REVIEW URRENT C OPINION
Diagnostic modalities for the evaluation of small bowel disorders Uri Kopylov a and Ernest G. Seidman b
Purpose of review This review summarizes the recent developments in the evaluation of small bowel disorders using videocapsule endoscopy (VCE) and serological and breath-test biomarkers. Recent findings The ability to visualize the small bowel was revolutionized with the introduction of VCE technology. VCE allows for accurate, noninvasive visualization of the small bowel mucosa. This device is invaluable in the investigation of obscure gastrointestinal bleeding (OGIB), occult bleeding with iron deficiency anaemia, small bowel Crohn’s disease (CD), small bowel neoplasms and other mucosal disorders. Recent studies underscored the utility of VCE for documenting the extent and severity of small bowel CD as well as monitoring activity after therapy. The accuracy of the discrimination between small bowel tumours and benign bulges has been improved by a novel endoscopic algorithm. The accuracy of VCE was also evaluated as a potential noninvasive alternative to small bowel biopsies in suspected celiac disease. New findings have been made using breath tests and other biomarkers for the diagnosis of celiac disease, irritable bowel syndrome and bacterial overgrowth. Summary VCE as well as breath-test biomarkers play a major and expanding role in the diagnosis and monitoring of various small bowel disorders. Keywords breath test biomarkers, celiac disease, Crohn’s disease, obscure gastrointestinal bleeding, videocapsule endoscopy
INTRODUCTION Technological developments over the last 2 decades have revolutionized our ability to visualize and diagnose small bowel disorders. Recent reviews in this journal have described advances in cross-sectional imaging and small bowel endoscopy. Herein, we focus on recent publications on videocapsule endoscopy (VCE) studies of the small bowel as well as recent advances in serological biomarkers and breath testing.
VIDEOCAPSULE ENDOSCOPY OF THE SMALL BOWEL The first VCE system [1] manufactured by Given Imaging (Yokneam, Israel) was initially approved for clinical use in 2001. Several additional manufacturers have since released other VCE devices. These include the Olympus EndoCapsule (Olympus, Japan), OMOM pill (Jinshan, China), MiroCam (Seoul, Korea) and CapsoCam (Saratoga, California, USA) [2].
The clinical utility of VCE technology is increasingly recognized and its diagnostic capabilities and clinical indications are expanding [3] (Table 1).
Occult gastrointestinal bleeding VCE is the modality of choice in patients with occult gastrointestinal bleeding (OGIB) when no source of bleeding has been identified by esophagogastroduodenoscopy and ileocolonoscopy [4]. It has been
a
Division of Gastroenterology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel and bDivision of Gastroenterology, McGill University Health Center, McGill Faculty of Medicine, Montreal, Quebec, Canada Correspondence to Ernest G. Seidman, MDCM, FRCPC, FACG, Research Institute of McGill Univ Health Center, MGH Campus, 1650 Cedar Avenue, C10.145 Montreal, QC H3G 1A4, Canada. Tel: +1 514 934 1934 x44385; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:111–117 DOI:10.1097/MOG.0000000000000159
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KEY POINTS VCE is an accurate, well tolerated and noninvasive evaluation of the entire length of the small bowel and is superior to small bowel follow through CT enterography and MR enterography for the diagnosis of CD. VCE is the modality of choice for evaluation of iron deficiency anaemia and obscure or occult gastrointestinal bleeding in patients with negative bidirectional endoscopy.
The most common VCE findings in OGIB are angiodysplasia (50%), ulcers (26.8%) and neoplastic lesions (8.8%) [17]. VCE may also play a role in patients with active gastrointestinal bleeding. Although patients presenting with a high-risk clinical scenario require urgent upper endoscopy, less severe patients pose a dilemma regarding the necessity of hospitalization and the optimal timing of endoscopy [18 ]. VCE revealed blood in the upper gastrointestinal tract significantly more than nasogastric aspiration (83.3 versus 33.3%; P ¼ 0.035) [19 ]. Nongastroenterologist physicians were able to interpret VCE findings accurately in this setting [20 ]. &
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Introduction of VCE resulted in a dramatic improvement in detection of small bowel neoplasms. Hydrogen breath testing provides the simplest, noninvasive and most widely available diagnostic modality for suspected SIBO. REG Ia is a novel biomarker potentially useful for diagnosis of celiac disease.
shown to be superior to push enteroscopy for establishing the cause of OGIB [5–8]. A meta-analysis of 14 studies on patients with OGIB reported yields of 63% for VCE and 28% for push enteroscopy [9]. The diagnostic accuracy of VCE is similar to that of double balloon enteroscopy (DBE) for most indications, including the evaluation of OGIB [10]. However, both the safety profile and the tolerability of VCE are superior to that of DBE, and thus, the latter is generally reserved for interventional purposes, tissue sampling or investigation of patients with a nondiagnostic VCE examination. The use of both modalities further increases the diagnostic yield in OGIB [11 ]. VCE was demonstrated to be superior to both small-bowel follow-through and computed tomography (CT) enteroclysis [9,12–14]. A repeat VCE examination may lead to a diagnosis in up to 30–62.5% of the patients with initial nondiagnostic workup, including a negative initial VCE [15,16]. &
Table 1. Clinical indications for videocapsule endoscopy of the small bowel Major
Occult or obscure gastrointestinal bleeding Iron deficiency anaemia Crohn’s disease Suspected small bowel tumour
Minor
Inherited polyposis syndromes Celiac disease Protein-losing enteropathy Acute gastrointestinal bleeding Hypertensive gastropathy Dysmotility
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Crohn’s disease Crohn’s disease (CD) is limited to the small bowel in at least 30% of cases [21]. In addition, inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis (UC) or CD (IBD-unclassified, IBDU) occurs in up to 15% patients. After VCE, the diagnosis is changed from UC/IBDU to CD in up to 13% of cases [22,23]. Findings associated with CD on VCE include ulcerations, erythema, mucosal oedema, loss of villi, stricture, mucosal fissuring and, rarely, a fistulous opening [23]. VCE for the diagnosis of CD should be reserved for patients with high clinical index of suspicion, due to the relatively low specificity of the findings. The most common mimicker of CD in the small bowel is NSAIDS-induced enteropathy that may manifest with very similar lesions as early as 2 weeks after onset of therapy [24–26]. Several VCE scoring systems have been proposed to establish the diagnosis of CD. The earliest, suggested by Mow et al. [27], relied on presence of more than three ulcerations in the small bowel. Two additional scoring systems, the Lewis score [28] and the Capsule Endoscopy Crohn’s Disease Activity Index (CECDAI) [29], are quantitative and more complex and have largely supplanted the simple score [28] (Table 2). The superiority of VCE over small-bowel follow-through and CT enterography for the diagnosis of CD has been repeatedly demonstrated [12,13,30–32]. Although the accuracy of MRE is generally comparable to that of VCE, the latter was found to be significantly more sensitive for the detection of proximal small bowel involvement [33], an important prognostic factor for more severe CD [34]. VCE can also be used for monitoring known cases of CD. VCE was carried out prospectively in patients with CD starting therapy with an immunomodulator or a biological. The authors used the Volume 31 Number 2 March 2015
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Evaluation of small bowel disorders Kopylov and Seidman Table 2. Scoring indices for quantification of mucosal inflammation using capsule endoscopy Lewis score [28]
CECDAI [29]
Parameter
Number/quality
Longitudinal extent
Descriptors
Villous appearance
Normal/edematous
Short/long segment/ whole tertile
Single/patchy/ diffuse
Inflammation score
None to large ulcer (>2 cm)
Ulceration
Non/single/few/ multiple
Short/long segment/ whole tertile
50%
Extent of disease
No disease to diffuse
Stricture
Non/single/few/ multiple
Ulcerated/nonulcerated
Traversed/ nontraversed
Stricture score
None to complete obstruction
Small bowel segmentation
Tertiles (strictures for the entire length of the examination)
Proximal/distal small bowel
Score significance
790: moderate to severe
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CECDAI score to evaluate mucosal healing [35 ,36 ]. Complete mucosal healing was defined as an absence of ulcers. By week 12, no patient achieved complete mucosal healing, although mean CECDAI score decreased significantly [35 ]. By week 52, mucosal healing was achieved by 42% of the patients [36 ]. In patients with CD after ileocolonic resection, VCE detected CD recurrence in 15 (62%) patients, whereas ileocolonoscopy detected inflammatory lesions in the neo-terminal ileum in only six (25%) patients [37]. VCE may be useful to rule out active small bowel inflammation and guide treatment in patients with CD with suspected functional symptoms. Overall, VCE results led to a change in treatment in over 50% of patients with established CD [38 ]. &&
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Celiac disease
Small bowel tumours The rate of detection of small bowel tumours increased almost threefold since the introduction of VCE [2]. The tumours are usually detected by VCE performed for OGIB after negative bi-directional endoscopy. In other cases, VCE uncovered a tumour following a suspicious finding on cross-sectional imaging. Over half of these tumours are found to be malignant [45,46]. Small bowel polyps and tumours are at times easy to confuse with benign bulges, posing a diagnostic dilemma. To this aim, a novel video-endoscopic index for bulges called SPICE was recently reported (smooth, protruding lesion index on capsule endoscopy) [47]. VCE was also evaluated for surveillance of small bowel polyps in patients with familial polyposis syndromes such as Peutz–Jeghers syndrome (PJS) and familial adenomatous polyposis (FAP) [48–53,54 ]. In PJS, VCE identified significantly more small bowel polyps than MRE [55 ]. &
VCE is capable of capturing the subtle mucosal details characteristic of celiac disease, such as focal loss of folds, mucosal nodularity, scalloping or a mosaic pattern. Upper endoscopy with duodenal biopsies is the current gold standard approach to diagnosis. However, VCE can provide a well tolerated and accurate diagnostic alternative for selective cases. A recent meta-analysis compiling the data from six studies demonstrated an overall pooled sensitivity of 89% and specificity of 95% for VCE, compared with traditional endoscopy with biopsies [39]. Moreover, VCE can be very useful in monitoring complications of celiac disease such as ulcerative jejunoileitis and small bowel tumours [40–42]. Extensive small bowel involvement can be demonstrated by VCE in a significant proportion of celiac patients (up to 45% involvement of the jejunum, and involvement of the entire small bowel in rare cases) [43]. Recently, a first case of ulcerative jejunitis was uncovered by VCE in a child found to have celiac disease [44 ]. &
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Motility Another potential application of VCE technology is the evaluation of gastrointestinal motility [56 ]. A motility capsule that includes pH, temperature and pressure sensors instead of a camera was approved by the U.S. Food and Drug Administration (FDA) for gastric transit and the characterization of constipation [57]. &
Safety of videocapsule endoscopy The main potential complication of VCE is capsule retention, defined as failure to excrete the capsule within 2 weeks or earlier if medical, endoscopic or surgical intervention was required [58]. The risk of capsule retention is increased in patients with
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known bowel strictures, a history of small bowel obstruction, previous abdominal radiation or known CD. A history of abdominal surgery and chronic NSAID use are other risk factors for VCE retention [2,23]. In patients with one of the aforementioned risk factors, cross-sectional imaging might be considered before VCE. The indications for gastrointestinal tract patency evaluation before performance of VCE are as follows: (1) (2) (3) (4) (5) (6) (7)
History of small bowel obstruction; Recent abdominal surgery; History of abdominal radiation; Suspected small bowel tumour; Suspected small bowel strictures; Established small bowel CD; Suspected NSAID-induced enteropathy.
However, the absence of strictures on cross-sectional imaging does not preclude capsule retention [59]. Another modality that may reduce the risk of retention is the patency capsule (Agile capsule; Given Imaging, Yokneam, Israel). The patency capsule has the same shape and dimensions as the regular capsule. It is composed of a dissolvable body and an identification tag detectable by radiography or using a real-time viewer. If the patency capsule is not detectable in the small bowel within 30 h, a diagnostic VCE can be safely performed [60 ]. However, the utilization of a patency capsule does not completely preclude the risk of VCE retention, with a very rare risk of symptomatic patency capsule retention [61 ]. Slow transit of the capsule with the capsule being inadvertently excreted after several days is significantly more common than symptomatic retention and may occur in up to 20% of the cases [2]. No consensus on the timing of intervention exists, and it is unclear how long one should wait before intervention in asymptomatic patients. A case of capsule extraction after 2.5 years has been described [62]. Swallowing problems, oesophageal diseases such as webs and rings, and postsurgical alterations of the gastroduodenal anatomy (e.g. following Bilroth-II procedure, bariatric surgery and so on) may lead to capsule aspiration or upper gastrointestinal retention [63]. In these cases, capsule insertion can be facilitated endoscopically, using a specialized device such as AdvanCE (Given Imaging) [64]. There is a theoretical concern of possible interference by VCE with the function of cardiac pacemakers and implanted defibrillators. However, no clinically relevant interference with pacing activity has been reported to date; in rare cases, interference with telemetry tracing or interference with image quality of the VCE recording was demonstrated [65–67,68 ]. &&
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BREATH TESTS AS BIOMARKERS OF SMALL BOWEL DISORDERS Breath tests are noninvasive and can measure H2 and CH4 gases produced by bacterial fermentation of unabsorbed intestinal carbohydrate. These tests are used in the diagnosis of carbohydrate malabsorption, small intestinal bacterial overgrowth (SIBO) and for measuring the orocecal transit time. A recent review [69 ] suggests that patients with persistent irritable bowel syndrome (IBS)-like symptoms of abdominal bloating and distension despite dietary interventions should be referred for H2 breath testing. If SIBO is identified, patients are typically treated with antibiotics. The authors suggest that a glucose breath test is better for detecting SIBO than the lactulose breath test, which more often gives false positive results [69 ]. The current gold standard, small-bowel aspiration and quantitative culture, is limited by its high cost, invasive nature, lack of standardization, sampling error and need for dedicated infrastructure. Although not without shortcomings, hydrogen testing provides the simplest, noninvasive and widely available diagnostic modality for suspected SIBO. It has been suggested that measurement of methane in addition to hydrogen can increase the sensitivity of breath testing for SIBO [70 ]. In gastrointestinal motor disorders, delayed gastric emptying may cause false negative tests, and rapid transit through small bowel may result in false positive tests. Another limitation is that false positive results may also occur if the individual does not adhere to a low-fibre diet the day before the test. Moreover, accurate results are not obtained if the patient has recently taken antibiotics that change intestinal flora. Antibiotics are thus avoided within 4 weeks prior to testing. Another recent study [71 ] examined the methodological and clinical validity of the combined lactulose hydrogen breath test with scintigraphic oro-cecal transit test for diagnosing SIBO in IBS patients. At least 5 ppm H2 increase prior to the appearance of cecal contrast was detected in more IBS patients than healthy volunteers (35/89 vs. 1/13; P ¼ 0.026). IBS patients with SIBO, compared with those without SIBO, reported significantly greater improvement in abdominal symptoms following rifaximin therapy (P < 0.002 overall IBS symptom severity). This improvement was most marked in diarrhoea-predominant IBS patients, in whom both stool frequency and consistency improved (all P < 0.004). Identification of a biomarker that is accessible, easy to measure and that accurately identifies intestinal mucosal damage would allow for improved diagnosis of mucosal toxicities. The effectiveness of urine and breath tests as potential clinically &
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Evaluation of small bowel disorders Kopylov and Seidman &
effective biomarkers was recently reviewed [72 ], with a significant focus on the emerging role of the carbon-13 sucrose breath test (13C SBT). The 13 C SBT provides a simple, noninvasive and integrated measure of gut function. It has the potential to monitor gut function in the setting of cytotoxic therapy induced mucositis, or in the assessment of the efficacy of agents to treat mucositis.
BIOMARKERS FOR IRRITABLE BOWEL SYNDROME AND CELIAC DISEASE A recent study set out to assess the performance of a set of 34 potential biological markers of IBS in terms of differentiating IBS from healthy volunteers [73 ]. The identification of an array of biological markers that would achieve these differentiations with high sensitivity and specificity would transform IBS from a symptom-based diagnosis of exclusion in clinical practice into a regular medical disease and provide avenues of investigation into possible new pathophysiological mechanisms. Of individuals eligible for analysis (N ¼ 244), 168 met criteria for IBS, while 76 were free of any functional gastrointestinal disorder. A total of 34 genetic and serological markers were selected on the basis of pathways implicated in pathophysiology of IBS or whole human genome screening. The performance of the combination of biomarkers was promising in differentiating IBS from health (Area under the curve (AUC) ¼ 0.81) [73 ]. A systematic literature review examined the prevalence of celiac disease in individuals with type 1 diabetes [74 ]. A pooled analysis of 27 studies including 26 605 patients with type 1 diabetes found a prevalence of biopsy-confirmed celiac disease of 6.0% [95% confidence interval (95% CI) 5.0–6.9]. The prevalence was lower in adults (2.7%) than in children (6.2%) with type 1 diabetes (P < 0.001) [74 ]. Dividing the studies according to the antibodies first used for screening, the following pooled CD prevalences were found: anti-endomysial antibodies (EMA): 6.1%; tissue transglutamimase (TTG): 3.2%; EMA and TTG: 6.2%. The data suggest that screening with TTG only is a less robust method in type I diabetes mellitus. A provocative study [75 ] was recently reported that investigated whether serology screen-detected and apparently asymptomatic adults with EMA benefit from a gluten-free diet (GFD). A prospective trial was undertaken in 3031 individuals at risk for celiac disease based on screens for EmA. Of 148 seropositive individuals, 40 fulfilled inclusion criteria and were assigned randomly to groups placed on a GFD or gluten-containing diets. After 1 year on the GFD, the mean mucosal villous height:crypt depth values &&
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increased (P < 0.001), levels of celiac-associated antibodies decreased (P < 0.003) and gastrointestinal symptoms improved to a greater extent than in patients on gluten-containing diets (P ¼ 0.003). The authors concluded that GFD benefits asymptomatic EMA-positive patients, supporting the active serological screening of patients at risk for celiac disease [75 ]. Despite the outstanding utility of specific IgA anti-TTG, antiendomysium and antideaminated forms of gliadin peptide antibodies as diagnostic aids in celiac patients, novel biomarkers may help in the follow-up of the disease. Recently, the molecule REG Ia, involved in tissue regeneration, has been proposed as a new biomarker of CD [76 ]. REG Ia expression is increased in the target tissue and in the sera of celiac patients during damage and inflammation, decreasing after GFD. &&
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CONCLUSION VCE is invaluable for evaluation of small bowel disorders. Ongoing technological and scientific developments are constantly expanding the clinical applications of this modality for both diagnostic and monitoring purposes. Breath tests as well as novel serum biomarkers further expand the diagnostic armamentarium for the workup of celiac disease, IBS and SIBO. Acknowledgements None. Financial support and sponsorship Dr Ernest Seidman holds a Canada Research Chair in immune-mediated gastrointestinal disorders. Dr Uri Kopylov was the postdoctoral fellow of the Advanced IBD Fellowship at McGill University sponsored by Janssen Inc. Conflicts of interest Dr Ernest Seidman is a consultant for Given Imaging (now part of Covidien Inc.), and Dr Uri Kopylon has no conflicts of interest to disclose.
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Evaluation of postsurgical recurrence in Crohn’s disease: a new indication for capsule endoscopy? Gastrointest Endosc 2007; 66:533–540. 38. Kopylov UNA, Koulaouzidis A, Mackins R, et al. Small bowel capsule endo&& scopy in the management of established Crohn’s disease: clinical impact, safety and correlation with inflammatory biomarkers. Inflamm Bowel Dis 2015; 21:93–100. The largest study to date to evaluate the clinical yield of VCE in patients with established CD. In addition, the study describes the correlation of VCE findings with inflammatory biomarkers in this patient cohort. 39. 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. 40. 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. 41. Apostolopoulos P, Alexandrakis G, Giannakoulopoulou E, et al. 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Evaluation of small bowel disorders Kopylov and Seidman 54. Yamada A, Watabe H, Iwama T, et al. The prevalence of small intestinal polyps in patients with familial adenomatous polyposis: a prospective capsule endoscopy study. Fam Cancer 2014; 13:23–28. A study describing the detection of small bowel polyps by VCE in FAP patients. 55. Urquhart P, Grimpen F, Lim GJ, et al. Capsule endoscopy versus magnetic & resonance enterography for the detection of small bowel polyps in PJS. Fam Cancer 2014; 13:249–255. A comparison of VCE and MRE for detection of small bowel polyps in PJS. 56. Lee YY, Erdogan A, Rao SS. How to assess regional and whole gut transit & time with wireless motility capsule. J Neurogastroenterol Motil 2014; 20:265–270. A review of the clinical applications of the motility capsule for evaluation of dysmotility. 57. Saad RJ, Hasler WL. A technical review and clinical assessment of the wireless motility capsule. Gastroenterol Hepatol 2011; 7:795–804. 58. Cave D, Legnani P, de Franchis R, Lewis BS. ICCE consensus for capsule retention. Endoscopy 2005; 37:1065–1067. 59. Sidhu R, Sanders DS, McAlindon ME, Kapur K. Capsule endoscopy for the evaluation of nonsteroidal anti-inflammatory drug-induced enteropathy: United Kingdom pilot data. Gastrointest Endosc 2006; 64:1035. 60. Kopylov U, Seidman E. Role of capsule endoscopy in inflammatory bowel && disease. World J Gastroenterol 2014; 20:1155–1164. A comprehensive overview of the utilization of VCE for the diagnosis and management of IBD. 61. Hall B, Holleran G, McNamara D. Current applications and potential future && role of wireless capsule technology in Crohn’s disease. Scand J Gastroenterol 2014; 49:1275–1284. A recent comprehensive review on the role of VCE in diagnosis and monitoring of Crohn’s disease. 62. Boivin ML, Lochs H, Voderholzer WA. Does passage of a patency capsule indicate small-bowel patency? A prospective clinical trial? Endoscopy 2005; 37:808–815. 63. Stanich PP, Kleinman B, Porter KM, Meyer MM. Video capsule endoscopy after bariatric and gastric surgery: oral ingestion is associated with satisfactory completion rate. J Clin Gastroenterol 2015; 49:31–33. 64. Holden JP, Dureja P, Pfau PR, et al. Endoscopic placement of the small-bowel video capsule by using a capsule endoscope delivery device. Gastrointest Endosc 2007; 65:842–847. 65. Bandorski D, Irnich W, Bruck M, et al. Capsule endoscopy and cardiac pacemakers: investigation for possible interference. Endoscopy 2008; 40:36–39. 66. Bandorski D, Lotterer E, Hartmann D, et al. Capsule endoscopy in patients with cardiac pacemakers and implantable cardioverter-defibrillators: a retrospective multicenter investigation. J Gastrointestin Liver Dis 2011; 20:33–37. &
67. Payeras G, Piqueras J, Moreno VJ, et al. Effects of capsule endoscopy on cardiac pacemakers. Endoscopy 2005; 37:1181–1185. 68. Stanich PP, Kleinman B, Betkerur K, et al. Video capsule endoscopy is & successful and effective in outpatients with implantable cardiac devices. Dig Endosc 2014; 26:726–730. A case series describing the safety of VCE in patients with pacemakers and implanted defibrillators. 69. Rana SV, Malik A. Breath tests and irritable bowel syndrome. World J & Gastroenterol 2014; 20:7587–7601. A review on the clinical utility of breath tests in the diagnosis of the IBS. 70. Saad RJ, Chey WD. Breath testing for small intestinal bacterial overgrowth: & maximizing test accuracy. Clin Gastroenterol Hepatol 2014; 12:1964–1972. A review on the use of breath tests in the diagnosis of SIBO. 71. Zhao J, Zheng X, Chu H, et al. A study of the methodological and clinical & validity of the combined lactulose hydrogen breath test with scintigraphic orocecal transit test for diagnosing small intestinal bacterial overgrowth in IBS patients. Neurogastroenterol Motil 2014; 26:794–802. A prospective study that investigated the diagnostic strategy that combined hydrogen breath testing with scintgraphic evaluation for the detection of SIBO. 72. Wardill HR, Bowen JM, Gibson RJ. Biomarkers of small intestinal mucosal & damage induced by chemotherapy: an emerging role for the 13C sucrose breath test. J Support Oncol 2013; 11:61–67. The role of 13C sucrose breath test for detection of chemotherapy-induced mucosal damage. 73. Jones MP, Chey WD, Singh S, et al. A biomarker panel and psychological && morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads. Aliment Pharmacol Ther 2014; 39:426–437. A study utilizing a novel concept of combining genetic and serological biomarkers with psychological profiling for the diagnosis of IBS. 74. Elfstrom P, Sundstrom J, Ludvigsson JF. Systematic review with meta-ana& lysis: associations between coeliac disease and type 1 diabetes. Aliment Pharmacol Ther 2014; 40:1123–1132. A systematic review and meta-analysis of the association between celiac disease and type 1 diabetes. 75. Kurppa K, Paavola A, Collin P, et al. Benefits of a gluten-free diet for && asymptomatic patients with serologic markers of celiac disease. Gastroenterology 2014; 147:610–617. A prospective study investigating the clinical and histological benefit of a glutenfree diet in asymptomatic patients positive for celiac biomarkers. 76. Vives-Pi M, Takasawa S, Pujol-Autonell I, et al. Biomarkers for diagnosis and && monitoring of celiac disease. J Clin Gastroenterol 2013; 47:308–313. A comprehensive overview of the established and novel biomarkers for celiac disease.
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Diagnostic modalities for the evaluation of small bowel disorders Uri Kopylov a and Ernest G. Seidman b
Purpose of review This review summarizes the recent developments in the evaluation of small bowel disorders using videocapsule endoscopy (VCE) and serological and breath-test biomarkers. Recent findings The ability to visualize the small bowel was revolutionized with the introduction of VCE technology. VCE allows for accurate, noninvasive visualization of the small bowel mucosa. This device is invaluable in the investigation of obscure gastrointestinal bleeding (OGIB), occult bleeding with iron deficiency anaemia, small bowel Crohn’s disease (CD), small bowel neoplasms and other mucosal disorders. Recent studies underscored the utility of VCE for documenting the extent and severity of small bowel CD as well as monitoring activity after therapy. The accuracy of the discrimination between small bowel tumours and benign bulges has been improved by a novel endoscopic algorithm. The accuracy of VCE was also evaluated as a potential noninvasive alternative to small bowel biopsies in suspected celiac disease. New findings have been made using breath tests and other biomarkers for the diagnosis of celiac disease, irritable bowel syndrome and bacterial overgrowth. Summary VCE as well as breath-test biomarkers play a major and expanding role in the diagnosis and monitoring of various small bowel disorders. Keywords breath test biomarkers, celiac disease, Crohn’s disease, obscure gastrointestinal bleeding, videocapsule endoscopy
INTRODUCTION Technological developments over the last 2 decades have revolutionized our ability to visualize and diagnose small bowel disorders. Recent reviews in this journal have described advances in cross-sectional imaging and small bowel endoscopy. Herein, we focus on recent publications on videocapsule endoscopy (VCE) studies of the small bowel as well as recent advances in serological biomarkers and breath testing.
VIDEOCAPSULE ENDOSCOPY OF THE SMALL BOWEL The first VCE system [1] manufactured by Given Imaging (Yokneam, Israel) was initially approved for clinical use in 2001. Several additional manufacturers have since released other VCE devices. These include the Olympus EndoCapsule (Olympus, Japan), OMOM pill (Jinshan, China), MiroCam (Seoul, Korea) and CapsoCam (Saratoga, California, USA) [2].
The clinical utility of VCE technology is increasingly recognized and its diagnostic capabilities and clinical indications are expanding [3] (Table 1).
Occult gastrointestinal bleeding VCE is the modality of choice in patients with occult gastrointestinal bleeding (OGIB) when no source of bleeding has been identified by esophagogastroduodenoscopy and ileocolonoscopy [4]. It has been
a
Division of Gastroenterology, Sheba Medical Center, Sackler School of Medicine, Tel Aviv, Israel and bDivision of Gastroenterology, McGill University Health Center, McGill Faculty of Medicine, Montreal, Quebec, Canada Correspondence to Ernest G. Seidman, MDCM, FRCPC, FACG, Research Institute of McGill Univ Health Center, MGH Campus, 1650 Cedar Avenue, C10.145 Montreal, QC H3G 1A4, Canada. Tel: +1 514 934 1934 x44385; e-mail: [email protected] Curr Opin Gastroenterol 2015, 31:111–117 DOI:10.1097/MOG.0000000000000159
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KEY POINTS VCE is an accurate, well tolerated and noninvasive evaluation of the entire length of the small bowel and is superior to small bowel follow through CT enterography and MR enterography for the diagnosis of CD. VCE is the modality of choice for evaluation of iron deficiency anaemia and obscure or occult gastrointestinal bleeding in patients with negative bidirectional endoscopy.
The most common VCE findings in OGIB are angiodysplasia (50%), ulcers (26.8%) and neoplastic lesions (8.8%) [17]. VCE may also play a role in patients with active gastrointestinal bleeding. Although patients presenting with a high-risk clinical scenario require urgent upper endoscopy, less severe patients pose a dilemma regarding the necessity of hospitalization and the optimal timing of endoscopy [18 ]. VCE revealed blood in the upper gastrointestinal tract significantly more than nasogastric aspiration (83.3 versus 33.3%; P ¼ 0.035) [19 ]. Nongastroenterologist physicians were able to interpret VCE findings accurately in this setting [20 ]. &
&&
Introduction of VCE resulted in a dramatic improvement in detection of small bowel neoplasms. Hydrogen breath testing provides the simplest, noninvasive and most widely available diagnostic modality for suspected SIBO. REG Ia is a novel biomarker potentially useful for diagnosis of celiac disease.
shown to be superior to push enteroscopy for establishing the cause of OGIB [5–8]. A meta-analysis of 14 studies on patients with OGIB reported yields of 63% for VCE and 28% for push enteroscopy [9]. The diagnostic accuracy of VCE is similar to that of double balloon enteroscopy (DBE) for most indications, including the evaluation of OGIB [10]. However, both the safety profile and the tolerability of VCE are superior to that of DBE, and thus, the latter is generally reserved for interventional purposes, tissue sampling or investigation of patients with a nondiagnostic VCE examination. The use of both modalities further increases the diagnostic yield in OGIB [11 ]. VCE was demonstrated to be superior to both small-bowel follow-through and computed tomography (CT) enteroclysis [9,12–14]. A repeat VCE examination may lead to a diagnosis in up to 30–62.5% of the patients with initial nondiagnostic workup, including a negative initial VCE [15,16]. &
Table 1. Clinical indications for videocapsule endoscopy of the small bowel Major
Occult or obscure gastrointestinal bleeding Iron deficiency anaemia Crohn’s disease Suspected small bowel tumour
Minor
Inherited polyposis syndromes Celiac disease Protein-losing enteropathy Acute gastrointestinal bleeding Hypertensive gastropathy Dysmotility
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Crohn’s disease Crohn’s disease (CD) is limited to the small bowel in at least 30% of cases [21]. In addition, inflammatory bowel disease (IBD) restricted to the colon that cannot be characterized as either ulcerative colitis (UC) or CD (IBD-unclassified, IBDU) occurs in up to 15% patients. After VCE, the diagnosis is changed from UC/IBDU to CD in up to 13% of cases [22,23]. Findings associated with CD on VCE include ulcerations, erythema, mucosal oedema, loss of villi, stricture, mucosal fissuring and, rarely, a fistulous opening [23]. VCE for the diagnosis of CD should be reserved for patients with high clinical index of suspicion, due to the relatively low specificity of the findings. The most common mimicker of CD in the small bowel is NSAIDS-induced enteropathy that may manifest with very similar lesions as early as 2 weeks after onset of therapy [24–26]. Several VCE scoring systems have been proposed to establish the diagnosis of CD. The earliest, suggested by Mow et al. [27], relied on presence of more than three ulcerations in the small bowel. Two additional scoring systems, the Lewis score [28] and the Capsule Endoscopy Crohn’s Disease Activity Index (CECDAI) [29], are quantitative and more complex and have largely supplanted the simple score [28] (Table 2). The superiority of VCE over small-bowel follow-through and CT enterography for the diagnosis of CD has been repeatedly demonstrated [12,13,30–32]. Although the accuracy of MRE is generally comparable to that of VCE, the latter was found to be significantly more sensitive for the detection of proximal small bowel involvement [33], an important prognostic factor for more severe CD [34]. VCE can also be used for monitoring known cases of CD. VCE was carried out prospectively in patients with CD starting therapy with an immunomodulator or a biological. The authors used the Volume 31 Number 2 March 2015
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Evaluation of small bowel disorders Kopylov and Seidman Table 2. Scoring indices for quantification of mucosal inflammation using capsule endoscopy Lewis score [28]
CECDAI [29]
Parameter
Number/quality
Longitudinal extent
Descriptors
Villous appearance
Normal/edematous
Short/long segment/ whole tertile
Single/patchy/ diffuse
Inflammation score
None to large ulcer (>2 cm)
Ulceration
Non/single/few/ multiple
Short/long segment/ whole tertile
50%
Extent of disease
No disease to diffuse
Stricture
Non/single/few/ multiple
Ulcerated/nonulcerated
Traversed/ nontraversed
Stricture score
None to complete obstruction
Small bowel segmentation
Tertiles (strictures for the entire length of the examination)
Proximal/distal small bowel
Score significance
790: moderate to severe
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&
CECDAI score to evaluate mucosal healing [35 ,36 ]. Complete mucosal healing was defined as an absence of ulcers. By week 12, no patient achieved complete mucosal healing, although mean CECDAI score decreased significantly [35 ]. By week 52, mucosal healing was achieved by 42% of the patients [36 ]. In patients with CD after ileocolonic resection, VCE detected CD recurrence in 15 (62%) patients, whereas ileocolonoscopy detected inflammatory lesions in the neo-terminal ileum in only six (25%) patients [37]. VCE may be useful to rule out active small bowel inflammation and guide treatment in patients with CD with suspected functional symptoms. Overall, VCE results led to a change in treatment in over 50% of patients with established CD [38 ]. &&
&
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Celiac disease
Small bowel tumours The rate of detection of small bowel tumours increased almost threefold since the introduction of VCE [2]. The tumours are usually detected by VCE performed for OGIB after negative bi-directional endoscopy. In other cases, VCE uncovered a tumour following a suspicious finding on cross-sectional imaging. Over half of these tumours are found to be malignant [45,46]. Small bowel polyps and tumours are at times easy to confuse with benign bulges, posing a diagnostic dilemma. To this aim, a novel video-endoscopic index for bulges called SPICE was recently reported (smooth, protruding lesion index on capsule endoscopy) [47]. VCE was also evaluated for surveillance of small bowel polyps in patients with familial polyposis syndromes such as Peutz–Jeghers syndrome (PJS) and familial adenomatous polyposis (FAP) [48–53,54 ]. In PJS, VCE identified significantly more small bowel polyps than MRE [55 ]. &
VCE is capable of capturing the subtle mucosal details characteristic of celiac disease, such as focal loss of folds, mucosal nodularity, scalloping or a mosaic pattern. Upper endoscopy with duodenal biopsies is the current gold standard approach to diagnosis. However, VCE can provide a well tolerated and accurate diagnostic alternative for selective cases. A recent meta-analysis compiling the data from six studies demonstrated an overall pooled sensitivity of 89% and specificity of 95% for VCE, compared with traditional endoscopy with biopsies [39]. Moreover, VCE can be very useful in monitoring complications of celiac disease such as ulcerative jejunoileitis and small bowel tumours [40–42]. Extensive small bowel involvement can be demonstrated by VCE in a significant proportion of celiac patients (up to 45% involvement of the jejunum, and involvement of the entire small bowel in rare cases) [43]. Recently, a first case of ulcerative jejunitis was uncovered by VCE in a child found to have celiac disease [44 ]. &
&
Motility Another potential application of VCE technology is the evaluation of gastrointestinal motility [56 ]. A motility capsule that includes pH, temperature and pressure sensors instead of a camera was approved by the U.S. Food and Drug Administration (FDA) for gastric transit and the characterization of constipation [57]. &
Safety of videocapsule endoscopy The main potential complication of VCE is capsule retention, defined as failure to excrete the capsule within 2 weeks or earlier if medical, endoscopic or surgical intervention was required [58]. The risk of capsule retention is increased in patients with
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known bowel strictures, a history of small bowel obstruction, previous abdominal radiation or known CD. A history of abdominal surgery and chronic NSAID use are other risk factors for VCE retention [2,23]. In patients with one of the aforementioned risk factors, cross-sectional imaging might be considered before VCE. The indications for gastrointestinal tract patency evaluation before performance of VCE are as follows: (1) (2) (3) (4) (5) (6) (7)
History of small bowel obstruction; Recent abdominal surgery; History of abdominal radiation; Suspected small bowel tumour; Suspected small bowel strictures; Established small bowel CD; Suspected NSAID-induced enteropathy.
However, the absence of strictures on cross-sectional imaging does not preclude capsule retention [59]. Another modality that may reduce the risk of retention is the patency capsule (Agile capsule; Given Imaging, Yokneam, Israel). The patency capsule has the same shape and dimensions as the regular capsule. It is composed of a dissolvable body and an identification tag detectable by radiography or using a real-time viewer. If the patency capsule is not detectable in the small bowel within 30 h, a diagnostic VCE can be safely performed [60 ]. However, the utilization of a patency capsule does not completely preclude the risk of VCE retention, with a very rare risk of symptomatic patency capsule retention [61 ]. Slow transit of the capsule with the capsule being inadvertently excreted after several days is significantly more common than symptomatic retention and may occur in up to 20% of the cases [2]. No consensus on the timing of intervention exists, and it is unclear how long one should wait before intervention in asymptomatic patients. A case of capsule extraction after 2.5 years has been described [62]. Swallowing problems, oesophageal diseases such as webs and rings, and postsurgical alterations of the gastroduodenal anatomy (e.g. following Bilroth-II procedure, bariatric surgery and so on) may lead to capsule aspiration or upper gastrointestinal retention [63]. In these cases, capsule insertion can be facilitated endoscopically, using a specialized device such as AdvanCE (Given Imaging) [64]. There is a theoretical concern of possible interference by VCE with the function of cardiac pacemakers and implanted defibrillators. However, no clinically relevant interference with pacing activity has been reported to date; in rare cases, interference with telemetry tracing or interference with image quality of the VCE recording was demonstrated [65–67,68 ]. &&
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BREATH TESTS AS BIOMARKERS OF SMALL BOWEL DISORDERS Breath tests are noninvasive and can measure H2 and CH4 gases produced by bacterial fermentation of unabsorbed intestinal carbohydrate. These tests are used in the diagnosis of carbohydrate malabsorption, small intestinal bacterial overgrowth (SIBO) and for measuring the orocecal transit time. A recent review [69 ] suggests that patients with persistent irritable bowel syndrome (IBS)-like symptoms of abdominal bloating and distension despite dietary interventions should be referred for H2 breath testing. If SIBO is identified, patients are typically treated with antibiotics. The authors suggest that a glucose breath test is better for detecting SIBO than the lactulose breath test, which more often gives false positive results [69 ]. The current gold standard, small-bowel aspiration and quantitative culture, is limited by its high cost, invasive nature, lack of standardization, sampling error and need for dedicated infrastructure. Although not without shortcomings, hydrogen testing provides the simplest, noninvasive and widely available diagnostic modality for suspected SIBO. It has been suggested that measurement of methane in addition to hydrogen can increase the sensitivity of breath testing for SIBO [70 ]. In gastrointestinal motor disorders, delayed gastric emptying may cause false negative tests, and rapid transit through small bowel may result in false positive tests. Another limitation is that false positive results may also occur if the individual does not adhere to a low-fibre diet the day before the test. Moreover, accurate results are not obtained if the patient has recently taken antibiotics that change intestinal flora. Antibiotics are thus avoided within 4 weeks prior to testing. Another recent study [71 ] examined the methodological and clinical validity of the combined lactulose hydrogen breath test with scintigraphic oro-cecal transit test for diagnosing SIBO in IBS patients. At least 5 ppm H2 increase prior to the appearance of cecal contrast was detected in more IBS patients than healthy volunteers (35/89 vs. 1/13; P ¼ 0.026). IBS patients with SIBO, compared with those without SIBO, reported significantly greater improvement in abdominal symptoms following rifaximin therapy (P < 0.002 overall IBS symptom severity). This improvement was most marked in diarrhoea-predominant IBS patients, in whom both stool frequency and consistency improved (all P < 0.004). Identification of a biomarker that is accessible, easy to measure and that accurately identifies intestinal mucosal damage would allow for improved diagnosis of mucosal toxicities. The effectiveness of urine and breath tests as potential clinically &
&
&
&
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Evaluation of small bowel disorders Kopylov and Seidman &
effective biomarkers was recently reviewed [72 ], with a significant focus on the emerging role of the carbon-13 sucrose breath test (13C SBT). The 13 C SBT provides a simple, noninvasive and integrated measure of gut function. It has the potential to monitor gut function in the setting of cytotoxic therapy induced mucositis, or in the assessment of the efficacy of agents to treat mucositis.
BIOMARKERS FOR IRRITABLE BOWEL SYNDROME AND CELIAC DISEASE A recent study set out to assess the performance of a set of 34 potential biological markers of IBS in terms of differentiating IBS from healthy volunteers [73 ]. The identification of an array of biological markers that would achieve these differentiations with high sensitivity and specificity would transform IBS from a symptom-based diagnosis of exclusion in clinical practice into a regular medical disease and provide avenues of investigation into possible new pathophysiological mechanisms. Of individuals eligible for analysis (N ¼ 244), 168 met criteria for IBS, while 76 were free of any functional gastrointestinal disorder. A total of 34 genetic and serological markers were selected on the basis of pathways implicated in pathophysiology of IBS or whole human genome screening. The performance of the combination of biomarkers was promising in differentiating IBS from health (Area under the curve (AUC) ¼ 0.81) [73 ]. A systematic literature review examined the prevalence of celiac disease in individuals with type 1 diabetes [74 ]. A pooled analysis of 27 studies including 26 605 patients with type 1 diabetes found a prevalence of biopsy-confirmed celiac disease of 6.0% [95% confidence interval (95% CI) 5.0–6.9]. The prevalence was lower in adults (2.7%) than in children (6.2%) with type 1 diabetes (P < 0.001) [74 ]. Dividing the studies according to the antibodies first used for screening, the following pooled CD prevalences were found: anti-endomysial antibodies (EMA): 6.1%; tissue transglutamimase (TTG): 3.2%; EMA and TTG: 6.2%. The data suggest that screening with TTG only is a less robust method in type I diabetes mellitus. A provocative study [75 ] was recently reported that investigated whether serology screen-detected and apparently asymptomatic adults with EMA benefit from a gluten-free diet (GFD). A prospective trial was undertaken in 3031 individuals at risk for celiac disease based on screens for EmA. Of 148 seropositive individuals, 40 fulfilled inclusion criteria and were assigned randomly to groups placed on a GFD or gluten-containing diets. After 1 year on the GFD, the mean mucosal villous height:crypt depth values &&
&&
&
&
increased (P < 0.001), levels of celiac-associated antibodies decreased (P < 0.003) and gastrointestinal symptoms improved to a greater extent than in patients on gluten-containing diets (P ¼ 0.003). The authors concluded that GFD benefits asymptomatic EMA-positive patients, supporting the active serological screening of patients at risk for celiac disease [75 ]. Despite the outstanding utility of specific IgA anti-TTG, antiendomysium and antideaminated forms of gliadin peptide antibodies as diagnostic aids in celiac patients, novel biomarkers may help in the follow-up of the disease. Recently, the molecule REG Ia, involved in tissue regeneration, has been proposed as a new biomarker of CD [76 ]. REG Ia expression is increased in the target tissue and in the sera of celiac patients during damage and inflammation, decreasing after GFD. &&
&&
CONCLUSION VCE is invaluable for evaluation of small bowel disorders. Ongoing technological and scientific developments are constantly expanding the clinical applications of this modality for both diagnostic and monitoring purposes. Breath tests as well as novel serum biomarkers further expand the diagnostic armamentarium for the workup of celiac disease, IBS and SIBO. Acknowledgements None. Financial support and sponsorship Dr Ernest Seidman holds a Canada Research Chair in immune-mediated gastrointestinal disorders. Dr Uri Kopylov was the postdoctoral fellow of the Advanced IBD Fellowship at McGill University sponsored by Janssen Inc. Conflicts of interest Dr Ernest Seidman is a consultant for Given Imaging (now part of Covidien Inc.), and Dr Uri Kopylon has no conflicts of interest to disclose.
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29. Gal E, Geller A, Fraser G, et al. Assessment and validation of the new capsule endoscopy Crohn’s disease activity index (CECDAI). Dig Dis Sci 2008; 53:1933–1937. 30. de Melo SW Jr, Di Palma JA. The role of capsule endoscopy in evaluating inflammatory bowel disease. Gastroenterol Clin N Am 2012; 41:315–323. 31. 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 nonstricturing small bowel Crohn’s disease. Am J Gastroenterol 2006; 101:954–964. 32. 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 meta-analysis. Am J Gastroenterol 2010; 105:1240–1248. 33. Jensen MD, Nathan T, Rafaelsen SR, Kjeldsen J. 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. 34. Lazarev M, Huang C, Bitton A, et al. Relationship between proximal Crohn’s disease location and disease behavior and surgery: a cross-sectional study of the IBD Genetics Consortium. Am J Gastroenterol 2013; 108:106–112. 35. Hall BJ, Holleran GE, Smith SM, et al. A prospective 12-week mucosal healing && assessment of small bowel Crohn’s disease as detected by capsule endoscopy. Eur J Gastroenterol Hepatol 2014; 26:1253–1259. A prospective evaluation of small bowel mucosal healing by VCE in IBD patients commencing immunomodulatory or biological therapy. 36. Hall B, Holleran G, Chin JL, et al. A prospective 52week mucosal healing & assessment of small bowel Crohn’s disease as detected by capsule endoscopy. J Crohns Colitis 2014; 8:1601–1609. A prospective study of the role of VCE in monitoring mucosal healing after therapy. 37. Beltran VP, Nos P, Bastida G, et al. Evaluation of postsurgical recurrence in Crohn’s disease: a new indication for capsule endoscopy? Gastrointest Endosc 2007; 66:533–540. 38. Kopylov UNA, Koulaouzidis A, Mackins R, et al. Small bowel capsule endo&& scopy in the management of established Crohn’s disease: clinical impact, safety and correlation with inflammatory biomarkers. Inflamm Bowel Dis 2015; 21:93–100. The largest study to date to evaluate the clinical yield of VCE in patients with established CD. In addition, the study describes the correlation of VCE findings with inflammatory biomarkers in this patient cohort. 39. 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. 40. 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. 41. Apostolopoulos P, Alexandrakis G, Giannakoulopoulou E, et al. 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Evaluation of small bowel disorders Kopylov and Seidman 54. Yamada A, Watabe H, Iwama T, et al. The prevalence of small intestinal polyps in patients with familial adenomatous polyposis: a prospective capsule endoscopy study. Fam Cancer 2014; 13:23–28. A study describing the detection of small bowel polyps by VCE in FAP patients. 55. Urquhart P, Grimpen F, Lim GJ, et al. Capsule endoscopy versus magnetic & resonance enterography for the detection of small bowel polyps in PJS. Fam Cancer 2014; 13:249–255. A comparison of VCE and MRE for detection of small bowel polyps in PJS. 56. Lee YY, Erdogan A, Rao SS. How to assess regional and whole gut transit & time with wireless motility capsule. J Neurogastroenterol Motil 2014; 20:265–270. A review of the clinical applications of the motility capsule for evaluation of dysmotility. 57. Saad RJ, Hasler WL. A technical review and clinical assessment of the wireless motility capsule. Gastroenterol Hepatol 2011; 7:795–804. 58. Cave D, Legnani P, de Franchis R, Lewis BS. ICCE consensus for capsule retention. Endoscopy 2005; 37:1065–1067. 59. Sidhu R, Sanders DS, McAlindon ME, Kapur K. Capsule endoscopy for the evaluation of nonsteroidal anti-inflammatory drug-induced enteropathy: United Kingdom pilot data. Gastrointest Endosc 2006; 64:1035. 60. Kopylov U, Seidman E. Role of capsule endoscopy in inflammatory bowel && disease. World J Gastroenterol 2014; 20:1155–1164. A comprehensive overview of the utilization of VCE for the diagnosis and management of IBD. 61. Hall B, Holleran G, McNamara D. Current applications and potential future && role of wireless capsule technology in Crohn’s disease. Scand J Gastroenterol 2014; 49:1275–1284. A recent comprehensive review on the role of VCE in diagnosis and monitoring of Crohn’s disease. 62. Boivin ML, Lochs H, Voderholzer WA. Does passage of a patency capsule indicate small-bowel patency? A prospective clinical trial? Endoscopy 2005; 37:808–815. 63. Stanich PP, Kleinman B, Porter KM, Meyer MM. Video capsule endoscopy after bariatric and gastric surgery: oral ingestion is associated with satisfactory completion rate. J Clin Gastroenterol 2015; 49:31–33. 64. Holden JP, Dureja P, Pfau PR, et al. Endoscopic placement of the small-bowel video capsule by using a capsule endoscope delivery device. Gastrointest Endosc 2007; 65:842–847. 65. Bandorski D, Irnich W, Bruck M, et al. Capsule endoscopy and cardiac pacemakers: investigation for possible interference. Endoscopy 2008; 40:36–39. 66. Bandorski D, Lotterer E, Hartmann D, et al. Capsule endoscopy in patients with cardiac pacemakers and implantable cardioverter-defibrillators: a retrospective multicenter investigation. J Gastrointestin Liver Dis 2011; 20:33–37. &
67. Payeras G, Piqueras J, Moreno VJ, et al. Effects of capsule endoscopy on cardiac pacemakers. Endoscopy 2005; 37:1181–1185. 68. Stanich PP, Kleinman B, Betkerur K, et al. Video capsule endoscopy is & successful and effective in outpatients with implantable cardiac devices. Dig Endosc 2014; 26:726–730. A case series describing the safety of VCE in patients with pacemakers and implanted defibrillators. 69. Rana SV, Malik A. Breath tests and irritable bowel syndrome. World J & Gastroenterol 2014; 20:7587–7601. A review on the clinical utility of breath tests in the diagnosis of the IBS. 70. Saad RJ, Chey WD. Breath testing for small intestinal bacterial overgrowth: & maximizing test accuracy. Clin Gastroenterol Hepatol 2014; 12:1964–1972. A review on the use of breath tests in the diagnosis of SIBO. 71. Zhao J, Zheng X, Chu H, et al. A study of the methodological and clinical & validity of the combined lactulose hydrogen breath test with scintigraphic orocecal transit test for diagnosing small intestinal bacterial overgrowth in IBS patients. Neurogastroenterol Motil 2014; 26:794–802. A prospective study that investigated the diagnostic strategy that combined hydrogen breath testing with scintgraphic evaluation for the detection of SIBO. 72. Wardill HR, Bowen JM, Gibson RJ. Biomarkers of small intestinal mucosal & damage induced by chemotherapy: an emerging role for the 13C sucrose breath test. J Support Oncol 2013; 11:61–67. The role of 13C sucrose breath test for detection of chemotherapy-induced mucosal damage. 73. Jones MP, Chey WD, Singh S, et al. A biomarker panel and psychological && morbidity differentiates the irritable bowel syndrome from health and provides novel pathophysiological leads. Aliment Pharmacol Ther 2014; 39:426–437. A study utilizing a novel concept of combining genetic and serological biomarkers with psychological profiling for the diagnosis of IBS. 74. Elfstrom P, Sundstrom J, Ludvigsson JF. Systematic review with meta-ana& lysis: associations between coeliac disease and type 1 diabetes. Aliment Pharmacol Ther 2014; 40:1123–1132. A systematic review and meta-analysis of the association between celiac disease and type 1 diabetes. 75. Kurppa K, Paavola A, Collin P, et al. Benefits of a gluten-free diet for && asymptomatic patients with serologic markers of celiac disease. Gastroenterology 2014; 147:610–617. A prospective study investigating the clinical and histological benefit of a glutenfree diet in asymptomatic patients positive for celiac biomarkers. 76. Vives-Pi M, Takasawa S, Pujol-Autonell I, et al. Biomarkers for diagnosis and && monitoring of celiac disease. J Clin Gastroenterol 2013; 47:308–313. A comprehensive overview of the established and novel biomarkers for celiac disease.
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