Gastrointestinal Imaging

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1 Endoscopic Imaging of Gastroesophageal Reflux Disease Kerry B Dunbar, MD Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine Abstract Gastroesophageal reflux disease (GERD) is a common problem and a frequent cause of visits to the gastroenterologist. Newer endoscopic imaging techniques that have been used to study a number of gastrointestinal disorders are now being applied to patients with GERD. Magnification endoscopy, chromoendoscopy, narrow-band imaging, and confocal endomicroscopy are some of the techniques being applied to study acid reflux, erosive reflux disease (ERD), and non-erosive reflux disease (NERD). While these techniques hold promise for the diagnosis of GERD, additional study is warranted to determine the effect on patient treatment and outcomes. Keywords Gastroesophageal reflux disease (GERD), acid reflux, narrow-band imaging, chromoendoscopy, magnification endoscopy, endomicroscopy, endoscopic imaging Disclosure: The author has no conflicts of interest to declare. Received: July 10, 2009 Accepted: July 24, 2009 Citation: US Radiology, 2010;2(1):62 6 Correspondence: Kerry B Dunbar, MD, Assistant Professor of Medicine, Division of Gastroenterology and Hepatology, Johns Hopkins University School of Medicine, 1830 East Monument Street, Room 436, Baltimore, MA E: kdunbar@jhmi.edu Symptoms of gastroesophageal reflux disease (GERD) affect 20% of the US population. 1 While some patients can be diagnosed and treated by symptoms alone, endoscopy has been used to assess the severity of GERD and screen for complications, such as erosive esophagitis, strictures, and Barrett s esophagus. Patients with GERD symptoms are typically categorized into two groups: those with erosive reflux disease (ERD) and those with non-erosive reflux disease (NERD). The distinction between these groups is made by standard upper endoscopic examination of the esophagus to evaluate for features of ERD. Between 53 and 70% of patients with GERD symptoms have NERD, with no evidence of mucosal breaks during standard endoscopy. 2,3 Classificaton of Erosive Reflux Disease by Standard Endoscopy For patients with ERD there are numerous endoscopic classification systems, many with significant problems with interobserver and intraobserver agreement. One of the most frequently used is the Los Angeles Classification System of esophagitis, 4,5 which is the standard grading system used for most of the studies in this article. This grading system uses breaks in the esophageal mucosa to determine the extent of esophagitis (see Table 1). Evaluation of the grading system has been performed several times, with variable interobserver agreement. 4,5 Interobserver agreement in two studies of mucosa found the agreement for mucosal breaks to range between κ=0.4 (fair) to κ=0.84 (almost perfect). Minimal changes in the esophageal mucosa suspected to be related to reflux such as friability, erythema, blurring of the squamocolumnar junction (SCJ), reddening of the cardia, erythema and increased vascularity of the distal esophagus, and edema of the mucosal folds were also examined. Kappa scores in one study were as high as 0.8 (substantial agreement) 4 but near zero for the individual minimal changes in a subsequent study 5 (see Table 2). Los Angeles classes A though C of erosive esophagitis were found to be associated with symptom severity, treatment outcomes, extent of acid exposure, and risk for symptom relapse. 5 Thus, although not perfect, the Los Angeles Classification has been a widely adopted standard for grading ERD and has been used in numerous studies. Novel Endoscopic Technology and Gastroesophageal Reflux Disease With the advent of several new endoscopic technologies, more detailed imaging of the esophageal mucosa is available. Improvements in endoscopic technology such as high-resolution, high-definition, and high-magnification endoscopy, chromoendoscopy, narrow-band imaging (NBI), and confocal endomicroscopy and digital image enhancement technologies such as Fuji intelligent chromoendoscopy (FICE) and i-scan have led to a re-examination of the esophageal mucosa in a variety of esophageal disorders, including GERD. Several recent studies have combined techniques such as NBI with magnification or chromoendoscopy with high-resolution endoscopy to evaluate the mucosal changes seen in patients with symptoms of GERD and in patients with endoscopic evidence of ERD and NERD. 62 TOUCH BRIEFINGS 2010

2 Endoscopic Imaging of Gastroesophageal Reflux Disease Magnification Endoscopy Magnification endoscopy has been used in several studies to evaluate the esophageal mucosa for subtle changes of GERD. Magnification endoscopes are equipped with a lever that can increase the magnification at close distances up to 150-fold. One study of magnification endoscopy examined endoscopic and histological markers in NERD patients. 6 Patients with GERD underwent magnification endoscopy ( fold magnification). Characteristics of minimal change esophagitis were examined. These included increased vascular markings and punctate erythema above the squamocolumnar junction (SCJ), and increased vascular markings, villous mucosa, and squamous islands below the SCJ. Mucosal biopsies were taken above and below the SCJ and examined for histological changes of NERD. Patients were then treated with proton-pump inhibitor therapy and repeat endoscopy was performed. After excluding patients with ERD and Barrett s esophagus, 39 patients with NERD and 39 non-reflux controls were analyzed. Of the NERD patients, 27 of 39 (69%) had endoscopic features of minimal change esophagitis, compared with eight of 39 normal controls (21%). Punctate erythema above the SCJ was seen significantly more often in NERD patients than controls. 6 Using magnification endoscopy, the criteria for minimal change esophagitis predicted NERD with a sensitivity of 64%, specificity of 85%, positive predictive value of 80%, negative predictive value of 70%, and accuracy of 74% (see Table 3). Histological examination of mucosal biopsies found that increased papillae length and basal cell hyperplasia were more common in NERD patients than in controls. After treatment with a proton-pump inhibitor, there were no significant endoscopic or histological differences identified between treated NERD patients and the control patients. In this study, the combination of endoscopic changes of minimal change esophagitis and histological changes predicted NERD with a sensitivity of 62%, specificity of 74%, positive predictive value of 67%, negative predictive value of 67%, and accuracy of 68%. In a second study of magnification endoscopy, high-resolution magnification endoscopy was used to examine potential endoscopic characteristics of NERD and the interobserver variability of these findings. 7 Eleven patients with GERD, confirmed by questionnaire and ph monitoring, and 10 healthy controls were evaluated with a highresolution 35-fold magnification endoscope with two-fold optical zoom. Still images of the distal esophagus were examined for potential endoscopic changes associated with NERD. These included triangular indentations into the squamous mucosa by villiform columnar mucosa, apical mucosal breaks at the top of the indentation, decreased palisade blood vessels, pinpoint or comma-shaped blood vessels in the mucosa above the SCJ, a serrated SCJ, branching blood vessels in the columnar mucosa below the SCJ, and villiform mucosa below the gastroesophageal junction. Classification of results by GERD symptoms (symptom-positive versus symptom-negative patients) did not show any statistically significant Table 1: Los Angeles Classification of Esophagitis 2 Grade A Grade B Grade C Grade D One (or more) mucosal break no longer than 5mm that does not extend between the tops of two mucosal folds One (or more) mucosal break more than 5mm long that does not extend between the tops of two mucosal folds One (or more) mucosal break that is continuous between the tops of two or more mucosal folds, but involves <75% of the circumference One (or more) mucosal break involves at least 75% of the esophageal circumference Reproduced from Gut, Lundell LR, Dent J, et al., 1999;45:172 80, with permission from BMJ Publishing Group Ltd. Table 2: Interobserver Agreement for Endoscopic Features of Gastroesophageal Reflux Disease Study and Feature Interobserver Agreement (κ) Los Angeles Classification 4,5 Mucosal breaks Minor changes Magnification endoscopy 7 Absent palisade blood vessels 0.49 Triangular lesions above SCJ 0.28 Apical mucosal breaks 0.18 Pinpont blood vessels at SCJ 0.28 Standard endoscopy Standard endoscopy + NBI NBI with magnification 16 Microerosions 0.88 Increased SCJ vascularity 0.67 Increased IPCLs 0.58 Tortuous IPCLs 0.48 Dilated IPCLs 0.75 NBI with magnification 17 Microerosions 0.89 Increased SCJ vascularity 0.95 Pit pattern type 0.59 Round pit type 0.8 Villous pit type 0.82 IPCL = intrapapillary capillary loops; NBI = narrow-band imaging; SCJ = squamocolumnar junction. Landis and Koch kappa value interpretation: κ<0 = poor, = slight, = fair, moderate, = substantial, = almost perfect. 22 difference in endoscopic features suggestive of GERD. Analysis of the data stratified by ph-monitoring results showed significantly more triangular lesions, apical mucosal breaks, and pinpoint blood vessels near the SCJ in patients with NERD than controls. These lesions were significantly reduced after treatment with proton-pump inhibitors. While these endoscopic features were suggestive of NERD, the interobserver agreement was low. The absence of palisade blood vessels showed moderate interobserver agreement (κ=0.49), but the remainder of the characteristics had slight to fair agreement (κ= ) (see Table 2). In these two studies, magnification endoscopy allowed increased visualization of subtle mucosal changes. Lack of specificity and lower interobserver agreement, however, limit the usefulness of magnification endoscopy alone. US RADIOLOGY 63

3 Table 3: Performance Characteristics of Endoscopic Technologies in Gastroesophageal Reflux Disease Study Sensitivity Specificity PPV NPV Accuracy (%) (%) (%) (%) (%) Magnification endoscopy 6 NBI with magnification (>125 IPCLs per image field) 16 NBI with magnification (increased SCJ vascularity + absence of round pit pattern) 17 Endomicroscopy (>5 IPCLs per field + dilated intracellular spaces) 18 IPCL= intrapapillary capillary loop; NPV = negative predictive value; PPV = positive predictive value; SCJ = squamocolumnar junction. Lugol s solution application. The number and severity of mucosal breaks and the presence of circumscribed lesions identified were recorded for each method of examination. Of the 50 patients, mucosal breaks suggestive of esophagitis were identified in nine patients using HD endoscopy alone. Mucosal breaks were found in 12 patients using HD with i-scan and in 25 patients using HD with Lugol s chromoendoscopy. The grade of esophagitis was increased in five patients using HD with i-scan and 14 patients using HD with chromoendoscopy. Other mucosal lesions such as punctate erythema, small lesions, and flat mucosal streaks were more frequently found with HD with i-scan (48 lesions) and HD with Lugol s staining (85 lesions) than with HD endoscopy alone (21 lesions). Biopsy-confirmed Barrett s esophagus was also more frequently identified with HD chromoendoscopy (20 cases) than HD endoscopy alone (14 cases) or HD endoscopy with i-scan (16 cases). In these studies, chromoendoscopy identified additional endoscopic detail not visualized by standard and HD endoscopy alone. Additional mucosal breaks and small lesions were identified with digital image enhancement and chromoendoscopy. Additional study of the value of identifying additional mucosal breaks and non-neoplastic lesions in the treatment of GERD patients is warranted. Chromoendoscopy Chromoendoscopy, which involves the application of topical dyes to the gastrointestinal mucosa, has been used in a number of gastrointestinal diseases, including Barrett s esophagus and esophageal squamous cell carcinoma. 8,9 Lugol s iodine solution has been used to identify squamous cell carcinoma and squamous dysplasia of the esophagus, where a lack of Lugol s staining identifies abnormal mucosa. 9 Lugol s solution also shows less mucosal staining in esophageal inflammation. 10 In one study, 61 patients with a history of GERD and 42 controls underwent standard upper endoscopy. 11 Chromoendoscopy with Lugol s solution was performed and biopsies were taken of stained and unstained areas. Standard upper endoscopy identified mucosal breaks in 36% of reflux patients and 10% of controls, who were classified as having ERD and were not studied further. The remaining 39 patients with reflux classified as NERD and 38 control patients then underwent chromoendoscopy. Unstained streaks on the mucosal folds >3cm in length were identified in 49% of NERD patients and 3% of controls. Biopsies of the unstained streaks and normal stained mucosa were compared and the histopathological changes were suggestive of GERD, with increased basal zone thickness and prominent elongated esophageal papillae. The presence of unstained streaks in the distal esophagus was felt to be suggestive of NERD. One recent study of GERD patients compared the endoscopic findings using high-definition (HD) endoscopy, HD with i-scan digital image enhancement, and HD with chromoendoscopy with Lugol s iodine solution. 12 A high-definition endoscope and processor were used, which included i-scan for post-processing image enhancement, including a surface enhancement feature. Fifty patients were examined sequentially with HD endoscopy, followed by HD with i-scan surface enhancement, then HD with 1.5% Narrow-band Imaging Use of NBI for diagnosis of gastrointestinal disorders has spread rapidly, with several studies on Barrett s esophagus and diseases of the colon. 13,14 NBI uses restricted wavelengths of light to view the mucosa, emphasizing both the vascular pattern and the surface mucosal pattern. Several recent studies have examined the role of NBI in GERD. The intraobserver and interobserver agreement of standard endoscopy and standard endoscopy plus NBI for grading of esophagitis was examined in one study. 15 Two hundred and thirty patients with GERD symptoms had standard endoscopy and then NBI. The collected images were reviewed by seven observers and graded using the Los Angeles Classification of esophagitis. Intraobserver agreement was fair to moderate using standard endoscopy alone (κ= ). There was significant improvement in agreement with the addition of NBI, particularly in the raters with the lowest initial kappa scores. The interobserver agreement for the group improved from moderate (κ=0.45) for standard endoscopy to substantial (κ=0.62) with standard endoscopy plus NBI (see Table 2). There were also more cases of Los Angeles grade A esophagitis detected with NBI compared with standard endoscopy. In this study, the addition of NBI increased the detection of minor esophagitis and improved interobserver agreement. NBI with magnification endoscopy has also been used to study endoscopic changes associated with GERD. 16 NBI with magnification endoscopy of 115-fold was used to examine 30 patients with erosive esophagitis, 20 NERD patients, and 30 normal controls. The magnified NBI images were recorded. Several endoscopic features significantly associated with GERD were identified. Increased numbers of intrapapillary capillary loops (IPCLs) were identified in 66% of GERD patients compared with 13% of normal controls. Tortuous IPCLs were seen in 80% of GERD patients compared with 37% of controls. IPCLs were dilated in 80% of GERD patients versus 17% of controls. 64 US RADIOLOGY

4 Endoscopic Imaging of Gastroesophageal Reflux Disease Microerosions, or small breaks near the gastroesophageal junction not seen with standard endoscopy, were seen in 52% of GERD patients and no controls. Increased vascularity was seen in 40% of GERD patients and 7% of normal controls. The presence of columnar islands or a ridged or villous pattern just below the gastroesophageal junction was not significantly associated with GERD. Using multivariate analysis, an increased number or dilation of IPCLs or microerosions was the most sensitive and specific combination of factors for diagnosing GERD using NBI. endoscopic changes in GERD was high, and GERD changes were reliably identified in this study. These three studies show that NBI is a promising modality for identifying endoscopic features associated with GERD and NERD, as well as improving detection of ERD. The interobserver agreement for the findings in these studies was moderate to almost perfect, suggesting that NBI changes of GERD may be more easily identified by multiple observers than with other imaging modalities. Patients were also analyzed by subgroup. 16 Patients with ERD and patients with NERD were compared with normal controls. An increased number of IPCLs was seen in 73% of ERD patients, 55% of NERD patients, and 13% of controls. Tortuous IPCLs were seen in 87% of ERD patients, 70% of NERD patients, and 37% of controls. Dilated IPCLs were seen in 90% of ERD patients, 65% of NERD patients, and 17% of controls. Microerosions were present in 67% of ERD patients, 30% of NERD patients, and no controls. Individual IPCLs per imaging field were counted during the study and ROC analysis showed a higher number of IPCLs per screen in ERD versus NERD versus normal controls. ROC analysis, using a cut-off of 125 IPCLs, gave the most sensitive (82%) and specific (72%) diagnosis of GERD (see Table 3). Interobserver agreement for these findings ranged from moderate to almost perfect (κ= ) (see Table 2). Intraobserver agreement for these findings ranged from 0.39 to 0.52 (fair to moderate). This study identified several endoscopic features visible with NBI that are seen more frequently in GERD patients than controls. Endoscopic changes were more prominent in ERD than in NERD patients and the interobserver agreement for the findings was good. One other study of NBI in GERD used the NBI system with digital magnification that is more widely available to examine patients with GERD and asymptomatic controls. 17 ERD patients (n=41), NERD patients (n=36), and normal controls (n=30) were examined using NBI with 1.5-fold digital magnification. Microerosions, increased vascularity at the SCJ, and mucosal islands were more visible using NBI than standard endoscopy. Mucosal breaks and microerosions seen in 100% of ERD, 53% of NERD, and 23% of control patients were significantly different between groups. A significant difference was also seen in the endoscopic feature of increased SCJ vascularity, which was seen in 95% of ERD, 91.7% of NERD, and 36.7% of control patients. Pit patterns just below the SCJ in controls were more likely to be round (70%), while only 6% of NERD patients and 5% of ERD patients had round pit patterns. Increased vascularity of the SCJ and the absence of a round pit pattern had a sensitivity of 86%, specificity of 83%, positive predictive value of 86%, and negative predictive value of 83% for distinguishing NERD patients from controls (see Table 3). The only distinguishing characteristics between ERD and NERD were mucosal breaks and microerosions (100 versus 53%). Interobserver agreement was substantial for the presence of microerosions (κ=0.89) and increased vascularity of the SCJ (κ=0.95). Pit pattern type just below the SCJ showed moderate agreement, with a κ of 0.59, with substantial agreement for identification of round (κ=0.8) and villous (κ=0.82) pit types (see Table 2). Interobserver agreement for the Confocal Endomicroscopy Confocal endomicroscopy has also been used to evaluate patients with GERD symptoms. In one study, 68 patients with GERD symptoms underwent endomicroscopy 18 and 30 patients were identified as having NERD. Patients with NERD were more likely to have more than five capillary loops per imaging screen and the intracellular spaces were dilated to a width of >7μm. The presence of these two endomicroscopic features predicted histological findings of NERD with a sensitivity of 95%, specificity of 85%, and accuracy of 92% (see Table 3). Additional studies of endomicroscopy in GERD are ongoing. Conclusions New endoscopic developments have shown increased detection of ERD and subtle endoscopic findings of NERD not seen by standard endoscopy. The value of these technologies is as yet unclear, but they have the potential to change the management of GERD patients. Studies of GERD are hampered by the lack of a true gold standard, particularly in reference to NERD patients. Histology, ph testing, and response to proton-pump inhibitor therapy all have limitations when diagnosing GERD and NERD The majority of the studies in this article used postprocedure image review for diagnosis, so it is unclear how well the endoscopic changes identified will be incorporated into in vivo diagnosis and eventually standard endoscopic practice. There is significant variability in the technology available, such as magnification difference ranging from 1.5-fold to 150-fold, making technology comparisons challenging. There are also a wide range of potential endoscopic features suggestive of GERD and NERD. At this time, the interobserver agreement appears to be highest for several of the endoscopic features identified by NBI. It is currently not feasible to measure the width of intracellular spaces nor to count IPCLs during endoscopy, but additional technology improvements in image processing could some day automate this process. It is also unclear whether better detection of minor grades of esophagitis (Los Angeles grade A) will result in better outcomes for patients: will it help us determine who truly has GERD and needs proton-pump inhibitor therapy? Further study of these exciting new technologies is needed before they can be applied widely. New endoscopic technologies, however, hold promise for improved diagnosis and care of patients in the future. n Kerry B Dunbar, MD, is an Assistant Professor of Medicine in the Division of Gastroenterology and Hepatology at the Johns Hopkins University School of Medicine. She has received an American Society for Gastrointestinal Endoscopy (ASGE) Research Outcomes and Effectiveness Award and an American College of Gastroenterology (ACG) Clinical Research Award. Her research interests include endomicroscopy, novel imaging, Barrett s esophagus, and gastroesophageal reflux disease. US RADIOLOGY 65

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