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

      Standard endoscopy has a limited capability to evaluate mucosal lesions, because the low-magnification view may fail to highlight the mucosal disorder.
      Standard endoscopy has been a robust method for the detection of macroscopic lesions, such as peptic ulcer disease, strictures, and tumors.
      • Brugge W.
      • Dam J.V.
      Medical progress: endoscopy of the upper gastrointestinal tract.
      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.
      • Oberhuber G.
      • Granditsch G.
      • Vogelsang H.
      The histopathology of celiac disease: time for a standardized report scheme for pathologists.
      Although the endoscopist is up close to the diseased mucosa, standard endoscopy has limited capability to evaluate mucosal lesions, because the low-magnification view may fail to highlight the mucosal disorder.
      • Dickey W.
      • Hughes D.
      Prevalence of celiac disease and its endoscopic markers among patients having routine upper gastrointestinal endoscopy.
      Furthermore, the intestinal lesions can be patchy, and the macroscopic features are highly dependent on the degree/severity of the histologic lesion.
      • Dickey W.
      • Hughes D.
      Disappointing sensitivity of endoscopic markers of villous atrophy in a high risk population: implications for celiac disease diagnosis during routine endoscopy.
      To detect these disorders, either the endoscopist must routinely take biopsy specimens from 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
      • Lo A.
      • Guelrud M.
      • Essenfeld H.
      • et al.
      Classification of villous atrophy with enhanced magnification endoscopy in patients with celiac disease and tropical sprue.
      in this issue of Gastrointestinal Endoscopy demonstrates that the technique of enhanced magnification endoscopy 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 precise evaluation of the duodenal mucosa, including the immersion technique, chromoscopic endoscopy, magnification endoscopy, wireless capsule endoscopy (CE), double-balloon enteroscopy, and combined magnification endoscopy (eg, enhanced magnification endoscopy).

      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.
      • Rostom A.
      • Murray J.A.
      • Kagnoff M.F.
      American Gastroenterological Association (AGA) Institute technical review on diagnosis and management of celiac disease.
      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.
      • Ramakrishna B.S.
      • Venkataraman S.
      • Mukhopadhya A.
      Tropical malabsorption.
      Although these disorders result in villous atrophy that could be detected macroscopically by endoscopy, at the present, the criterion standard for diagnosis remains the duodenal biopsy.
      Table 1Differential 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

      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).
      • Siegel L.M.
      • Stevens P.D.
      • Lightdale C.J.
      • et al.
      Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption.
      These changes include reduced Kerckring's folds, scalloping of the mucosa on circular folds, mucosal fissures, and mosaic pattern.
      • Brocchi E.
      • Corazza G.R.
      • Caletti G.
      • et al.
      Endoscopic demonstration of loss of duodenal folds in the diagnosis of celiac disease.
      • Jabbari M.
      • Wild G.
      • Goresky C.A.
      • et al.
      Scalloped valvulae conniventes: an endoscopic marker of celiac sprue.
      • Oxentenko A.S.
      • Grisolano S.W.
      • Murray J.A.
      • et al.
      The insensitivity of endoscopic markers in celiac disease.
      • Olds G.
      • McLoughlin R.
      • O'Morian C.
      • et al.
      Celiac disease for the endoscopist.
      The sensitivity of the standard endoscopy to detect macroscopic features consistent with villous atrophy varies substantially (50%-94%), in part, because partial villous atrophy may elude detection.
      • Lee S.K.
      • Green P.H.
      Endoscopy in celiac disease.
      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%).
      • Dickey W.
      Endoscopic markers for celiac disease.
      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.
      • Owens S.R.
      • Greenson J.K.
      The pathology of malabsorption: current concepts.
      This issue of Gastrointestinal Endoscopy includes a novel study on the promising results of enhanced magnification endoscopy (EME) for the detection of intestinal atrophy in patients with CD and TS.
      • Lo A.
      • Guelrud M.
      • Essenfeld H.
      • et al.
      Classification of villous atrophy with enhanced magnification endoscopy in patients with celiac disease and tropical sprue.
      EME involves the combined use of magnification with acetic-acid instillation.
      • Guelrud M.
      • Ehrlich E.E.
      Enhanced magnification endoscopy in the upper gastrointestinal tract.
      The exact mechanism of action through which acetic acid works as a dye in the mucosa (“acetowhitening”) is unknown.
      • Kaufman H.B.
      • Harper D.M.
      Magnification and chromoscopy with the acetic acid test.
      This technique has been used for detection of specialized intestinal metaplasia in Barrett's esophagus,
      • Guerlrud M.
      • Herrera I.
      • Essenfeld H.
      • et al.
      Enhanced magnification endoscopy: a new technique to identify specialized intestinal metaplasia in Barrett's esophagus.
      but its use in small-bowel disorders has not been previously reported. In the paper by Lo et al,
      • Lo A.
      • Guelrud M.
      • Essenfeld H.
      • et al.
      Classification of villous atrophy with enhanced magnification endoscopy in patients with celiac disease and tropical sprue.
      3 patterns of abnormal mucosal appearance (“stubbed,” “ridged,” and “foveolar”) correlated more accurately with intestinal villous atrophy than did standard endoscopy. This applied to both patients with CD (100% vs 58%) and patients with TS (93% vs 20%). Most significantly, EME was superior to standard endoscopy 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 of the villi after the rapid introduction of water (usually 100-200 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 endoscopy.
      • Cammarota G.
      • Pirozzi G.A.
      • Martino A.
      • et al.
      Reliability of the “immersion technique” during routine upper endoscopy for detection of abnormalities of duodenal villi in patients with dyspepsia.
      Recently, this technique very accurately predicted the histologic recovery (or not) of patients with treated CD.
      • Cammarota G.
      • Cuoco L.
      • Cesaro P.
      • et al.
      A highly accurate method for monitoring histological recovery in patients with celiac disease on a gluten-free diet using an endoscopic approach that avoids the need for biopsy: a double-center study.
      Chromoscopic endoscopy relies on the instillation of a dye (eg, indigo carmine or methylene blue) to highlight the superficial details and improve visualization of the mucosa.
      • Tada M.
      • Kawai K.
      Research with the endoscope: new techniques using magnification and chromoscopy.
      Magnification endoscopy 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.
      • Kiesslich R.
      • Jung M.
      Magnification endoscopy: does it improve mucosal surface analysis for the diagnosis of gastrointestinal neoplasias?.
      The combined magnification endoscopy (range ×1.5 to ×35) with indigo carmine spraying increases the accuracy to detect villous atrophy (sensitivity, 94%; specificity, 88%) in TS and CD.
      • Siegel L.M.
      • Stevens P.D.
      • Lightdale C.J.
      • et al.
      Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption.
      This technique was also more accurate (91% vs 9%) in identifying partial villous atrophy than standard endoscopy.
      • Siegel L.M.
      • Stevens P.D.
      • Lightdale C.J.
      • et al.
      Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption.
      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 endoscopy and magnification endoscopy (range ×1 to ×105) if the dye was used in both procedures.
      • Kiesslich R.
      • Mergener K.
      • Naumann C.
      • et al.
      Value of chromoendoscopy and magnification endoscopy in the evaluation of duodenal abnormalities: a prospective, randomized comparison.
      When a high-power magnification (range ×1 to ×115) videoendoscope (the so-called zoom endoscopy) 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.
      • Badreldin R.
      • Barrett P.
      • Wooff D.A.
      • et al.
      How good is zoom endoscopy for assessment of villous atrophy in celiac disease?.
      CE is a noninvasive technology that can provide a painless, endoscopic, magnified (×8) image of the entire intestinal mucosa.
      • Iddan G.
      • Meron G.
      • Glukhovsky A.
      • et al.
      Wireless capsule endoscopy.
      Its utility in the diagnosis of small-bowel diseases (eg, CD)
      • Gong F.
      • Swain P.
      • Mills T.
      Wireless endoscopy.
      and the value in patients with complicated CD has been demonstrated.
      • Culliford A.
      • Daly J.
      • Diamond B.
      • et al.
      The value of wireless capsule endoscopy in patients with complicated celiac disease.
      CE had the highest specificity for the detection of total villous atrophy in patients with CD.
      • Petroniene R.
      • Dubcenco E.
      • Baker J.P.
      • et al.
      Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement.
      • Hopper A.D.
      • Sidhu R.
      • Hurlstone D.P.
      • et al.
      Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in celiac disease?.
      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.
      • Cellier C.
      • Green P.H.R.
      • Collin P.
      • et al.
      ICCE consensus for celiac disease.
      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 endoscopy.
      • Yamamoto H.
      • Yano T.
      • Kita H.
      • et al.
      New system of double-balloon enteroscopy for diagnosis and treatment of small intestinal disorders.
      The principal limitations are the need for expertise, its duration, and the cost. The rate of observation of the entire intestine varies but is high for experienced endoscopists (50%-86%).
      • Yamamoto H.
      • Kita H.
      • Sunada K.
      • et al.
      Clinical outcomes of double-balloon endoscopy for the diagnosis and treatment of small-intestinal diseases.
      • Akahoshi K.
      • Kubokawa M.
      • Matsumoto M.
      • et al.
      Double-balloon endoscopy in the diagnosis and management of GI tract diseases: methodology, indications, safety, and clinical impact.
      The complication rate is low (1.1%-3.4%), occurring principally after intervention (eg, polypectomy of large polyps).
      • May A.
      • Nachbar L.
      • Pohl J.
      • et al.
      Endoscopic interventions in the small bowel using double-balloon enteroscopy: feasibility and limitations.
      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.
      Table 2Overall sensitivity and specificity for the detection of villous atrophy among diverse endoscopic tools
      Endoscopic toolSensitivity, %Specificity, %Study
      Standard endoscopy5992Oxentenko et al
      • Oxentenko A.S.
      • Grisolano S.W.
      • Murray J.A.
      • et al.
      The insensitivity of endoscopic markers in celiac disease.
      Enhanced-magnification endoscopy96N/ALo et al
      • Lo A.
      • Guelrud M.
      • Essenfeld H.
      • et al.
      Classification of villous atrophy with enhanced magnification endoscopy in patients with celiac disease and tropical sprue.
      Water-immersion endoscopy90.999.5Cammarota et al
      • Cammarota G.
      • Pirozzi G.A.
      • Martino A.
      • et al.
      Reliability of the “immersion technique” during routine upper endoscopy for detection of abnormalities of duodenal villi in patients with dyspepsia.
      Magnification endoscopy with dye spraying9488Siegel et al
      • Siegel L.M.
      • Stevens P.D.
      • Lightdale C.J.
      • et al.
      Combined magnification endoscopy with chromoendoscopy in the evaluation of patients with suspected malabsorption.
      Zoom endoscopy90.762.9Badreldin et al
      • Badreldin R.
      • Barrett P.
      • Wooff D.A.
      • et al.
      How good is zoom endoscopy for assessment of villous atrophy in celiac disease?.
      CE70100Petroniene et al
      • Petroniene R.
      • Dubcenco E.
      • Baker J.P.
      • et al.
      Given capsule endoscopy in celiac disease: evaluation of diagnostic accuracy and interobserver agreement.
      85100Hopper et al
      • Hopper A.D.
      • Sidhu R.
      • Hurlstone D.P.
      • et al.
      Capsule endoscopy: an alternative to duodenal biopsy for the recognition of villous atrophy in celiac disease?.
      N/A, Not available.
      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 endoscopy 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 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 biopsy-proven 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 endoscopy 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-57892 and DK-071003 (J.A.M.).

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