- Email: [email protected]
Lower esophageal sphincter resting pressure and esophageal acid and bile exposure in patients with short and long segment Barrett's esophagus
A170 AGAABSTRACTS • G0694 AGGRAVATION OF INDOMETHACIN-1NDUCED GASTRIC MUCOSAL LESIONS IN ADJUVANT ARTHRITIC RATS. S. Kato, A. Tanaka, A. Konaka, K. Takeuchi, Department of Pharmacology & Experimental Therapeutics, Kyoto Pharmaceutical University, Yamashina, Kyoto, Japan. Gastroenteropathy is the most common among patients who used nonsteroidal antiinflammatory drugs (NSAIDs) for treatment of arthritis. In particular, the patients with rheumatoid arthritis have been reported to be more susceptible to NSAID-induced gastric ulcers than other NSAID users. The purpose of the present study was 1) to examine whether or not the gastric mucosal lesions induced by indomethacin were aggravated in arthritic animals and 2) tO investigate the undedying mechanisms for aggravation of gastric lesions, in relation to inflammatory mediators such as nitric oxide (NO) and prostaglandins (PGs). METHODS: Male DA rats (180~200 g) were used. Arthritis (AA) was induced by injection of Freund's complete adjuvant into right hind paw. The animals were fasted overnight on various days after adjuvant injection, then given IM (1-25 mg/kg, SC) or HCl/ethanol (60% in 150 mM HCI, PO), and killed 4 h or 1 h later, respectively. In a separate study, AA rats were subjected to pylorus ligation on various days, and the luminal levels of NOx and PGE z were measured by Griess reaction and EIA, respectively. RESULTS: Apparent arthritic changes in the paw (paw edema) were first observed on day 10 and reached maximum on day 14 after the injection of adjuvant. Indomethacin (25 mg/kg) caused hemorrhagic lesions in the gastric mucosa in normal rats, but this ulcerogenic response was significantly potentiated in AA rats, in parallel with the development of arthritis, reaching maximum 14 days following adjuvant injection. The worsening effect of AA on indomethacin-induced gastric lesions was similarly observed even in the presence of exogenous HC1 (150 raM), but significantly attenuated by subcutaneous pretreatment of AA rats with NGnitro-L-arginine methyl ester (L-NAME: 20 mg/kg), aminoguanidine (20 mg/kg) and dexamethasone (3 mg/kg) but not by FR167653, IL-1/TNF- ct synthesis inhibitor. On the other hand, AA rats showed a mucosal protective activity against HCl-ethanol-induced gastric lesions on day 14, and this effect was mitigated by prior administration of L-NAME and dexamethasone as well as a non-ulcerogenic dose of indomethacin (l mg/kg). In addition, a marked increase of NOx and PGE z release into gastric lumen was observed in AA rats. CONCLUSION: These results suggest that gastric ulcerogenic response to indomethacin was markedly enhanced in AA rats, and the underlying mechanism involves endogenous NO derived from inducible NO synthase. Less ulcerogenic response to HCl/ethanol in AA rat stomachs may be associated with the increased production of endogenous PGs as well as NO. • G0695 P Y L O R I REINFECTION AND ULCER RECURENCE IN CHILDREN FOLLOWING ERADICATION THERAPY. S. Kato, D. Abukawa, N. Furuyama, K. Iinuma. Department of Pediatrics, Tohoku University School of Medicine, and Department of Pediatrics, Sendal City Hospital, Sendal, Japan.
HELICOBACTER
Back~roud: There are few studies of Helicobacter pylori reinfection and ulcer recurrence after successful eradication in childhood. We investigated the reinfection rate of H. pylori and ulcer recurrence during a follow-up period of 12 months Or more in children with eradication therapy. Methods: Twenty three patients aged 7-16 years (5 with gastric ulcer, 12 with duodenal ulcer, and 6 with nodular gastritis) were studied. Biopsy-based tests demonstrated that eradication was successful in 19 patients and unsuccessful in 4. Nineteen successfully treated patients were followed for a mean of 19.5 months (a total of 30.8 patient years of follow-up). To assess 1f. pylori status, the patients underwent a 13C-urea breath test at 12-19 months; 6 patients also underwent a second follow-up test at 24-28 months. Endoscopy was performed if a patient complained of symptoms suggesting ulcer recurrence. Results: The initial follow-up 13C-urea breath tests showed that all 19 patients remained free of infection; the second test confirmed reinfection in one patient at 28 months. The reinfection rate was 3.2% per patient year. Ulcer recurrence was found in 2 of 3 ulcer patients with eradication failure (3 and 6 months after eradication therapy ended, respectively) but in none of the 14 patients with successful eradication. The recurrence rate was significantly lower in successfully treated patients than in unsuccessfully treated patients (p < 0.05). Conclusion: Reinfection with 14. pylori is rare in children above 7 years, and successful eradication significantly reduces ulcer recurrence. This study supports the benefit of eradication therapy for the elder children. • G0696 LOWER ESOPHAGEAL SPHINCTER RESTING PRESSURE AND ESOPHAGEAL ACID AND BILE EXPOSURE IN PATIENTS WITH SHORT AND LONG SEGMENT BARRETT'S ESOPHAGUS. Kauer WKH, Stein HJ, Dittler HJ, Siewert JR. Department of Surgery, Technical University Munich, Germany It is widely accepted, that the presence of Barrett's esophagus is associated with long lasting reflux disease. However, there is still controversy whether there are differences in patients with short and long segment Barrett's esophagus.
GASTROENTEROLOGYVol. 114, No. 4 The resting pressure of the lower esophageal sphincter (LES) as well as the exposition of the distal esophagus to both gastric and duodenal juice was measured. Twenty patients with histologically proven short segment Barrett's esophagus (length of Barrett<3 crn) and 15 patients with histologically proven long segment Barrett's esophagus (length of Barrett > 3 cm) were studied. Twenty patients with reflux esophagitis but no Barrett's esophagus served as a control group. The LES resting pressure was measured by stationary manometry, the exposition of gastric and duodenal juice by longterm pH and bilirubin (Bilitec) monitoring respectively. All patients underwent endoscopy and representative biopsy samples were taken at the Zline. When Barrett's esophagus was present macroscopically biopsies were taken in lcm intervals. The LES resting pressure showed gradual decrease from patients with esophagitis to those with short and long segments of Barrett's esophagus (10 mmHg, 7 mmHg, 5 mmHg). The % time pH < 4 was 5%, 8% and 10.5% in the 3 patient groups. In 7% of the study time duodenal juice was present in the distal esophagus of patients with esophagitis compared to 16% in patients with short segment and 17.5% in patients with long segment Barrett esophagus (p <0.05 esophagitis vs. patients with long segment Barrett's esophagus). This study showed, that patients with Barrett's esophagus have a decreased LES pressure compared to patients with esophagitis alone as well as increased exposition to both gastric and duodenal juice in the distal esophagus. There was no significant difference between patients with short and long segments Barrett' s esophagus. • G0697 BILE SALTS INDUCE OR BLUNT CELL PROLIFERATION IN BARRETT'S ESOPHAGUS IN AN ACID-DEPENDENT FASHION. B~ Kaur, R. Ouatu-Lascar, R. C. Fitzgerald, M.B. Omary, G. Triadafilopoulos. Gastroenterology Section, VA Pa[o Alto Health Care System and Stanford University, Palo Alto, CA. Back~,round: Barrett's esophagus (BE) is a complication of gastroesophageal reflux disease (GERD) and predisposes to dysplasia and esophageal adenocarcinoma. We previously showed that acid has a dynamic effect on cell proliferation of BE ex vivo depending on the pattern of acid exposure (J. Clin. Invest. 1996; 98: 2120-28). The role of duodenogastric refluxate in GERD and BE remains controversial. Aims: To investigate the effect of bile salts with or without acid on cell proliferation in BE, and to assess the possible mechanism(s) involved. Methods: To mimic known physiologic conditions, endoscopic biopsies of normal esophagus, BE and normal duodenum were exposed to a bile salt mixture (sodium glycocholate and tanrocholate, glycocholic acid and deoxycholate; final concentration lmM; pH 7.4) either continuously, or as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h. Similar experiments were also performed with acidified media (pH 3.5) that was combined with the bile salt mixture either continuously or as a 1-h pulse, followed by exposure to pH 7.4 for up to 24 h. Cell proliferation was assessed by 3H-thymidine incorporation assay in the presence or absence of bisindolylmaleimide (BIM), a selective protein kinase C (PKC) inhibitor. Explant integrity was assessed by morphology using light microsocpy and by measuring lactate dehydrogenase release. Results: Bile salt pulse enhanced cell proliferation in BE (4,292 cpm/mg protein vs 2,269 cpm/mg protein at 24 h, p < 0.001) starting as early as 1-h after exposure and without evidence of morphologic damage. In contrast, bile salts had no effect on cell proliferation of normal esophagus (2,209 vs 2,421) or duodenum (2,487 vs 2,441). In the presence of BIM, there was complete obliteration of the bile salt-induced hyperproliferation of BE biopsies (1,807 cprrdmg protein vs 2,359 with BIM alone). Continuous exposure to bile salts for 24 h had no effect on proliferation or morphology. In contrast, 1-h pulses of bile salts in combination with acid significantly inhibited proliferation in BE explants (24 h: 1,197 cpm/mg protein vs 4,743 cpm/mg protein with BS alone or 4,658 cpm/mg protein with acid alone, p < 0.001) but had no effect on esophageal or duodenal explants. Conclusions: Bile salts, administered as 1-h pulse, induce cell proliferation in BE possibly through a PKC-dependent mechanism yet have no effect on cell proliferation of normal esophagus or duodenum. Paradoxically, bile salts that are mixed with acid block each other's pulse-induced proliferative burst in BE explants. We postulate that bile salts, independent of acid, contribute to the proliferative alterations in BE in a dynamic fashion but manifest a complex effect when they interact with acid. This research was funded in part by TAP Pharmaceuticals, Inc., and by the Estelle B. Simon Fund at Stanford University.
HELICOBACTER
Back~roud: There are few studies of Helicobacter pylori reinfection and ulcer recurrence after successful eradication in childhood. We investigated the reinfection rate of H. pylori and ulcer recurrence during a follow-up period of 12 months Or more in children with eradication therapy. Methods: Twenty three patients aged 7-16 years (5 with gastric ulcer, 12 with duodenal ulcer, and 6 with nodular gastritis) were studied. Biopsy-based tests demonstrated that eradication was successful in 19 patients and unsuccessful in 4. Nineteen successfully treated patients were followed for a mean of 19.5 months (a total of 30.8 patient years of follow-up). To assess 1f. pylori status, the patients underwent a 13C-urea breath test at 12-19 months; 6 patients also underwent a second follow-up test at 24-28 months. Endoscopy was performed if a patient complained of symptoms suggesting ulcer recurrence. Results: The initial follow-up 13C-urea breath tests showed that all 19 patients remained free of infection; the second test confirmed reinfection in one patient at 28 months. The reinfection rate was 3.2% per patient year. Ulcer recurrence was found in 2 of 3 ulcer patients with eradication failure (3 and 6 months after eradication therapy ended, respectively) but in none of the 14 patients with successful eradication. The recurrence rate was significantly lower in successfully treated patients than in unsuccessfully treated patients (p < 0.05). Conclusion: Reinfection with 14. pylori is rare in children above 7 years, and successful eradication significantly reduces ulcer recurrence. This study supports the benefit of eradication therapy for the elder children. • G0696 LOWER ESOPHAGEAL SPHINCTER RESTING PRESSURE AND ESOPHAGEAL ACID AND BILE EXPOSURE IN PATIENTS WITH SHORT AND LONG SEGMENT BARRETT'S ESOPHAGUS. Kauer WKH, Stein HJ, Dittler HJ, Siewert JR. Department of Surgery, Technical University Munich, Germany It is widely accepted, that the presence of Barrett's esophagus is associated with long lasting reflux disease. However, there is still controversy whether there are differences in patients with short and long segment Barrett's esophagus.
GASTROENTEROLOGYVol. 114, No. 4 The resting pressure of the lower esophageal sphincter (LES) as well as the exposition of the distal esophagus to both gastric and duodenal juice was measured. Twenty patients with histologically proven short segment Barrett's esophagus (length of Barrett<3 crn) and 15 patients with histologically proven long segment Barrett's esophagus (length of Barrett > 3 cm) were studied. Twenty patients with reflux esophagitis but no Barrett's esophagus served as a control group. The LES resting pressure was measured by stationary manometry, the exposition of gastric and duodenal juice by longterm pH and bilirubin (Bilitec) monitoring respectively. All patients underwent endoscopy and representative biopsy samples were taken at the Zline. When Barrett's esophagus was present macroscopically biopsies were taken in lcm intervals. The LES resting pressure showed gradual decrease from patients with esophagitis to those with short and long segments of Barrett's esophagus (10 mmHg, 7 mmHg, 5 mmHg). The % time pH < 4 was 5%, 8% and 10.5% in the 3 patient groups. In 7% of the study time duodenal juice was present in the distal esophagus of patients with esophagitis compared to 16% in patients with short segment and 17.5% in patients with long segment Barrett esophagus (p <0.05 esophagitis vs. patients with long segment Barrett's esophagus). This study showed, that patients with Barrett's esophagus have a decreased LES pressure compared to patients with esophagitis alone as well as increased exposition to both gastric and duodenal juice in the distal esophagus. There was no significant difference between patients with short and long segments Barrett' s esophagus. • G0697 BILE SALTS INDUCE OR BLUNT CELL PROLIFERATION IN BARRETT'S ESOPHAGUS IN AN ACID-DEPENDENT FASHION. B~ Kaur, R. Ouatu-Lascar, R. C. Fitzgerald, M.B. Omary, G. Triadafilopoulos. Gastroenterology Section, VA Pa[o Alto Health Care System and Stanford University, Palo Alto, CA. Back~,round: Barrett's esophagus (BE) is a complication of gastroesophageal reflux disease (GERD) and predisposes to dysplasia and esophageal adenocarcinoma. We previously showed that acid has a dynamic effect on cell proliferation of BE ex vivo depending on the pattern of acid exposure (J. Clin. Invest. 1996; 98: 2120-28). The role of duodenogastric refluxate in GERD and BE remains controversial. Aims: To investigate the effect of bile salts with or without acid on cell proliferation in BE, and to assess the possible mechanism(s) involved. Methods: To mimic known physiologic conditions, endoscopic biopsies of normal esophagus, BE and normal duodenum were exposed to a bile salt mixture (sodium glycocholate and tanrocholate, glycocholic acid and deoxycholate; final concentration lmM; pH 7.4) either continuously, or as a 1-h pulse and compared with exposure to pH 7.4 for up to 24 h. Similar experiments were also performed with acidified media (pH 3.5) that was combined with the bile salt mixture either continuously or as a 1-h pulse, followed by exposure to pH 7.4 for up to 24 h. Cell proliferation was assessed by 3H-thymidine incorporation assay in the presence or absence of bisindolylmaleimide (BIM), a selective protein kinase C (PKC) inhibitor. Explant integrity was assessed by morphology using light microsocpy and by measuring lactate dehydrogenase release. Results: Bile salt pulse enhanced cell proliferation in BE (4,292 cpm/mg protein vs 2,269 cpm/mg protein at 24 h, p < 0.001) starting as early as 1-h after exposure and without evidence of morphologic damage. In contrast, bile salts had no effect on cell proliferation of normal esophagus (2,209 vs 2,421) or duodenum (2,487 vs 2,441). In the presence of BIM, there was complete obliteration of the bile salt-induced hyperproliferation of BE biopsies (1,807 cprrdmg protein vs 2,359 with BIM alone). Continuous exposure to bile salts for 24 h had no effect on proliferation or morphology. In contrast, 1-h pulses of bile salts in combination with acid significantly inhibited proliferation in BE explants (24 h: 1,197 cpm/mg protein vs 4,743 cpm/mg protein with BS alone or 4,658 cpm/mg protein with acid alone, p < 0.001) but had no effect on esophageal or duodenal explants. Conclusions: Bile salts, administered as 1-h pulse, induce cell proliferation in BE possibly through a PKC-dependent mechanism yet have no effect on cell proliferation of normal esophagus or duodenum. Paradoxically, bile salts that are mixed with acid block each other's pulse-induced proliferative burst in BE explants. We postulate that bile salts, independent of acid, contribute to the proliferative alterations in BE in a dynamic fashion but manifest a complex effect when they interact with acid. This research was funded in part by TAP Pharmaceuticals, Inc., and by the Estelle B. Simon Fund at Stanford University.