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Su1109 Dysphagia in patients with Non-Erosive Gastro-Esophageal Reflux Disease (NERD)
statements for management of Barrett's dysplasia and early-stage esophageal adenocarcinoma, based on a Delphi process. Gastroenterology. 2012;143(2):336-346.
AGA Abstracts
Su1108 Reflux Esophagitis (RE) Patients Showed a More Rapid Worsening of Clinical Parameters Associated With Lifestyle Diseases Compared With Non-RE Subjects for Years Before RE Onset Takeshi Kamiya, Yuzuru Toki, Ryo Yamauchi, Eizo Kayashima, Kiyohiko Kishi, Hiroshi Suetsugu, Tsuneya Wada, Hiroyoshi Endo, Hajime Yamada, Satoshi Osaga, Koji Nakada, Katsuhiko Iwakiri, Ken Haruma, Takashi Joh, Kyoichi Adachi Background: Although risk factors of reflux esophagitis (RE) have been investigated in numerous cross-sectional studies, little is known about predictive factors associated with future onset of RE. We investigated time courses of clinical parameters before RE onset by a longitudinal case-control study using long-term health checkup records. Methods: We used health checkup records between April 2004 and March 2014 at nine institutions in Japan. Subjects who were newly diagnosed as RE between April 2009 and March 2014 were included in the analysis as case subjects. For each case subject, two subjects who had no RE diagnosis between April 2004 and March 2014 and were matched for age, sex, and participating institutions with the corresponding case were included as control subjects. The time courses of clinical parameters of case group were compared with those of control group by the restricted maximum likelihood method for repeated measures or multivariate logistic analysis. We also implemented cross-sectional comparisons for each of the five years prior to RE onset. Results: Initial data were obtained from 230,056 individuals, and 2,066 case subjects and 4,132 control subjects were included in the analysis. The time courses of body mass index (BMI) (p < 0.001), abdominal circumference (AC) (p < 0.001), fasting blood sugar (FBS) (p = 0.039), serum triglyceride (TG) (p = 0.010), glutamate oxaloacetate transaminase (p = 0.044), glutamic pyruvic transaminase (GPT) (p = 0.005), g-glutamyl transpeptidase (p < 0.001), and percentages with acid reflux symptoms (p =0.004), feeling of fullness (p = 0.019), and hiatal hernia (p < 0.001) in the case group were significantly worse than in the control group. In cross-sectional comparisons at the year of RE onset, BMI (p < 0.001), AC (p < 0.001), FBS (p = 0.006), systolic blood pressure (p = 0.011), TG (p < 0.001), uric acid (p = 0.002), GOT (p < 0.001), GPT (p < 0.001), g-GTP (p < 0.001), amount of alcohol (p < 0.001), smoking (p = 0.008), and percentage with acid reflux symptoms (p <0.001), feeling of fullness (p = 0.046), hiatal hernia (p < 0.001), hypertension (p = 0.003), and hyperlipidemia (p = 0.044) in the case group were higher than in the control group, and high-density lipoprotein cholesterol (p = 0.007) and percentage with atrophic gastritis (p < 0.001) in the case group were lower. Among them, BMI, AC, TG, GPT, and percentages with acid reflux symptoms and atrophic gastritis showed significant differences for five years prior to RE onset consecutively between the groups. Conclusions: The RE group displayed a more rapid worsening of the clinical parameters associated with lifestyle diseases, including obesity, diabetes, hyperlipidemia, and fatty liver compared with the non-RE group. These results suggest that RE is a lifestyle disease and thus lifestyle guidance may help to prevent RE onset.
Su1110 Intramucosal IgG4 Expression in Patients With Gastroesophageal Reflux Disease Huaibin M. Ko, Hongfa Zhu, Noam Harpaz INTRODUCTION: Tissue expression of IgG4 is associated with a variety of fibrosing disorders. Granular extracellular deposition of IgG4 in the esophageal squamous epithelium (SE) has been reported in 88% of patients with eosinophilic esophagitis (EoE) (Clayton et al., Gastroenterol. 2014; 147:602-9) and may play a role in the development of its fibrotic complications. We have previously confirmed this finding and also demonstrated a close correlation between SE IgG4 and density of IgG4 positive lamina propria plasma cells (LPPCs) (Ko et al., Gastroenterol. 2015;148:S414). Since increased eosinophils occur in GERD as well as in EoE, IgG4 expression in EoE has recently been proposed as a discriminating feature of EoE for diagnostic purposes (Zuckerberg et al, Histopathology, 2015; 10.1111/ his.12892). We therefore evaluated IgG4 deposition in a series of patients with GERD. MATERIALS & METHODS: Esophageal biopsies of 17 consecutive adult patients (8M, 9F; mean age 50.6y) with an established clinical diagnosis of GERD and no clinical or endoscopic suspicion of EoE underwent immunohistochemical staining for MUM1, CD138, and IgG4. The biopsies were evaluated for: (1) fraction of the total area of squamous epithelium containing granular extracellular IgG4+ deposits (negative, <5%; focal, 5-10%; positive, >10%) and (2) density of IgG4 positive LPPCs (negative, <10/HPF; positive >10/ HPF). Available corresponding cardiac mucosa was also evaluated for the presence of IgG4 positive LPPCs. Peak eosinophil densities were determined by manual count. RESULTS: Of the 17 patients with GERD, 3 were positive for SE IgG4 (17.6%). Compared to negative patients, these patients were older (64y vs. 48y, P<0.05), but there were no corresponding differences in peak eosinophil densities (3.67/HPF vs. 7.23/HPF, P=0.99). IgG4 was expressed in the cardiac mucosa in 5/9 patients with GERD (56%) but only 2 were positive and 3 negative for SE IgG4. None of the patients with SE or cardiac IgG4 expression had clinical evidence of stricture. CONCLUSION: IgG4 expression, which occurs frequently in EoE, also occurs in a subset of patients with GERD alone and therefore may not be useful in distinguishing between the two disorders. Cardiac IgG4 expression also occurs in patients with GERD but seems to be independent of its expression in SE. The clinical and pathogenetic significance of IgG4 expression in GERD and EoE remains an enigma.
Su1109 Dysphagia in patients with Non-Erosive Gastro-Esophageal Reflux Disease (NERD) Kornilia Nikaki, Joanne L. Ooi, Yasmin Soozandehfar, Philip Woodland, Daniel Sifrim
Su1111
Background/Aims: Dysphagia is commonly reported by patients with NERD. In the absence of mechanical obstruction or erosions, the mechanism underlying dysphagia in NERD is not clear. Impaired oesophageal motility with delayed bolus clearance, increased resistance at the OGJ or impairment of mucosal integrity could potentially underlie this symptom. The aim of this study was to evaluate these potential causes of dysphagia in patients with "true NERD" (endoscopy negative and increased acid exposure). Methods: All adult patients, presenting to the Upper GI Physiology unit between January 2014 and October 2015, with typical GERD symptoms, normal upper GI endoscopy, increased acid exposure time (>4.2%), without major manometric abnormalities and without structural, systemic or neurologic abnormalities were included. Patients were divided in two groups based on the presence or absence of dysphagia. A composite dysphagia score (Dakkak and Bennett 1992) was prospectively recorded (from 0 to 45). Motility was evaluated using HRM and Chicago classification 2015. Bolus clearance was assessed from the 24h pH-impedance monitoring using the bolus exposure time and the post-reflux peristaltic wave (PSPW) score. Mucosal integrity was evaluated using Mean Nocturnal Baseline Impedance (MNBI). Results: Out of the 76 eligible patients, 17 patients (8M:9F) with typical GERD and dysphagia symptoms (Group A) and 26 patients (15M:11F) with GERD only symptoms (Group B) fulfilled the inclusion criteria. The mean age for both groups was 49 years (NS difference). There was no statistically significant difference in acid exposure time and number of reflux episodes between groups. The median composite dysphagia score for Group A was 19.5 (range 3.545). Minor abnormalities of oesophageal motility (i.e. ineffective motility and fragmented peristalsis) were identified in 10/17 patients from Group A and 12/26 patients from Group B (P>0.05). The median IRP was 6 mmHg in group A and 7mmHg in group B (NS). There was no statistically significant difference in the bolus exposure time and PSPW index. Mucosal integrity evaluated with baseline impedance (MNBI) was slightly low in the distal esophagus, without difference between groups. MNBI in the proximal esophagus was normal and not different between groups (Table). Conclusion: 40% of our selected patients with "true NERD" (endoscopy negative and increased acid exposure) reported dysphagia, with the majority of patients reporting moderately severe symptoms. Impairment of oesophageal motility, bolus clearance and mucosal integrity do not seem to explain the pathophysiology of dysphagia in these patients. Esophageal hypersensitivity to mechanical stimulation and/ or hypervigilance remained as potential causes of dysphagia in patients with NERD.
AGA Abstracts
Relative Intercellular Space Area in Gastroesophageal Reflux Disease: A New Standardized Method for the Evaluation of the Intercellular Space Diameter Nicolaas F. Rinsma, Liyanne Laarschot van de, José M. Conchillo, Ad Masclee, Ricard Farré Background: Dilation of intercellular spaces (DIS) in esophageal mucosa is considered as an early histological marker for impaired mucosal integrity in patients with gastroesophageal reflux disease (GERD). Evaluation of intercellular space diameter (ISD) in esophageal biopsies is classically performed by placement of 10 random transects in 10 transmission electron microscopy (TEM) photographs per subject. This method is time consuming and the randomly placed transects may not take the irregularity of the delineation of the intercellular space fully into account. In the present study we present the "relative intercellular space area" as an alternative method for the evaluation of ISD and compare it to the classical method. Methods: 21 patients with chronic GERD (13 male, mean age 54 (range 28-77) and 10 healthy controls (5 male, mean age 35 (range 21-65)) were enrolled. Esophageal biopsies from macroscopically normal mucosa were obtained during endoscopy at 5 cm above the gastroesophageal junction and prepared for TEM. Of each biopsy 10 TEMphotographs were obtained from the basal layer of the epithelium by an independent researcher. ISD was assessed in 10 TEM-photographs per subject using the classical (ISDc) method and in 3 TEM-photographs using the alternative (ISDa) method by two investigators that worked independently of each other. ISDa was assessed by measuring the area of the intercellular space around the cells divided by its corresponding length, using customwritten image analysis software in IGOR Pro (WaveMetrics Inc., Oregon, USA) (Figure 1). Correlation of ISD values obtained with both methods as well as intra- and interobserver agreement were evaluated. Results: ISDa-values showed a high correlation with corresponding ISDc-values (r:0.81, p<0.001). However, ISDc-values were significantly larger when compared to ISDa-values (1.35 µm ± 0.05 vs. 0.90 µm ± 0.04, p<0.001). Both methods showed an excellent intraobserver agreement, with comparable K-values (ISDa: 0.91 and ISDc: 0.92). Interobserver agreement of both methods was good, with comparable K-values (ISDa: 0.81 and ISDc 0.80). The analysis per microphotograph using the ISDa method was more time consuming when compared to ISDc (ISDa: 119 s ± 8 vs. ISDc: 63 s ± 2, p<0.001). However, when comparing the time consumption of the analysis of the mandatory 10 microphotographs per subject with ISDc versus 3 microphotographs with ISDa, the latter is less time consuming (ISDa: 350 s ± 13 vs. ISDc: 628 s ± 15, p<0.001). Conclusion: Evaluation of the intercellular space diameter using the relative intercellular space area showed a high intra- and interobserver agreement and a strong correlation with ISD values
S-472
AGA Abstracts
Su1108 Reflux Esophagitis (RE) Patients Showed a More Rapid Worsening of Clinical Parameters Associated With Lifestyle Diseases Compared With Non-RE Subjects for Years Before RE Onset Takeshi Kamiya, Yuzuru Toki, Ryo Yamauchi, Eizo Kayashima, Kiyohiko Kishi, Hiroshi Suetsugu, Tsuneya Wada, Hiroyoshi Endo, Hajime Yamada, Satoshi Osaga, Koji Nakada, Katsuhiko Iwakiri, Ken Haruma, Takashi Joh, Kyoichi Adachi Background: Although risk factors of reflux esophagitis (RE) have been investigated in numerous cross-sectional studies, little is known about predictive factors associated with future onset of RE. We investigated time courses of clinical parameters before RE onset by a longitudinal case-control study using long-term health checkup records. Methods: We used health checkup records between April 2004 and March 2014 at nine institutions in Japan. Subjects who were newly diagnosed as RE between April 2009 and March 2014 were included in the analysis as case subjects. For each case subject, two subjects who had no RE diagnosis between April 2004 and March 2014 and were matched for age, sex, and participating institutions with the corresponding case were included as control subjects. The time courses of clinical parameters of case group were compared with those of control group by the restricted maximum likelihood method for repeated measures or multivariate logistic analysis. We also implemented cross-sectional comparisons for each of the five years prior to RE onset. Results: Initial data were obtained from 230,056 individuals, and 2,066 case subjects and 4,132 control subjects were included in the analysis. The time courses of body mass index (BMI) (p < 0.001), abdominal circumference (AC) (p < 0.001), fasting blood sugar (FBS) (p = 0.039), serum triglyceride (TG) (p = 0.010), glutamate oxaloacetate transaminase (p = 0.044), glutamic pyruvic transaminase (GPT) (p = 0.005), g-glutamyl transpeptidase (p < 0.001), and percentages with acid reflux symptoms (p =0.004), feeling of fullness (p = 0.019), and hiatal hernia (p < 0.001) in the case group were significantly worse than in the control group. In cross-sectional comparisons at the year of RE onset, BMI (p < 0.001), AC (p < 0.001), FBS (p = 0.006), systolic blood pressure (p = 0.011), TG (p < 0.001), uric acid (p = 0.002), GOT (p < 0.001), GPT (p < 0.001), g-GTP (p < 0.001), amount of alcohol (p < 0.001), smoking (p = 0.008), and percentage with acid reflux symptoms (p <0.001), feeling of fullness (p = 0.046), hiatal hernia (p < 0.001), hypertension (p = 0.003), and hyperlipidemia (p = 0.044) in the case group were higher than in the control group, and high-density lipoprotein cholesterol (p = 0.007) and percentage with atrophic gastritis (p < 0.001) in the case group were lower. Among them, BMI, AC, TG, GPT, and percentages with acid reflux symptoms and atrophic gastritis showed significant differences for five years prior to RE onset consecutively between the groups. Conclusions: The RE group displayed a more rapid worsening of the clinical parameters associated with lifestyle diseases, including obesity, diabetes, hyperlipidemia, and fatty liver compared with the non-RE group. These results suggest that RE is a lifestyle disease and thus lifestyle guidance may help to prevent RE onset.
Su1110 Intramucosal IgG4 Expression in Patients With Gastroesophageal Reflux Disease Huaibin M. Ko, Hongfa Zhu, Noam Harpaz INTRODUCTION: Tissue expression of IgG4 is associated with a variety of fibrosing disorders. Granular extracellular deposition of IgG4 in the esophageal squamous epithelium (SE) has been reported in 88% of patients with eosinophilic esophagitis (EoE) (Clayton et al., Gastroenterol. 2014; 147:602-9) and may play a role in the development of its fibrotic complications. We have previously confirmed this finding and also demonstrated a close correlation between SE IgG4 and density of IgG4 positive lamina propria plasma cells (LPPCs) (Ko et al., Gastroenterol. 2015;148:S414). Since increased eosinophils occur in GERD as well as in EoE, IgG4 expression in EoE has recently been proposed as a discriminating feature of EoE for diagnostic purposes (Zuckerberg et al, Histopathology, 2015; 10.1111/ his.12892). We therefore evaluated IgG4 deposition in a series of patients with GERD. MATERIALS & METHODS: Esophageal biopsies of 17 consecutive adult patients (8M, 9F; mean age 50.6y) with an established clinical diagnosis of GERD and no clinical or endoscopic suspicion of EoE underwent immunohistochemical staining for MUM1, CD138, and IgG4. The biopsies were evaluated for: (1) fraction of the total area of squamous epithelium containing granular extracellular IgG4+ deposits (negative, <5%; focal, 5-10%; positive, >10%) and (2) density of IgG4 positive LPPCs (negative, <10/HPF; positive >10/ HPF). Available corresponding cardiac mucosa was also evaluated for the presence of IgG4 positive LPPCs. Peak eosinophil densities were determined by manual count. RESULTS: Of the 17 patients with GERD, 3 were positive for SE IgG4 (17.6%). Compared to negative patients, these patients were older (64y vs. 48y, P<0.05), but there were no corresponding differences in peak eosinophil densities (3.67/HPF vs. 7.23/HPF, P=0.99). IgG4 was expressed in the cardiac mucosa in 5/9 patients with GERD (56%) but only 2 were positive and 3 negative for SE IgG4. None of the patients with SE or cardiac IgG4 expression had clinical evidence of stricture. CONCLUSION: IgG4 expression, which occurs frequently in EoE, also occurs in a subset of patients with GERD alone and therefore may not be useful in distinguishing between the two disorders. Cardiac IgG4 expression also occurs in patients with GERD but seems to be independent of its expression in SE. The clinical and pathogenetic significance of IgG4 expression in GERD and EoE remains an enigma.
Su1109 Dysphagia in patients with Non-Erosive Gastro-Esophageal Reflux Disease (NERD) Kornilia Nikaki, Joanne L. Ooi, Yasmin Soozandehfar, Philip Woodland, Daniel Sifrim
Su1111
Background/Aims: Dysphagia is commonly reported by patients with NERD. In the absence of mechanical obstruction or erosions, the mechanism underlying dysphagia in NERD is not clear. Impaired oesophageal motility with delayed bolus clearance, increased resistance at the OGJ or impairment of mucosal integrity could potentially underlie this symptom. The aim of this study was to evaluate these potential causes of dysphagia in patients with "true NERD" (endoscopy negative and increased acid exposure). Methods: All adult patients, presenting to the Upper GI Physiology unit between January 2014 and October 2015, with typical GERD symptoms, normal upper GI endoscopy, increased acid exposure time (>4.2%), without major manometric abnormalities and without structural, systemic or neurologic abnormalities were included. Patients were divided in two groups based on the presence or absence of dysphagia. A composite dysphagia score (Dakkak and Bennett 1992) was prospectively recorded (from 0 to 45). Motility was evaluated using HRM and Chicago classification 2015. Bolus clearance was assessed from the 24h pH-impedance monitoring using the bolus exposure time and the post-reflux peristaltic wave (PSPW) score. Mucosal integrity was evaluated using Mean Nocturnal Baseline Impedance (MNBI). Results: Out of the 76 eligible patients, 17 patients (8M:9F) with typical GERD and dysphagia symptoms (Group A) and 26 patients (15M:11F) with GERD only symptoms (Group B) fulfilled the inclusion criteria. The mean age for both groups was 49 years (NS difference). There was no statistically significant difference in acid exposure time and number of reflux episodes between groups. The median composite dysphagia score for Group A was 19.5 (range 3.545). Minor abnormalities of oesophageal motility (i.e. ineffective motility and fragmented peristalsis) were identified in 10/17 patients from Group A and 12/26 patients from Group B (P>0.05). The median IRP was 6 mmHg in group A and 7mmHg in group B (NS). There was no statistically significant difference in the bolus exposure time and PSPW index. Mucosal integrity evaluated with baseline impedance (MNBI) was slightly low in the distal esophagus, without difference between groups. MNBI in the proximal esophagus was normal and not different between groups (Table). Conclusion: 40% of our selected patients with "true NERD" (endoscopy negative and increased acid exposure) reported dysphagia, with the majority of patients reporting moderately severe symptoms. Impairment of oesophageal motility, bolus clearance and mucosal integrity do not seem to explain the pathophysiology of dysphagia in these patients. Esophageal hypersensitivity to mechanical stimulation and/ or hypervigilance remained as potential causes of dysphagia in patients with NERD.
AGA Abstracts
Relative Intercellular Space Area in Gastroesophageal Reflux Disease: A New Standardized Method for the Evaluation of the Intercellular Space Diameter Nicolaas F. Rinsma, Liyanne Laarschot van de, José M. Conchillo, Ad Masclee, Ricard Farré Background: Dilation of intercellular spaces (DIS) in esophageal mucosa is considered as an early histological marker for impaired mucosal integrity in patients with gastroesophageal reflux disease (GERD). Evaluation of intercellular space diameter (ISD) in esophageal biopsies is classically performed by placement of 10 random transects in 10 transmission electron microscopy (TEM) photographs per subject. This method is time consuming and the randomly placed transects may not take the irregularity of the delineation of the intercellular space fully into account. In the present study we present the "relative intercellular space area" as an alternative method for the evaluation of ISD and compare it to the classical method. Methods: 21 patients with chronic GERD (13 male, mean age 54 (range 28-77) and 10 healthy controls (5 male, mean age 35 (range 21-65)) were enrolled. Esophageal biopsies from macroscopically normal mucosa were obtained during endoscopy at 5 cm above the gastroesophageal junction and prepared for TEM. Of each biopsy 10 TEMphotographs were obtained from the basal layer of the epithelium by an independent researcher. ISD was assessed in 10 TEM-photographs per subject using the classical (ISDc) method and in 3 TEM-photographs using the alternative (ISDa) method by two investigators that worked independently of each other. ISDa was assessed by measuring the area of the intercellular space around the cells divided by its corresponding length, using customwritten image analysis software in IGOR Pro (WaveMetrics Inc., Oregon, USA) (Figure 1). Correlation of ISD values obtained with both methods as well as intra- and interobserver agreement were evaluated. Results: ISDa-values showed a high correlation with corresponding ISDc-values (r:0.81, p<0.001). However, ISDc-values were significantly larger when compared to ISDa-values (1.35 µm ± 0.05 vs. 0.90 µm ± 0.04, p<0.001). Both methods showed an excellent intraobserver agreement, with comparable K-values (ISDa: 0.91 and ISDc: 0.92). Interobserver agreement of both methods was good, with comparable K-values (ISDa: 0.81 and ISDc 0.80). The analysis per microphotograph using the ISDa method was more time consuming when compared to ISDc (ISDa: 119 s ± 8 vs. ISDc: 63 s ± 2, p<0.001). However, when comparing the time consumption of the analysis of the mandatory 10 microphotographs per subject with ISDc versus 3 microphotographs with ISDa, the latter is less time consuming (ISDa: 350 s ± 13 vs. ISDc: 628 s ± 15, p<0.001). Conclusion: Evaluation of the intercellular space diameter using the relative intercellular space area showed a high intra- and interobserver agreement and a strong correlation with ISD values
S-472