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Patterns of gas and liquid reflux in patients with gastroesohageal reflux disease
Esophageal, Gastric, and Duodenal Disorders A289
April 1998 regimen. One-week triple therapy is efficient for healing duodenal ulcers. LAC15 therapy is an efficient, well tolerated and economical regimen for the treatment of outpatients. This study was supported in part by Takeda Pharma, Aachen, Germany. • Gl185
PATTERNS OF GAS AND LIQUID REFLUX IN PATIENTS WITH GASTROESOHAGEAL REFLUX DISEASE. D Sifrim, RH Holloway*, J Silny#, T Lerut, J Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium, *Dept Gastro-intestinal Medicine, Royal Adelaide Hospital, Adelaide, South Australia and #Helmoltz-Institute for Biomedical Engineering, Aachen, Germany. Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of reflux and gas in normal subjects prompting the notion that acid reflux during TLESRs may be a variant of the belch reflux. The presence of intraesophageal gas during reflux, however, has largely been inferred from manometry. We recently investigated reflux of gas and liquids in normal subjects using intraluminal electrical impedance and showed that gas was present in almost half of acid reflux episodes. Aim: to investigate the patterns of gas and liquid reflux using intraluminal electrical impedance in patients with reflux disease. Methods: We studied 10 patients with reflux disease (8M, 39-73 yrs) with erosive esophagitis (5), Barrett's esophagus (3) or abnormal pH monitoring (2). Ten healthy subjects (6M, 20-29-yrs) served as controls. Esophageal manometry, pH and intraluminal electrical impedance were recorded for 1/2 hr before and 2 hrs after a mixed nutrient meal (1000 kCal, 46% fat). Acid reflux was judged by the presence of a drop in pH of > 1 pH unit. Results: Patients with reflux disease had a higher rate of acid reflux episodes, a higher prevalence of pure liquid reflux and lower porportion of gas reflux than did controls. During mixed reflux, liquid commonly preceded gas in both groups, but significantly more so in the patients. The prevalence of gas and/or liquid reflux was not influenced by the presence of a hiatus hernia or the mechanism of reflux, and impedance patterns during TLESRs were similar in patients and controls. Acid reflux events (pH drops) Control (n = 60)
Pure liquid 14 (23%)
Reflux 67 (n= 170) (39%)* (* P < 0.05 vs control)
Gas ± Liquid 41 (68%) 73 (43%)*
Impedence patterns Mixed (liquid + gas) No. Gas ~ liquid Liquid -~ gas 36 14 19 (60%) (42%) (58%) 65 (38%)*
8 (12%)*
57 (88%) *
Conclusions: In patients with reflux disease: 1) the refluxate is more often liquid and contains gas less frequently than in controls and 2) when present together liquid almost always refluxes before gas. Acid reflux, therefore, occurs as a primary event and is not driven by reflux of gas. • Gl186
IN VITRO FUNCTION OF THE HUMAN LOWER ESOPHAGEAL SPHINCTER (LES) IN BARRET'S ESOPHAGUS. SD Staid, J. Dent and LA Blackshaw. Gastrointestinal Medicine, Royal Adelaide Hospital, Adelaide, South Australia 5000. Columnar-lined (Barrets) esophagus is often considered a sequel to severe reflux disease. Aberrant LES motility associated with Barrets esophagus includes reduced basal LES pressure and increased frequency of transient LES relaxations. Aim: to characterise neuromuscular function and tachykinin pharmacology of the LES in normal and Barrrets esophagus in vitro. Methods: Strips of LES muscle (mucosa removed) were prepared at biopsy following gastro-esophagectomy from 8 patients with squamnus cell carcinoma (control; mean age 66 years) and 4 patients with Barrets oesophagus (suspected adenocarcinoma indication for surgery; mean age 59 years). All Barrets patients had a history of reflux disease and only specimens that were free of malignancy were used. Muscle strips were mounted between square platinum electrodes and maintained in 10 ml organ baths containing carbogenated Krebs solution at 37°C. Following a 2g preload and 90 minute equilibration period LES muscle strips developed spontaneous tone and relaxed in response to electrical field stimulation (EFS). Smooth muscle responses were recorded in vitro to EFS (!-20 Hz), potassium chloride (KCI; 20 raM), DMPP (10 oM), tachykinins (substance P, [[3-AlaS]-neurokinin A 4-10 (NK-2 agonist), [succinyl-Asp 6, MePhe8]-substance P 6-11 (senktide; NK-3 agonist) and [Sat 9, Met (O2)ll]-substance P (NK-1 agonist), all 1 nM-1 taM). Results: Basal tension was reduced in the Burrers group (3.4 -+0.4g vs. 4.38 -+ 0.5g control; ns). EFS, DMPP and KCl-evoked relaxations were not significantly altered in LES muscle strips from the Buffets group. [[3-AlaS]Neurokinin A 4-10 also evoked similar dose-dependent contractions in LES muscle strips from the control and Barrets group. Substance P-mediated contractions were small in comparison (30% of maximal [[~-AlaS]-neurokinin A 4-10-evoked contraction), but were decreased overall in muscle strips from the Barrets group. [Sar9, Met (O2)ll]-Substance P and senktide were without effect on LES tone in vitro.
Conclusions: LES muscle strips from patients with Barrets esophagus exhibit
similar basal tone and functional inhibitory neural properties and demonstrate modest attenuation of substance P-mediated muscle contraction. NK-2 receptors predominate in the LES; no evidence for functional NK-1 or NK-3 receptors was demonstrated in human LES muscle strips in the present study. This research was supported by a grant from Astra Pharmaceuticals. Gl187 BARRETT'S OESOPIIAGUS: UNITED KINGDOM PHYSICIANS HAVE A WIDE VARIATION IN SURVEILLANCE PRACTICES. A. M. Smith, C. A. Maxwell - Armstrong, J. H. Scholefield. Department of Surgery, University Hospital, Nottingham, UK
Patients with Barrett's oesophagus are being offered endoscopic screening without evidence of efficacy for this type of follow-up. Barrett's oesophagus is not an ideal candidate for a screening programme, as the natural history is unclear, uncertainties surround the indicator for intervention and the treatment is associated with considerable morbidity and mortality. Aim. To determine the current practices that clinicians employ in the management of Barrett's oesophagus in the United Kingdom. Methods. Postal questionnaires were sent in May 1997 to 297 randomly selected members of the British Society of Gastroenterology asking their current practice. Results. Of 152 respondents, 106 (66.9%) performed Barrett's surveillance, 46 (30.3%) did not carry out screening. There was no difference in the practices carried out by physicians or surgeons, teaching or district general hospital clinicians or those with an upper gastrointestinal interest. There is a wide disparity in screening interval, just over half screen at yearly intervals (51.9%). Only 4 (3.8%) took 4 quadrant biopsies per centimetre of Barrett's. 45% clinicians manage mild dysplasia by increasing the frequency of endoscopy, only 7 (6.5%) placed patients on a proton pump inhibitor. Faced with severe dysplasia, 33 (31%) offered surgery immediately, 22 (20.7%) simply followed the patient by endoscopy. Those not choosing to perform screening most frequently cited lack of evidence of efficacy as the reason behind their decision. Conclusions. There is a wide variation in surveillance practices for Barrett's oesophagus. Some methods are clearly ineffectual. Guidelines based on available evidence and a consensus of expert opinion should be established, this was suggested by 38% of respondents who performed screening. Introduction.
• Gl188
CATALASE AND GLUTATHIONE PEROXIDASE ACTIVITY IN AGS CELLS IS ALTERED BY EXPOSURE TO cagA-NEGATIVE AND cagAPOSITIVE H. PYLORI STRAINS. D.T. Smoot, D. Jones, T. Elliott, C.R. Allen, H. Ashktorab. G.I. Division, Department of Medicine and Cancer Center, Howard University, Washington, D.C. 20060
fl. pylori infection of the gastric mucosa is associated with increased mucosal reactive oxygen species. Reactive oxygen species (ROS) have been implicated in gastric carcinogenesis and the interactions between H. pylori and reactive oxygen is not yet known. We recently showed that incubation of H. pylori with gastric epithelial cells increases their susceptibility to reactive oxygen induced cell injury; however, gastric cells exposed to cagA-neg H. pylori strains (cell viability: 39.5% of controls) were more susceptible to reactive oxygen cell injury than when exposed to cagA-pos H. pylori strains (cell viability: 73.7% of controls). The following study was conducted to determine if H. pylori impaired the activity of two oxygen scavenging enzymes (catalase & glutathione peroxidase) which protect cells from hydrogen peroxide. Methods: AGS cells grown on 96-well clusters were exposed overnight to H. pylori (3 cagA-pos & 3 cagA-neg strains) at a concentration of 100 bac/gastrlc cell. AGS cells not exposed to H. pylori served as controls. Afterwards, soluble cell protein was extracted and assayed for catalase and glutatbione peroxidase (GPx) activity. Results: Overnight exposure to cagA-neg H. pylori strains reduced catalase activity by 41% while exposure to cagA-pos [-1.pylori strains increased catalase activity by 50%. GPx activity increased with exposure to both cagA-neg and cagA-pos strains by 195% and 340%, respectively. Conclusion: These data suggest that the reduction in catalase activity with only a modest increase in GPx activity contributes to the increased susceptibility of AGS cells to ROS after exposure to cagA-neg H. pylori strains as compared with exposure to cagA-pos H. pylori strains. The increase in enzyme activities associated with exposure to cagA-pos H. pylori strains may be a result of increased generation of intracellular hydrogen peroxide (H202) from metabolism of toxins present in H. pylori strains with the cag pathogenicity island. This relative improvement in gastric cell survival associated with exposure to cagA-pos H. pylori strains in the presence of ROS may increase the risk of DNA damage which may lead to gastric cancer; one possible explanation for the strong association between cagA-pos H. pylori strains and gastric cancer. This study was supported by grant #CA68994 from the NCI, NIH, PHS.
April 1998 regimen. One-week triple therapy is efficient for healing duodenal ulcers. LAC15 therapy is an efficient, well tolerated and economical regimen for the treatment of outpatients. This study was supported in part by Takeda Pharma, Aachen, Germany. • Gl185
PATTERNS OF GAS AND LIQUID REFLUX IN PATIENTS WITH GASTROESOHAGEAL REFLUX DISEASE. D Sifrim, RH Holloway*, J Silny#, T Lerut, J Janssens. Center for Gastroenterological Research, K.U. Leuven, Belgium, *Dept Gastro-intestinal Medicine, Royal Adelaide Hospital, Adelaide, South Australia and #Helmoltz-Institute for Biomedical Engineering, Aachen, Germany. Transient lower esophageal sphincter relaxation (TLESR) is the major mechanism of reflux and gas in normal subjects prompting the notion that acid reflux during TLESRs may be a variant of the belch reflux. The presence of intraesophageal gas during reflux, however, has largely been inferred from manometry. We recently investigated reflux of gas and liquids in normal subjects using intraluminal electrical impedance and showed that gas was present in almost half of acid reflux episodes. Aim: to investigate the patterns of gas and liquid reflux using intraluminal electrical impedance in patients with reflux disease. Methods: We studied 10 patients with reflux disease (8M, 39-73 yrs) with erosive esophagitis (5), Barrett's esophagus (3) or abnormal pH monitoring (2). Ten healthy subjects (6M, 20-29-yrs) served as controls. Esophageal manometry, pH and intraluminal electrical impedance were recorded for 1/2 hr before and 2 hrs after a mixed nutrient meal (1000 kCal, 46% fat). Acid reflux was judged by the presence of a drop in pH of > 1 pH unit. Results: Patients with reflux disease had a higher rate of acid reflux episodes, a higher prevalence of pure liquid reflux and lower porportion of gas reflux than did controls. During mixed reflux, liquid commonly preceded gas in both groups, but significantly more so in the patients. The prevalence of gas and/or liquid reflux was not influenced by the presence of a hiatus hernia or the mechanism of reflux, and impedance patterns during TLESRs were similar in patients and controls. Acid reflux events (pH drops) Control (n = 60)
Pure liquid 14 (23%)
Reflux 67 (n= 170) (39%)* (* P < 0.05 vs control)
Gas ± Liquid 41 (68%) 73 (43%)*
Impedence patterns Mixed (liquid + gas) No. Gas ~ liquid Liquid -~ gas 36 14 19 (60%) (42%) (58%) 65 (38%)*
8 (12%)*
57 (88%) *
Conclusions: In patients with reflux disease: 1) the refluxate is more often liquid and contains gas less frequently than in controls and 2) when present together liquid almost always refluxes before gas. Acid reflux, therefore, occurs as a primary event and is not driven by reflux of gas. • Gl186
IN VITRO FUNCTION OF THE HUMAN LOWER ESOPHAGEAL SPHINCTER (LES) IN BARRET'S ESOPHAGUS. SD Staid, J. Dent and LA Blackshaw. Gastrointestinal Medicine, Royal Adelaide Hospital, Adelaide, South Australia 5000. Columnar-lined (Barrets) esophagus is often considered a sequel to severe reflux disease. Aberrant LES motility associated with Barrets esophagus includes reduced basal LES pressure and increased frequency of transient LES relaxations. Aim: to characterise neuromuscular function and tachykinin pharmacology of the LES in normal and Barrrets esophagus in vitro. Methods: Strips of LES muscle (mucosa removed) were prepared at biopsy following gastro-esophagectomy from 8 patients with squamnus cell carcinoma (control; mean age 66 years) and 4 patients with Barrets oesophagus (suspected adenocarcinoma indication for surgery; mean age 59 years). All Barrets patients had a history of reflux disease and only specimens that were free of malignancy were used. Muscle strips were mounted between square platinum electrodes and maintained in 10 ml organ baths containing carbogenated Krebs solution at 37°C. Following a 2g preload and 90 minute equilibration period LES muscle strips developed spontaneous tone and relaxed in response to electrical field stimulation (EFS). Smooth muscle responses were recorded in vitro to EFS (!-20 Hz), potassium chloride (KCI; 20 raM), DMPP (10 oM), tachykinins (substance P, [[3-AlaS]-neurokinin A 4-10 (NK-2 agonist), [succinyl-Asp 6, MePhe8]-substance P 6-11 (senktide; NK-3 agonist) and [Sat 9, Met (O2)ll]-substance P (NK-1 agonist), all 1 nM-1 taM). Results: Basal tension was reduced in the Burrers group (3.4 -+0.4g vs. 4.38 -+ 0.5g control; ns). EFS, DMPP and KCl-evoked relaxations were not significantly altered in LES muscle strips from the Buffets group. [[3-AlaS]Neurokinin A 4-10 also evoked similar dose-dependent contractions in LES muscle strips from the control and Barrets group. Substance P-mediated contractions were small in comparison (30% of maximal [[~-AlaS]-neurokinin A 4-10-evoked contraction), but were decreased overall in muscle strips from the Barrets group. [Sar9, Met (O2)ll]-Substance P and senktide were without effect on LES tone in vitro.
Conclusions: LES muscle strips from patients with Barrets esophagus exhibit
similar basal tone and functional inhibitory neural properties and demonstrate modest attenuation of substance P-mediated muscle contraction. NK-2 receptors predominate in the LES; no evidence for functional NK-1 or NK-3 receptors was demonstrated in human LES muscle strips in the present study. This research was supported by a grant from Astra Pharmaceuticals. Gl187 BARRETT'S OESOPIIAGUS: UNITED KINGDOM PHYSICIANS HAVE A WIDE VARIATION IN SURVEILLANCE PRACTICES. A. M. Smith, C. A. Maxwell - Armstrong, J. H. Scholefield. Department of Surgery, University Hospital, Nottingham, UK
Patients with Barrett's oesophagus are being offered endoscopic screening without evidence of efficacy for this type of follow-up. Barrett's oesophagus is not an ideal candidate for a screening programme, as the natural history is unclear, uncertainties surround the indicator for intervention and the treatment is associated with considerable morbidity and mortality. Aim. To determine the current practices that clinicians employ in the management of Barrett's oesophagus in the United Kingdom. Methods. Postal questionnaires were sent in May 1997 to 297 randomly selected members of the British Society of Gastroenterology asking their current practice. Results. Of 152 respondents, 106 (66.9%) performed Barrett's surveillance, 46 (30.3%) did not carry out screening. There was no difference in the practices carried out by physicians or surgeons, teaching or district general hospital clinicians or those with an upper gastrointestinal interest. There is a wide disparity in screening interval, just over half screen at yearly intervals (51.9%). Only 4 (3.8%) took 4 quadrant biopsies per centimetre of Barrett's. 45% clinicians manage mild dysplasia by increasing the frequency of endoscopy, only 7 (6.5%) placed patients on a proton pump inhibitor. Faced with severe dysplasia, 33 (31%) offered surgery immediately, 22 (20.7%) simply followed the patient by endoscopy. Those not choosing to perform screening most frequently cited lack of evidence of efficacy as the reason behind their decision. Conclusions. There is a wide variation in surveillance practices for Barrett's oesophagus. Some methods are clearly ineffectual. Guidelines based on available evidence and a consensus of expert opinion should be established, this was suggested by 38% of respondents who performed screening. Introduction.
• Gl188
CATALASE AND GLUTATHIONE PEROXIDASE ACTIVITY IN AGS CELLS IS ALTERED BY EXPOSURE TO cagA-NEGATIVE AND cagAPOSITIVE H. PYLORI STRAINS. D.T. Smoot, D. Jones, T. Elliott, C.R. Allen, H. Ashktorab. G.I. Division, Department of Medicine and Cancer Center, Howard University, Washington, D.C. 20060
fl. pylori infection of the gastric mucosa is associated with increased mucosal reactive oxygen species. Reactive oxygen species (ROS) have been implicated in gastric carcinogenesis and the interactions between H. pylori and reactive oxygen is not yet known. We recently showed that incubation of H. pylori with gastric epithelial cells increases their susceptibility to reactive oxygen induced cell injury; however, gastric cells exposed to cagA-neg H. pylori strains (cell viability: 39.5% of controls) were more susceptible to reactive oxygen cell injury than when exposed to cagA-pos H. pylori strains (cell viability: 73.7% of controls). The following study was conducted to determine if H. pylori impaired the activity of two oxygen scavenging enzymes (catalase & glutathione peroxidase) which protect cells from hydrogen peroxide. Methods: AGS cells grown on 96-well clusters were exposed overnight to H. pylori (3 cagA-pos & 3 cagA-neg strains) at a concentration of 100 bac/gastrlc cell. AGS cells not exposed to H. pylori served as controls. Afterwards, soluble cell protein was extracted and assayed for catalase and glutatbione peroxidase (GPx) activity. Results: Overnight exposure to cagA-neg H. pylori strains reduced catalase activity by 41% while exposure to cagA-pos [-1.pylori strains increased catalase activity by 50%. GPx activity increased with exposure to both cagA-neg and cagA-pos strains by 195% and 340%, respectively. Conclusion: These data suggest that the reduction in catalase activity with only a modest increase in GPx activity contributes to the increased susceptibility of AGS cells to ROS after exposure to cagA-neg H. pylori strains as compared with exposure to cagA-pos H. pylori strains. The increase in enzyme activities associated with exposure to cagA-pos H. pylori strains may be a result of increased generation of intracellular hydrogen peroxide (H202) from metabolism of toxins present in H. pylori strains with the cag pathogenicity island. This relative improvement in gastric cell survival associated with exposure to cagA-pos H. pylori strains in the presence of ROS may increase the risk of DNA damage which may lead to gastric cancer; one possible explanation for the strong association between cagA-pos H. pylori strains and gastric cancer. This study was supported by grant #CA68994 from the NCI, NIH, PHS.