Novel endoscopic methods for the evaluation of the small-bowel mucosa

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1 11. Achkar E, Carey WD, Petras R, et al. Comparison of suction capsule and endoscopic biopsy of small bowel mucosa. Gastrointest Endosc 1986;32: Dickey W, Hughes D. Prevalence of celiac disease and its endoscopic markers among patients having routine upper gastrointestinal. Am J Gastroenterol 1999;94: Cammarota G, Cesaro P, Martino A, et al. High accuracy and cost-effectiveness of a biopsy-avoiding endoscopic approach in diagnosing coeliac disease. Aliment Pharmacol Ther 2006;23: Kiesslich R, Mergener K, Naumann C, et al. Value of chromo and magnification in the evaluation of duodenal abnormalities: a prospective, randomized comparison. Endoscopy 2003;35: Badreldin R, Barrett P, Wooff DA, et al. How good is zoom for assessment of villous atrophy in coeliac disease? Endoscopy 2005; 37: Siegel LM, Stevens PD, Lightdale CJ, et al. Combined magnification with chromo in the evaluation of patients with suspected malabsorption. Gastrointest Endosc 1997;46: Guelrud M, Herrera I. Acetic acid improves identification of remnant islands of Barrett s epithelium after endoscopic therapy. Gastrointest Endosc 1998;47: Guelrud M, Herrera I, Essenfeld H, et al. Enhanced magnification : a new technique to identify specialized intestinal metaplasia in Barrett s esophagus. Gastrointest Endosc 2001;53: Toyoda H, Rubio C, Befrits R, et al. Detection of intestinal metaplasia in distal esophagus and esophagogastric junction by enhanced-magnification. Gastrointest Endosc 2004;59: Guelrud M, Herrera I, Essenfeld H, et al. Intestinal metaplasia of the gastric cardia: a prospective study with enhanced magnification. Am J Gastroenterol 2002;97: Lambert R, Rey JF, Sankaranarayanan R. Magnification and chromoscopy with the acetic acid test. Endoscopy 2003;35: Oxentenko AS, Grisolano SW, Murray JA, et al. The insensitivity of endoscopic markers in celiac disease. Am J Gastroenterol 2002;97: Mayinger B, Oezturk Y, Stolte M, et al. Evaluation of sensitivity and inter- and intra-observer variability in the detection of intestinal metaplasia and dysplasia in Barrett s esophagus with enhanced magnification. Scand J Gastroenterol 2006;41: Received October 10, Accepted February 9, Current affiliations: Department of Gastroenterology (A.L., M.G. P.B.), Tufts-New England Medical Center, Boston, Massachusetts, USA, Department of Pathology (H.E.), Policlínica Metropolitana, Caracas, Venezuela. Reprint requests: Moises Guelrud, MD, Department of Gastroenterology, Tufts-New England Medical Center, 750 Washington St, Box 233, Boston, MA EDITORIAL Novel endoscopic methods for the evaluation of the small-bowel mucosa Standard has been a robust method for the detection of macroscopic lesions, such as peptic ulcer disease, strictures, and tumors. 1 However, it has become apparent that, in the modern era, there is a necessity for more accurate endoscopic methods for the detection of subtle mucosal abnormalities. Indeed, the lack of an ability to visually detect clinically significant alterations in the intestinal mucosa, make the routine histologic assessment of biopsy specimens indispensable to detect and classify diseases of the small-bowel mucosa. 2 Although the endoscopist is up close to the diseased mucosa, standard has limited capability to evaluate mucosal lesions, because the low-magnification view may fail to highlight the mucosal disorder. 3 Furthermore, the intestinal lesions can be patchy, and the macroscopic features are highly dependent on the degree/severity of the histologic lesion. 4 To detect these disorders, either the endoscopist must routinely take biopsy specimens from Copyright ª 2007 by the American Society for Gastrointestinal Endoscopy /$32.00 doi: /j.gie the duodenum or use endoscopic techniques that provide a more sensitive evaluation of the mucosa. What new tools or techniques can the endoscopist use to allow detection of these diseases? The article by Lo et al 5 in this issue of Gastrointestinal Endoscopy demonstrates that the technique of Standard has a limited capability to evaluate mucosal lesions, because the lowmagnification view may fail to highlight the mucosal disorder. enhanced magnification can identify the subtle mucosal patterns of common duodenal mucosal disorders. This and other techniques are potentially useful tools to enhance the ability of the endoscopist to detect, although not necessarily classify, small-bowel mucosal disorders. Let us first describe the common mucosal disorders that might be of concern to endoscopists and then review the endoscopic tools and techniques that may allow a more 382 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 2 :

2 Editorial TABLE 1. Differential diagnosis of villous atrophy (partial list) Infectious Gastroenteritis Small-bowel bacterial overgrowth Giardiasis Tropical sprue HIV-related enteropathy Whipple s disease Immune-mediated diseases Celiac disease Eosinophilic gastroenteritis Autoimmune enteropathy Refractory sprue Food allergies Graft-versus-host disease Miscellaneous Bowel ischemia Lymphoma Nodular lymphoid hyperplasia Hypogammaglobulinemia Malnutrition precise evaluation of the duodenal mucosa, including the immersion technique, chromoscopic, magnification, wireless capsule (CE), double-balloon enteroscopy, and combined magnification (eg, enhanced magnification ). INTESTINAL MUCOSAL DISORDERS ASSOCIATED WITH VILLOUS ATROPHY There are many mucosal disorders associated with villous atrophy (Table 1). The 2 most common diseases that cause intestinal villous atrophy in developed and developing areas are celiac disease (CD) and tropical sprue (TS), respectively. CD, also known as gluten-sensitive enteropathy, is a permanent intolerance to gluten in susceptible individuals that predominantly affects the proximal small intestine, inducing crypt hyperplasia and villous atrophy. The symptoms and histologic alterations improve after gluten withdrawal. 6 TS is an acquired disease of unknown etiology, characterized by malabsorption, nutritional deficiencies, and mucosal abnormalities (chronic inflammation and villous atrophy) in the proximal and distal small bowel. The treatment of choice for TS is a combination of folic acid and antibiotics. 7 Although these disorders result in villous atrophy that could be detected macroscopically by, at the present, the criterion standard for diagnosis remains the duodenal biopsy. ENDOSCOPIC FINDINGS SUGGESTIVE OF VILLOUS ATROPHY Characteristic endoscopic findings have been well described in CD and to a lesser extent in TS (only 15% of the patients with TS exhibit the classical endoscopic features of atrophy vs 75% of the patients with CD). 8 These changes include reduced Kerckring s folds, scalloping of the mucosa on circular folds, mucosal fissures, and mosaic pattern The sensitivity of the standard to detect macroscopic features consistent with villous atrophy varies substantially (50%-94%), in part, because partial villous atrophy may elude detection. 13 Therefore, a normal endoscopic appearance of the mucosa does not necessarily imply normal histology. However, when the endoscopic signs are present, they have a high specificity for intestinal villous atrophy (95%-100%). 14 Thus, new techniques and/ or technologies that may improve the mucosal visualization of the intestine are needed, especially those that increase the sensitivity of the currently available methods. However, multiple conditions may alter villous morphology, and the detection of visible villous atrophy does not alone determine etiology. 15 This issue of Gastrointestinal Endoscopy includes a novel study on the promising results of enhanced magnification (EME) for the detection of intestinal atrophy in patients with CD and TS. 5 EME involves the combined use of magnification with acetic-acid instillation. 16 The exact mechanism of action through which acetic acid works as a dye in the mucosa ( acetowhitening ) is unknown. 17 This technique has been used for detection of specialized intestinal metaplasia in Barrett s esophagus, 18 but its use in small-bowel disorders has not been previously reported. In the paper by Lo et al, 5 3 patterns of abnormal mucosal appearance ( stubbed, ridged, and foveolar ) correlated more accurately with intestinal villous atrophy than did standard. This applied to both patients with CD (100% vs 58%) and patients with TS (93% vs 20%). Most significantly, EME was superior to standard for the detection of mucosal alterations when only partial villous atrophy was found on histology. No adverse clinical events associated with acetic-acid instillation were detected, though the technique added on average 7 minutes to the length of the standard examination. OTHER ENDOSCOPIC TECHNOLOGIES AND TECHNIQUES USED TO IMPROVE THE VISUALIZATION OF THE INTESTINAL MUCOSA The modified immersion technique is a simple, quick, and safe method. This consists in the visualization Volume 66, No. 2 : 2007 GASTROINTESTINAL ENDOSCOPY 383

3 of the villi after the rapid introduction of water (usually ml) into the lumen of the duodenum after removal of air by suction. This technique improves the rate of detection of total (sensitivity, 100%; specificity, 99.7%) and partial villous atrophy (sensitivity, 75%; specificity, 99.5%), and can be used routinely during upper. 19 Recently, this technique very accurately predicted the histologic recovery (or not) of patients with treated CD. 20 Chromoscopic relies on the instillation of a dye (eg, indigo carmine or methylene blue) to highlight the superficial details and improve visualization of the mucosa. 21 Magnification uses videoendoscopes with the capability to image magnification in a variable continuous range (from 1.5 to 150) by using a movable lens controlled by the endoscopist. 22 The combined magnification (range 1.5 to 35) with indigo carmine spraying increases the accuracy to detect villous atrophy (sensitivity, 94%; specificity, 88%) in TS and CD. 8 This technique was also more accurate (91% vs 9%) in identifying partial villous atrophy than standard. 8 In a recent study, chromoscopic evaluation of the duodenum with indigo carmine increased the rate of detection of a variety of duodenal abnormalities (eg, gastric metaplasia, hyperplastic Brunner s glands, and villous atrophy); however, no difference was found with regard to the number or extent of lesions identified between standard and magnification (range 1 to105) if the dye was used in both procedures. 23 When a high-power magnification (range 1 to 115) videoendoscope (the so-called zoom ) was used without staining, a positive predictive value of 83% and a negative predictive value of 77% was found for detecting villous atrophy in patients with CD (27.5% had partial villous atrophy), with a fairly good correlation (kappa score, 0.63) between macroscopic assessment of villous atrophy and the histology. 24 CE is a noninvasive technology that can provide a painless, endoscopic, magnified (8) image of the entire intestinal mucosa. 25 Its utility in the diagnosis of small-bowel diseases (eg, CD) 26 and the value in patients with complicated CD has been demonstrated. 27 CE had the highest specificity for the detection of total villous atrophy in patients with CD. 28,29 However, although CE is simple to perform and had a high acceptance by patients, it does have limitations, such as high cost, lower detection rate of minor degrees of atrophy, and the inability to take intestinal biopsy specimens or to perform therapeutic interventions. 30 Double-balloon enteroscopy is an invasive endoscopic method for the examination of the whole intestine (anterograde and retrograde approach), which can be used to take intestinal biopsy specimens and to perform other endoscopic procedures (eg, assessment of strictures) in hidden areas that cannot be reached by the standard. 31 The principal limitations are the need for expertise, its duration, and the cost. The rate of observation TABLE 2. Overall sensitivity and specificity for the detection of villous atrophy among diverse endoscopic tools Endoscopic tool Standard Enhancedmagnification Water-immersion Magnification with dye spraying Sensitivity, % Specificity, % Study Oxentenko et al N/A Lo et al Cammarota et al Siegel et al 8 Zoom Badreldin et al 24 CE Petroniene et al 28 N/A, Not available Hopper et al 29 of the entire intestine varies but is high for experienced endoscopists (50%-86%). 32,33 The complication rate is low (1.1%-3.4%), occurring principally after intervention (eg, polypectomy of large polyps). 34 The utility of this invasive tool for macroscopic detection of villous atrophy associated with small-bowel mucosal disorders remains to be proven, and its main utility is to target areas beyond the reach of other endoscopic methods. A summary of the sensitivity and specificity for the detection of villous atrophy among the available endoscopic methods is shown in Table 2. The principal applications of these new endoscopic approaches to improve the visualization of the mucosal abnormalities in the small intestine may be (1) to identify potential villous atrophy in patients for whom there is not an a priori indication for obtaining duodenal biopsy specimens, (2) to target duodenal biopsies to more abnormal areas, (3) to improve biopsy sampling in those patients in whom standard of randomly taken intestinal biopsy specimens showed normal histology or a poorly interpretable sample in patients with a high index of suspicion for the disease (symptoms or serology compatible). These novel endoscopic techniques will need more rigorous testing to consistently prove their ability, not only to better detect mucosal disease but to do so in a cost- and time-efficient manner. It would behoove gastroenterologists to become familiar with the subtle features of intestinal villous atrophy that can now be 384 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 2 :

4 Editorial appreciated with a higher sensitivity with newer techniques, especially the newer-generation endoscopes with magnification capabilities and possibly even high-definition imaging. The use of the immersion technique, if confirmed, is a simple method to increase the detection of villous atrophy in the routine endoscopic practice. The utility of special techniques that may require significantly extra time and expertise, such as dye spraying techniques, may not make it into routine use for the examination of the duodenum of patients without suspected small-bowel mucosal disease. We feel that it is the application of these newer-generation endoscopes with higher definition and magnification capabilities that provide an opportunity for identifying patients with CD not otherwise suspected. Whether endoscopic identification of villous atrophy alone seems adequate to make a precise etiologic diagnosis of CD, TS, or other mucosal diseases, is unclear and probably unlikely without the use of additional testing to determine etiology. However, one such approach might be to combine endoscopic detection of atrophy with highly specific serologic testing (eg, for CD, tissue transglutaminase or endomysial antibodies). Thus, if it was corroborated by a highly specific serologic test, then the combination might provide an alternative to biopsyproven disease in certain circumstances. Such circumstances could involve patients who are on anticoagulation therapy that cannot be safely interrupted or those who have a CE examination and cannot have a regular upper because of poor tolerance of intubation. In summary, these newer techniques are bringing what were previously considered histologic diagnoses into the hands of endoscopists. DISCLOSURE The authors have no disclosures to make. This article was supported in part by the American College of Gastroenterology International GI Training Grant 2006 (A.R.T.) and the National Institutes of Health grants DK and DK (J.A.M.). REFERENCES Alberto Rubio-Tapia, MD Joseph A. Murray, MD Division of Gastroenterology and Hepatology Mayo Clinic College of Medicine Rochester, Minnesota, USA 1. Brugge W, Dam JV. Medical progress: of the upper gastrointestinal tract. N Engl J Med 1999;341: Oberhuber G, Granditsch G, Vogelsang H. The histopathology of celiac disease: time for a standardized report scheme for pathologists. Eur J Gastroenterol Hepatol 1999;11: Dickey W, Hughes D. Prevalence of celiac disease and its endoscopic markers among patients having routine upper gastrointestinal. Am J Gastroenterol 1999;94: Dickey W, Hughes D. Disappointing sensitivity of endoscopic markers of villous atrophy in a high risk population: implications for celiac disease diagnosis during routine. 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5 26. Gong F, Swain P, Mills T. Wireless. Gastrointest Endosc 2000;51: Culliford A, Daly J, Diamond B, et al. The value of wireless capsule in patients with complicated celiac disease. Gastrointest Endosc 2005;62: Petroniene R, Dubcenco E, Baker JP, et al. Given capsule in celiac disease: evaluation of diagnostic accuracy and interobserver agreement. Am J Gastroenterol 2005;100: Hopper AD, Sidhu R, Hurlstone DP, et al. Capsule : an alternative to duodenal biopsy for the recognition of villous atrophy in celiac disease? Dig Liver Dis 2007;39: Cellier C, Green PHR, Collin P, et al. ICCE consensus for celiac disease. Endoscopy 2005;37: Yamamoto H, Yano T, Kita H, et al. New system of double-balloon enteroscopy for diagnosis and treatment of small intestinal disorders. Gastroenterology 2003;125: Yamamoto H, Kita H, Sunada K, et al. Clinical outcomes of double-balloon for the diagnosis and treatment of small-intestinal diseases. Clin Gastroenterol Hepatol 2004;2: Akahoshi K, Kubokawa M, Matsumoto M, et al. Double-balloon in the diagnosis and management of GI tract diseases: methodology, indications, safety, and clinical impact. World J Gastroenterol 2006;12: May A, Nachbar L, Pohl J, et al. Endoscopic interventions in the small bowel using double-balloon enteroscopy: feasibility and limitations. Am J Gastroenterol 2007;102:1-9. Results from GIE online polling We asked and you answered. Here are the results of the latest GIE online poll. What impact do you believe CT colonography will have on the number of patients undergoing colonoscopy (including screening, diagnostic, and therapeutic colonoscopy) over the next 5 to 10 years? d (7 votes, 5%) Dramatically decrease the number of patients undergoing colonoscopy (eg, loss of screening colonoscopies) d (24 votes, 19%) Decrease the number of patients undergoing colonoscopy somewhat d (39 votes, 30%) No real impact on the number of patients undergoing colonoscopy d (39 votes, 30%) Increase the number of patients undergoing colonoscopy somewhat d (20 votes, 16%) Dramatically increase the number of patients undergoing colonoscopy (eg, more CT screening results in more polypectomy) To participate in the current online poll, go to or www. asge.org. 386 GASTROINTESTINAL ENDOSCOPY Volume 66, No. 2 :