoscopy in detecting small bowel lesions is superior to radiology and CT scan Capsule endoscopy is more sensitive and specific also when compared with enteroscopy, 4,14 although it does not permit biopsies to be taken /$ -see front matter 2006 Elsevier Inc. All rights reserved. doi: /j.amjmed

2 342 The American Journal of Medicine, Vol 119, No 4, April 2006 The aims of this study were to describe the diagnostic efficiency of capsule endoscopy in a large group of patients with different indications, to assess the reliability of the procedure for excluding small bowel lesions, and to seek factors associated with the likelihood of finding significant lesions. METHODS Patients A total of 304 patients (141 female), mean age 55 years (range years) underwent capsule endoscopy for a total of 314 procedures. Patients were enrolled in 2 different Gastroenterology Units, in a tertiary center (Padova) and in a primary hospital (Feltre-BL) from September 2001 to November One hundred seventy-nine subjects (134 female), mean age 48 years (range 14-89) were outpatients; 125 (62F), mean age 58 years (range 15-91), were inpatients. In all patients, previous upper CLINICAL SIGNIFICANCE and lower GI endoscopies were negative. Findings of other investigations (Table 1) were not significant in explaining the clinical picture. Referral for the procedure, including those of patients who repeated capsule endoscopy, are listed in Table 2. One hundred five patients had co-morbidities, none of them contraindicating wireless endoscopy. Ten patients were on a nonsteroidal anti-inflammatory drug (NSAID), 5 were on anticoagulants, and 6 were on ticlopidine. All patients gave their informed consent (for underage patients, parental informed consent was obtained), and the study was approved by the Ethic Committees of the Azienda Ospedaliera of Padova and of Feltre. Capsule endoscopy allows a satisfactory exploration of the small bowel and is well tolerated by patients. The source of obscure GI bleeding can be identified in up to 58% of the cases within a month from the last episode. Small bowel diseases can be reliably ruled out if no lesions are detected by capsule. A critical clinical perspective is essential to fully exploit capsule endoscopy. Methods Bowel cleaning was carried out with PEG 4000 (Norgine Italia SrL, Milan, Italy) in all but 3 patients. A 4-liter solution was administered the day before capsule endoscopy. Metoclopramide 10 mg (Gruppo Lepetit SpA, Rome, Italy) was administered intramuscularly 10 minutes before swallowing the capsule. The M2A Given Capsule (Given Imaging Ltd, Yoqneam, Israel) was swallowed with a sip of water after an overnight fasting. Patients were allowed to drink or take medications 2 hours later and to eat a light snack 4 hours later, while continuing their usual activities. The time and nature of events, such as drinking or discomfort, were noted. After 8 hours from the ingestion of the capsule, the equipment was removed. Patients were asked to report the time of expulsion of the capsule (usually from 12 to 96 hours after the ingestion). If the device was not expelled within 4 days, direct abdominal radiology was obtained and the patient was closely observed until expulsion of the capsule. Patients with indications other than obscure GI bleeding were followed-up for a median period of 15 months (range 3-33). Interpretation of Results and Statistical Analysis The capsule video films were reviewed by four gastroenterologists, who were unaware of the clinical picture, at frames per second. Explorations were considered significant when sufficient to explain clinical presentation and negative if no lesions were found. Table 1 Investigations Performed Before Capsule Endoscopy Padova Feltre Total EGDS Colonoscopy Enteroclysis Small bowel follow through Barium enema Abdominal ultrasound Abdominal CT scan Abdominal MRI Scintigraphy Artheriography AngioMRI EGDS esophagogastroduodenoscopy; CT computed tomography; MRI magnetic resonance imaging. Table 2 Indications for Capsule Endoscopy Padova Feltre Total Overt obscure GI bleeding Occult obscure GI bleeding Suspected Crohn s disease Gastrointestinal polyposis Diarrhea Suspected malignancy Abdominal pain Malabsorption Intestinal lymphangectasia Vascular abnormalities Total GI gastrointestinal.

3 Sturniolo et al Usefulness of Capsule Endoscopy 343 Figure Type of lesions detected by capsule endoscopy in patients with obscure gastrointestinal bleeding. Data were analyzed by an SPSS program (SPSS Inc., Chicago, Ill). The chi-squared test was applied for categorical data. A P value.05 was considered significant. RESULTS Average recording time was 7 1 hours. None of the patients complained of discomfort during the procedure. Visualization of the small bowel was defined as sufficient and adequate by the endoscopists in 96% (301/314) of records, although caecum was not reached in 63/314 (20%) of cases. The most common causes for not reaching caecum during the recording time were luminal content (blood [13 patients] or bile/food [12 patients]: 40%), prolonged permanence of capsule in the stomach (9 patients: 14%), unsuspected stenosis (4 patients: 6.3%), and early battery depletion (3 patients: 4.7%). In 22 patients (32%), no clear cause for incomplete small bowel visualization could be recognized. In 13 patients, exploration was considered incomplete or insufficient to reach any conclusion. Eventually, 301 explorations were used for statistical evaluation. The capsule was spontaneously expelled in all but 4 patients, who had intestinal stenosis. None of them had history suggestive of intestinal subocclusion; 2 of them had negative small bowel follow-through before capsule endoscopy. These patients underwent surgery, one of them for clear signs of intestinal obstruction. Pathology on excised bowel diagnosed Crohn s disease (2 patients) and intestinal lymphoma (2 patients), confirming capsule findings. Endoscopic Findings and Diagnostic Yield According to Indications to Capsule Endoscopy Obscure GI bleeding. Obscure GI bleeding was defined according to the position of the American Gastroenterological Association. In particular, occult obscure bleeding was defined by the presence of positive fecal blood test and chronic iron-deficient anemia, without any clinically evident bleeding episode from at least 6 months, whereas overt obscure bleeding indicated a history of recurrent bleeding episodes of melena or lower GI bleeding in the last 6 months. Two hundred three procedures were performed to investigate obscure GI bleeding. Occult obscure GI bleeding was reported in 97 cases (40 female), mean age 61 years (range 12-89), mean Hb value g/dl, 68% of whom had had previous blood transfusions. Overt obscure GI bleeding, with the last episode within a month from the examination, was the indication in 106 cases (42 female), mean age 62 years (range 15-91), 71% with previous blood transfusion. Capsule endoscopy detected small bowel lesions in 141 explorations (69%), with similar frequency for overt (67%) and occult (71%) bleeding, whereas small bowel was free of lesions in 52 cases (26%). However, in this latter group, 17 gastroduodenal and 5 colonic abnormalities were found, of which 12 were significant enough to be included in the calculation of diagnostic yield. Exploration was considered insufficient in 10 procedures (5%). One hundred (52%) actively bleeding or high-risk bleeding lesions were discovered in the small bowel, mostly represented by angiomata, tumors, and ulcers (Figure). In 7 cases, lesions suggestive of Crohn s disease (CD) were found. Such diagnosis was confirmed by clinical history, pathology, and 18 months of follow-up. In 41 patients, findings (isolated hyperemic or lymphangecatsic areas, small and scattered erosions/small ulcers, single polyps, lipomas) were considered not related or adequate to explain the clinical picture. The overall diagnostic yield of wireless endoscopy in this group of patients was 58% (112 medical significant lesions/193 valid explorations). The diagnostic yield was 55% (56/101) for overt and 61% (56/92) for occult (chisquare 0.607, P.61) obscure GI bleeding (Table 3) and, among patients with overt GI bleeding, 51% and 57% for melena and bloody diarrhea, respectively (chi-square 0.113, P.73). Table 3 Significant Findings and Negative Explorations in the Group of Capsule Study Performed for Obscure GI Bleeding Total Number of Procedures Positive Findings (Diagnostic Yield) No Small Bowel Lesions (%) Overt-obscure (55%) 24 (23) Occult-obscure (61%) 16 (16) Total oscure (58%) 40 (20)

4 344 The American Journal of Medicine, Vol 119, No 4, April 2006 Table 4 Significant Findings and Negative Explorations in the Group of Patients who Underwent Capsule Endoscopy for Suspected Small Bowel Diseases According to the Type of Predominant Symptoms Total Number of Patients Positive Findings (Diagnostic Yield) No Small Bowel Lesions (%) Suspected CD (31%) 19 (54) Diarrhea 16 4 (25%) 4 (25) Abdominal pain 12 2 (17%) 7 (58) Malabsorption 11* 6 (54%) 1 (9) Total (31%) 31 (42) CD Crohn s disease. *Including patient with potential celiac disease. After stratifying patients as outpatients (120) and inpatients (83), who were more likely to be actively bleeding, the diagnostic power of capsule endoscopy was still unchanged (39% and 52% respectively, chi-square 1.523, P.46). Suspected Small Bowel Disease In 74 cases (38 female), mean age 40 years (range 14-77), capsule endoscopy was performed for persistent GI symptoms (eg, diarrhea, abdominal pain) or biochemical abnormalities (eg, increased inflammatory tests, low serum protein) suggestive of small bowel disease. In particular, the indication was chronic diarrhea in 16 cases, abdominal pain in 12, and malabsorption in 11. Crohn s disease was suspected in another 35 cases. Small bowel lesions were detected in 41 cases (55%), whereas the exploration was considered insufficient in 2 (3%) and negative in 31 (42%). In the latter group, 4 patients with minor gastroduodenal lesions (such as erythema) and 6 with ileal follicular hyperplasia were included. Capsule explorations were considered significant in 23 cases, final diagnosis being CD in 16 patients, intestinal diffuse lymphangectasia in 3, Whipple disease in 1, and NSAID enteropathy in 1. In 1 patient we made a final diagnosis of severe entheropathy, she presented with malabsorption and diarrhea. Capsule findings were suggestive of Crohn s disease (lymphangectasic villi and several erosions and petechiae through the whole small bowel). Enteroscopy and histology were nonspecific. After 23 months of therapy with 5ASA with partial clinical benefit, she underwent a second capsule endoscopy; findings were similar to the first ones, and the patient is currently under evaluation for lipid metabolism defects. Another patient with malabsorption had mosaic pattern with flattened mucosal folders in distal duodenum and ileum. Celiac and Crohn s diseases were excluded and the diagnosis of alcoholic enteropathy was suspected, as the patient was a heavy drinker. After 1 year s abstinence, the patient s clinical and biochemical condition had substantially improved. The overall diagnostic yield of capsule endoscopy for patients with suspected small bowel disease was 31%, there were no statistical differences between patients according to the type of referral to the procedure (Table 4) as either inpatients or outpatients. Other Indications Small bowel examination was satisfactory in all cases but one. Eighteen patients (13 female), mean age 43 years (range 18-67), underwent capsule endoscopy for staging gastrointestinal polyposis (13 of whom had familial adenomatous polyposis). In 12 patients with gastrointestinal polyposis (8 had familial adenomatous polyposis), further polyps were detected, and 2 had non-specific findings (erosions and small ulcers). Small bowel exploration was negative in 3 cases and insufficient in 1. Thirteen explorations were performed in 12 patients (7 female), mean age 59 years (range 23-77), who had suspected/previous intestinal or endocrine neoplasms. In 6 patients with suspected intestinal/endocrine neoplasms, the small bowel was free of lesions; whereas 1 had a small polypoid lesion of the terminal ileum, which resulted in a carcinoid tumor at surgery. In 1 patient active bleeding was demonstrated without evidence of the source. This patient, with severe anemia and lymphoadenomegalia in the mesenteric area detected by computed tomography (CT) scan and negative conventional endoscopy, died a few months later and autopsy diagnosed mesenteric diffusion of lung cancer. Four patients had a previous history of gastrointestinal neoplasm. One of them underwent capsule endoscopy before and after chemotherapy for metastasis discovered 3 years after colectomy for colonic adenocarcinoma. The bleeding polyps detected in the small bowel at the first examination had stopped bleeding after chemotherapy; no further investigations were performed. Three patients had had recent intestinal resections (1 for an appendicular carcinoid, 1 for colonic cancer, and 1 for small bowel adenocarcinoma), and no lesions were detected by capsule endoscopy. In 3 patients (2 female), mean age 37 years (range 31-43), with previously diagnosed intestinal lymphangectasia, capsule endoscopy gave a precise definition of the extent of the disease. Three patients (1 female), mean age 31 years (range 27-34), underwent procedure having already known vascular abnormalities: 1 had portal thrombosis after liver transplant, 1 had Behcet vasculitis, and 1 had blue rubber bleb nevi syndrome. Disseminate vascular abnormalities were

5 Sturniolo et al Usefulness of Capsule Endoscopy 345 detected in 2 patients, whereas the small bowel was free of lesions in the third. Outcome of Negative Explorations for Indications other than Obscure GI Bleeding Overall, capsule exploration was negative in 28% of cases (84/301 valid explorations). To define the clinical reliability of a negative exploration by capsule we strictly followed-up patients with indications other than obscure GI bleeding. This group comprised 44/84 patients, who were followed-up for a median period of 15 months (range 3-33). None of them needed a second procedure. Four patients, whose indication was chronic diarrhea, had gradual improvement, 2 with loperamide on demand. Among the 7 patients with abdominal pain and negative capsule endoscopy, 4 had undergone the procedure also because of increased intestinal permeability (measured by sugars test). All patients but 2 improved with antispastic therapy and diet. One patient had potential celiac disease (positive antitransglutaminases antibodies and mild hypoalbuminemia: normal duodenal histology) and the negative capsule endoscopy completely excluded celiac disease. The patients with Behcet vasculitis (1) and gastrointestinal polyposis (3) and no small bowel lesions at capsule endoscopy remained symptom free. In 19 patients with suspected CD, small bowel was lesion free. Five of them had a previous diagnosis of colonic CD and one of indeterminate colitis, and capsule ruled out a macroscopic small bowel involvement. The remaining patients were classified as having irritable bowel syndrome and treated with symptomatic drugs. Small bowel exploration was negative in 9 patients with suspected/previous intestinal/endocrine neoplasm. After a median follow-up of 21 months (range 16-32), 8 of them did not show symptoms or signs of recurrence, whereas 1 patient had a short follow-up (1 month) and was not included in the statistic evaluation. Predictive Factors for a Conclusive Diagnosis We considered conclusive 65% (195/301 valid explorations) of our diagnosis. Conclusive diagnosis included 154 explorations in which medically significant lesions were found (112 in the obscure GI bleeding group, 23 in the suspected small bowel disease group, 19 in the other indications group) and the 41 negative explorations who were confirmed during the follow-up. The only parameter associated with the likelihood of reaching a conclusive diagnosis was the indication to the procedure (overall chisquare 13.5, P.004). In particular, conclusive diagnoses were 58% for obscure GI bleeding, 75% for suspected small bowel disease, 77% for previous/suspected intestinal or endocrine neoplasm, and 90% for the group of other indications. DISCUSSION The main findings of this work are that the diagnostic capacity of capsule endoscopy is strictly related to the referral for the procedure and that a negative exploration rules out organic small bowel lesions in a convincing manner. From 2002, data on about 1500 patients with obscure GI bleeding investigated by capsule endoscopy have been reported in journals with peer reviewers. The average diagnostic yield was 54% (range 30-76), similar to ours, which was 58%. A recent work by Pennazio et al states a diagnostic yield of 92.3% for ongoing obscure-overt bleeding that decreased to 12.9% for patients with previous overtobscure bleeding, and was 44.2% for occult bleeding. 5 In our study, the patients with overt-obscure GI bleeding had the symptom within a month of the procedure, the different inclusion criteria could account for the difference of diagnostic yields between the two studies. However, the diagnostic yield was not significantly different between outpatients and inpatients who were more likely to be actively bleeding. Doubtless, timing in using the procedure is crucial and definitely influences its performance. However, it would not be inconceivable to find no lesions in the small bowel even with capsule endoscopy within 24 hours of the overt bleeding. Indeed, obscure GI bleeding is often intermittent, and blood has a cathartic effect, accelerating intestinal transit. Presence of abundant fresh blood may itself represent a limitation, although such a finding could be helpful to further orient investigations (ie, arteriography or intraoperative rather than push enteroscopy). Nevertheless, capsule endoscopy remains the only investigation comparable to conventional endoscopy when investigating mucosal sources of bleeding, which are located beyond the reach of enteroscopy in up to about 60% of cases. 15 We believe that a satisfactory diagnostic yield can be obtained if the procedure is performed within a month from the bleeding episode. To confirm that obscure GI bleeding represents the ideal field for capsule endoscopy, the diagnostic yield in the group of patients with suspect small bowel pathology was sensibly lower. The diagnostic yield states the number of procedures whose findings can explain the clinical picture. However, patients are also often investigated in order to exclude lesions. In our population, 28% of patients had negative small bowel exploration, ranging from 26% in the group of obscure GI bleeding to 50% in the group of suspected/ previous intestinal or endocrine neoplasm. As obscure GI bleeding is intermittent and a negative exploration cannot be considered conclusive when a source is not detected, we followed-up the 44 patients with indications other than obscure GI bleeding and negative small bowel exploration. Over a median period of 15 months, none of them underwent further procedures. Clinical pictures gradually improved in 24 patients, and capsule results were considered conclusive in ruling out small bowel vascular abnormalities and polyps, as well as CD and neoplastic lesions in the remaining 19 patients. We believe that, for these indications, such a result gives wireless endoscopy the same diagnostic weight as conventional endoscopy. On the other

6 346 The American Journal of Medicine, Vol 119, No 4, April 2006 hand, searching for a source of obscure GI bleeding is always problematic and up to 50% of cases remain unsolved, even after the advent of capsule endoscopy. 4,16-19 In our population, capsule endoscopy had similar performance in overt and occult bleeding, confirming already published data. 1,20,21 In a recent work, 17 patients with obscure GI bleeding and negative exploration were followed-up for 12 months; the authors concluded that capsule has a 100% negative predictive value for small bowel lesions. 22 This is an encouraging and amazing result, although it could be partially due to the recurrent bleeding rate of GI bleeding at 1 year, which is reported to be 9%. 23 Moreover, irondeficient anemia is either solved spontaneously in over 70% of cases or by iron supplementation. 24,25 As with most of the other works on GI bleeding, we choose not to consider conclusive a negative small bowel exploration in patients with obscure GI bleeding. Therefore, the group that had the best diagnostic yield in our work was also the one with the least number of conclusive diagnoses. A similar conclusion was made in the work by Adler et al, in which the number of definitive diagnoses by capsule endoscopy was low when strict standards of interpretation were used. 26 These results do not lessen the power of capsule endoscopy for obscure GI bleeding, as it has been shown to be definitely superior to all the other diagnostic procedures. Indeed, as recently suggested, capsule endoscopy could be effectively repeated in patients with persistent obscure GI bleeding with previous negative small bowel exploration. 27 On the other hand, our result strengthens the role of capsule endoscopy for investigating small bowel for all other indications. The usefulness of capsule endoscopy for diagnosing CD and its superiority compared with the most sophisticated radiology is described in several reports. 28,29 We had, in total, 26 newly diagnosed cases of small bowel CD, in 7 of whom indication for procedure was occult obscure GI bleeding, and in 2 a previous colonic CD was already known. All these patients benefited from therapy, including surgery in 2 cases, so we can definitely say that capsule endoscopy changed their management. It is less clear, however, what the role of capsule endoscopy is in the follow-up of CD patients, other than a better definition of the actual mucosal involvement. Morphology of lesions in CD is multiform and certainly not only mucosal, and some of them, such as stenosis and abscess, can only be seen by radiology. In particular, radiology allows selecting CD patients undergoing capsule endoscopy, 29 possibly decreasing complications due to intestinal stenosis. Treatment is led mainly by clinical status, and the endoscopic picture is more often supportive rather than determinant in the choices. 30 Therefore, capsule endoscopy should be considered one further powerful diagnostic tool in the battery of diagnostic tests for CD, though possibly not the most important. Other indications for capsule endoscopy are represented by malabsorption and neoplasms, as it can help in diagnosing, staging and guiding further testing. 31,32 It has been reported that the expertise of endoscopists who performed conventional endoscopy may affect capsule diagnostic yield for obscure GI bleeding. 33 Our study was performed in 2 gastroenterology units: 1 in a tertiary referral center, and 1 in a general district hospital. We could not find differences as far as indications for the procedure and type of findings between the 2 units (data not shown), proving similar clinical and endoscopic expertise in our area, in addition to diagnostic reliability of capsule endoscopy. In conclusion, we believe that wireless endoscopy can be considered as reliable as any other traditional diagnostic procedure. Moreover, it is better accepted by patients and can be used in the early diagnostic steps for many GI conditions. As suggested, this can provide economic and ethical benefits, 34,35 making more and more capsule endoscopy a diagnostic prototype for the future. ACKNOWLEDGMENT The authors thank the Azienda Ospedaliera of Padua, Italy for supplying the endoscopic capsules for the study. References 1. Mata A, Bordas JM, Feu F, et al. Wireless capsule endoscopy in patients with obscure gastrointestinal bleeding: a comparative study with push enteroscopy. 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Wireless capsule video endoscopy is a superior diagnostic tool in comparison to barium followthrough and computerized tomography in patients with suspected Crohn s disease. Eur J Gastroenterol Hepatol. 2003;15:

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