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Helicobacter pylori infection is a major risk factor in the decrease of gastric acid secretion in the elderly
A1306 AGA ABSTRACTS
GASTROENTEROLOGY Vol. 118, No.4
5960
5962
GASTRIC AMOXICILLIN TRANSFER IN HELICOBACTER LORI +VE PATIENTS: EFFECT OF BILE REFLUX. Paul V. Sherwood, Judata I. Wibawa, Darren P. Fowkes, Andrew F. Goddard, David A. Barrett, Paul N. Shaw, Robin C. Spiller, Div of Gastroenterology, Nottingham, United Kingdom; Dept of Pharm Sci, Nottingham, United Kingdom.
rr-
BARRETT'S EPITHELIUM, DYSPLASIA, AND MULTILAYERED EPITHELIUM: IS THERE A RELATIONSHIP? Helen M. Shields, Norman S. Nishioka, Stanley 1. Rosenberg, William P. Puricelli, Bernard J. Ransil, Felice R. Zwas, Melissa P. Upton, Beth Israel Deaconess Med Ctr, Boston, MA; Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA; Greenwich Hosp, Yale Univ Med Sch, Greenwich, CT.
Previous human studies of gastric amoxicillin transfer have largely been on H. pylori-negative volunteers and have measured gastric juice concentrations with relatively inaccurate bioassay techniques. Duodenal ulcer patients often have a deformed pylorus and bile reflux. We used a new high sensitivity HPLC assay to examine the effect of bile reflux on gastric amoxicillin transfer. Methods: 22 H. pylori-positive patients (II peptic ulcer, 9 erosive gastroduodenitis, 2 NUD) were given 5 days of omeprazole 20mg bid prior to fasting for the morning of the experiment. A triple-lumen oro-gastric tube was placed and phenol red was infused. For the first hour an i.v. infusion of 750mg amoxicillin was given; blood was taken for amoxicillin levels at 15 minute intervals throughout the 4 hour experiment. Gastric juice was aspirated continuously and collected in 15 minute aliquots. Pyloric losses were calculated by measuring phenol red recovery; the presence of bile staining was recorded. Amoxillin concentrations were determined by HPLC. Results: 12/22 patients (6 with a duodenal ulcer) showed bile staining of gastric juice during the experiment; for each patient visibly bile-stained samples showed higher amoxicillin levels than non bile-stained samples. The juice amoxicillin AUC was significantly higher for bile-refluxing patients compared with non bile-refluxers; when bilestained peaks were excluded, this difference diminished considerably. Conclusion: After omeprazole pre-treatment, H. pylori positive patients without bile reflux achieve gastric juice amoxicillin concentrations IO-fold above the MIC go for H. pylori via direct blood to lumen transfer. Bile reflux approximately doubles the gastric juice amoxicillin concentration.
Introduction: We demonstrated by morphology and immunocytochemistry multilayered epithelium (MLE) at the squamo-columnar junction in patients with Barrett's epithelium (Gastroenterology 1997;112:760-765). This hybrid epithelium has characteristics of both squamous and columnar epithelium. We recently showed that MLE is significantly associated with the presence of Barrett's epithelium (p<.OOl)(Gastroenterology 1999;116: G1354) and hypothesize that MLE represents an intermediate stage in the development of Barrett's epithelium. Aim: Our aim was to evaluate whether patients with Barrett's epithelium and low or high grade dysplasia or adenocarcinoma in their biopsies also simultaneously demonstrate MLE. Methods: Endoscopic biopsies were taken from the squamo-columnar junction in two groups of patients, non-Barrett's patients and patients with Barrett's epithelium who had not undergone photodynamic therapy prior to biopsy. Hematoxylin and eosin stained sections were evaluated for the presence of Barrett's epithelium, low or high grade dysplasia, adenocarcinoma, and MLE (multiple layers of cells with squamoid organization and mucus droplets). Results: Two observers reviewed 143 biopsies from 53 patients (16 non-Barrett's patients and 37 patients with Barrett's epithelium, including 11 without dysplasia, 3 with low grade dysplasia, and 23 with high grade dysplasia or adenocarcinoma). We identified the squamocolumnar junction in 64 biopsies from 40 patients, of whom 27 had Barrett's epithelium and 13 did not. Of the 27 patients with Barrett's epithelium, II had no dysplasia, 3 had low grade dysplasia, 12 had high grade dysplasia, and I had adenocarcinoma. MLE was identified in 4 of the 27 Barrett's patients (15%). However, MLE was noted in only 1 of 16 patients with dysplasia or adenocarcinoma (6%). This patient had a focal area of low grade dysplasia. MLE was found in 3 of the 11 patients with Barrett's epithelium without dysplasia or adenocarcinoma (27%). MLE was not identified in any of the 13 non-Barrett's patients, nor in any of the 13 patients with Barrett's epithelium and high grade dysplasia or adenocarcinoma. MLE was not identified in any of the 13 patients (79 biopsies) where the squamo-columnar junction was absent. Conclusions: Detection of MLE requires endoscopic biopsy sampling of the squamo-columnar junction. MLE is associated with Barrett's epithelium. MLE was not identified in any patient with Barrett's epithelium and high grade dysplasia or adenocarcinoma.
Amoxicillin pharmacokinetics
Plasma amoxicillin AUC l'Q.min/ml Juice amoxicillin AUC l'Q.min/ml Gastric clearance ml/min
Non bile·refluxers
Bilerefluxers
3532 ± 961 256 ± 97 0.10 + 0.05
3438±511 678 ± 494t 0.39 + 0.23'
t P= 0.01 vsnon bile-reftuxers , p = 001 vsnon bile-reftuxers
5963 5961 HEAT SHOCK PROTEIN EXPRESSION IN DIFFERENT SUSCEPTIBILITY TO STRESS IN GASTRIC ULCER FORMATION OF SPONTANEOUSLY HYPERTENSIVE RATS (SHR) AND WISTARKYOTO RATS (WKY), Kazuko Shichijo, Makoto Ihara, Mutsumi Matsuu, Masahiro Ito, Yutaka Okumura, Ichiro Sekine, Atomic Bomb Disease Inst, Nagasaki Univ Sch of Medicine, Nagasaki, Japan. We have previously reported that SHR, an animal model of essential hypertension in human, was markedly less susceptible to stress-induced gastric ulcer compared with WKY. The heat shock protein 70 (HSP70) is part of a very sensitive and phylogenetically highly preserved defense mechanism. In the present study the mechanism of the different susceptibility to stress in gastric ulcer formation of SHR and WKY was investigated relating to HSP70 expression in the stomach. Methods: Male SHR and WKY from Charles River Japan Inc. were used at the age of 7-9 weeks. The blood pressure was measured by the tail cuff method. Rats were exposed to the restraint and water immersion stress (RWIS) for 7 hours at 23°C after a 17-hour fast. The expression of protein and mRNA for HSP70 in the stomach was analyzed 0, I, 4 and 7 hours after RWIS using Western-blot and in situ hybridization, respectively. Results: The blood pressure of the non-stressed SHR (l43:!::5 mm Hg) was significantly (p < 0.01) higher than that of the non-stressed WKY (121:!::3 mm Hg). The protein expression of HSP70 both in the corpus and the antrum of the non-stressed SHR were remarkably higher than those of the non-stressed WKY. RWIS induced gastric ulcer (erosive lesion) in WKY (52:!::7 mrrr') but less frequent in SHR (3:!:: I mrrr') (p < 0.00l). The protein expression of HSP70 in the corpus of WKY increased 1,4 and 7 hours after RWIS, whereas the protein expression of HSP70 in the corpus of SHR increased I hour, decreased 4 hours and increased 7 hours after RWIS, but remained higher in SHR than in WKY. In situ hybridization showed that the gastric expression of HSP70mRNA was localized to the cytoplasm of the mucosal epithelial cells both in the corpus and the antrum, with maximal expression in the proliferative zone and that the expression was often observed in the nuclei of the mucosal epithelial cells in the stomach of SHR. Conclusion: These results indicate that the genetically over expression of HSP70 in the stomach contribute to the less susceptible to stress-induced gastric ulcer formation.
HELICOBACTER PYLORI INFECTION IS A MAJOR RISK FACTOR IN THE DECREASE OF GASTRIC ACID SECRETION IN THE ELDERLY, Tomohiko Shimatani, Masaki Inoue, Yoko Horikawa, Yukinobu Kawai, Nobue Harada, Goro Kajiyama, Hiroshima Univ Sch of Med, Hiroshima, Japan. BACKGROUND AND AIMS: Until now, it has been commonly accepted that the decrease of gastric acid secretion in the elderly must be due to aging. However, since the discovery of Helicobacter pylori (HP), our understanding of the pathophysiology of the stomach has been completely renewed. We examined the relation between the decrease of gastric acid secretion in the elderly and HP infection. SUBJECTS AND METHODS: 33 patients in their twenties (18 HP-negative and 15 HP-positive) and 48 patients over 70 years old (18 HP-negative and 30 HP-positive) without any ulcerous or tumorous lesions participated in this experiment with informed consent. According to the extent of gastric mucosal atrophy, patients with HP infection were classified into three groups; mild, moderate and severe atrophy. The intragastric pH was measured for 24 hours without any treatment and the percentages of times with pH>3 (pH 3 holding time: pH3HT) were calculated. The serum pepsinogen (PG)-1 and -2 concentration were also measured by radioimmunoassay. RESULTS: (I) In patients without HP infection, gastric mucosal atrophy was not endoscopically observed at all in the young and even in the elderly. (2) In patients without HP infection, gastric acid secretion did not significantly decrease even in the elderly (pH3HT in the nighttime: 16.5:!:: 14.0% in the young, 22.0:!:: 10.3% in the elderly (mean:!::SD)). In patients with HP infection in the elderly, gastric acid secretion, especially nocturnal acid secretion, gradually decreased in proportion to the development of gastric mucosal atrophy (pH3HT in the nighttime: 46.5:!:: 16.3% in mild atrophy, 74.3:!:: 12.8% in moderate atrophy, 96.2:!::6.8% in severe atrophy). (3) In patients without HP infection, the PG 1/2 ratio in the elderly was not significantly lower than that in the young. In patients with HP infection, it significantly fell down in proportion to the development of gastric mucosal atrophy. CONCLUSION: The decrease of gastric acid secretion in the elderly is not due to aging, but gastric mucosal atrophy with long-term HP infection.
GASTROENTEROLOGY Vol. 118, No.4
5960
5962
GASTRIC AMOXICILLIN TRANSFER IN HELICOBACTER LORI +VE PATIENTS: EFFECT OF BILE REFLUX. Paul V. Sherwood, Judata I. Wibawa, Darren P. Fowkes, Andrew F. Goddard, David A. Barrett, Paul N. Shaw, Robin C. Spiller, Div of Gastroenterology, Nottingham, United Kingdom; Dept of Pharm Sci, Nottingham, United Kingdom.
rr-
BARRETT'S EPITHELIUM, DYSPLASIA, AND MULTILAYERED EPITHELIUM: IS THERE A RELATIONSHIP? Helen M. Shields, Norman S. Nishioka, Stanley 1. Rosenberg, William P. Puricelli, Bernard J. Ransil, Felice R. Zwas, Melissa P. Upton, Beth Israel Deaconess Med Ctr, Boston, MA; Massachusetts Gen Hosp, Harvard Med Sch, Boston, MA; Greenwich Hosp, Yale Univ Med Sch, Greenwich, CT.
Previous human studies of gastric amoxicillin transfer have largely been on H. pylori-negative volunteers and have measured gastric juice concentrations with relatively inaccurate bioassay techniques. Duodenal ulcer patients often have a deformed pylorus and bile reflux. We used a new high sensitivity HPLC assay to examine the effect of bile reflux on gastric amoxicillin transfer. Methods: 22 H. pylori-positive patients (II peptic ulcer, 9 erosive gastroduodenitis, 2 NUD) were given 5 days of omeprazole 20mg bid prior to fasting for the morning of the experiment. A triple-lumen oro-gastric tube was placed and phenol red was infused. For the first hour an i.v. infusion of 750mg amoxicillin was given; blood was taken for amoxicillin levels at 15 minute intervals throughout the 4 hour experiment. Gastric juice was aspirated continuously and collected in 15 minute aliquots. Pyloric losses were calculated by measuring phenol red recovery; the presence of bile staining was recorded. Amoxillin concentrations were determined by HPLC. Results: 12/22 patients (6 with a duodenal ulcer) showed bile staining of gastric juice during the experiment; for each patient visibly bile-stained samples showed higher amoxicillin levels than non bile-stained samples. The juice amoxicillin AUC was significantly higher for bile-refluxing patients compared with non bile-refluxers; when bilestained peaks were excluded, this difference diminished considerably. Conclusion: After omeprazole pre-treatment, H. pylori positive patients without bile reflux achieve gastric juice amoxicillin concentrations IO-fold above the MIC go for H. pylori via direct blood to lumen transfer. Bile reflux approximately doubles the gastric juice amoxicillin concentration.
Introduction: We demonstrated by morphology and immunocytochemistry multilayered epithelium (MLE) at the squamo-columnar junction in patients with Barrett's epithelium (Gastroenterology 1997;112:760-765). This hybrid epithelium has characteristics of both squamous and columnar epithelium. We recently showed that MLE is significantly associated with the presence of Barrett's epithelium (p<.OOl)(Gastroenterology 1999;116: G1354) and hypothesize that MLE represents an intermediate stage in the development of Barrett's epithelium. Aim: Our aim was to evaluate whether patients with Barrett's epithelium and low or high grade dysplasia or adenocarcinoma in their biopsies also simultaneously demonstrate MLE. Methods: Endoscopic biopsies were taken from the squamo-columnar junction in two groups of patients, non-Barrett's patients and patients with Barrett's epithelium who had not undergone photodynamic therapy prior to biopsy. Hematoxylin and eosin stained sections were evaluated for the presence of Barrett's epithelium, low or high grade dysplasia, adenocarcinoma, and MLE (multiple layers of cells with squamoid organization and mucus droplets). Results: Two observers reviewed 143 biopsies from 53 patients (16 non-Barrett's patients and 37 patients with Barrett's epithelium, including 11 without dysplasia, 3 with low grade dysplasia, and 23 with high grade dysplasia or adenocarcinoma). We identified the squamocolumnar junction in 64 biopsies from 40 patients, of whom 27 had Barrett's epithelium and 13 did not. Of the 27 patients with Barrett's epithelium, II had no dysplasia, 3 had low grade dysplasia, 12 had high grade dysplasia, and I had adenocarcinoma. MLE was identified in 4 of the 27 Barrett's patients (15%). However, MLE was noted in only 1 of 16 patients with dysplasia or adenocarcinoma (6%). This patient had a focal area of low grade dysplasia. MLE was found in 3 of the 11 patients with Barrett's epithelium without dysplasia or adenocarcinoma (27%). MLE was not identified in any of the 13 non-Barrett's patients, nor in any of the 13 patients with Barrett's epithelium and high grade dysplasia or adenocarcinoma. MLE was not identified in any of the 13 patients (79 biopsies) where the squamo-columnar junction was absent. Conclusions: Detection of MLE requires endoscopic biopsy sampling of the squamo-columnar junction. MLE is associated with Barrett's epithelium. MLE was not identified in any patient with Barrett's epithelium and high grade dysplasia or adenocarcinoma.
Amoxicillin pharmacokinetics
Plasma amoxicillin AUC l'Q.min/ml Juice amoxicillin AUC l'Q.min/ml Gastric clearance ml/min
Non bile·refluxers
Bilerefluxers
3532 ± 961 256 ± 97 0.10 + 0.05
3438±511 678 ± 494t 0.39 + 0.23'
t P= 0.01 vsnon bile-reftuxers , p = 001 vsnon bile-reftuxers
5963 5961 HEAT SHOCK PROTEIN EXPRESSION IN DIFFERENT SUSCEPTIBILITY TO STRESS IN GASTRIC ULCER FORMATION OF SPONTANEOUSLY HYPERTENSIVE RATS (SHR) AND WISTARKYOTO RATS (WKY), Kazuko Shichijo, Makoto Ihara, Mutsumi Matsuu, Masahiro Ito, Yutaka Okumura, Ichiro Sekine, Atomic Bomb Disease Inst, Nagasaki Univ Sch of Medicine, Nagasaki, Japan. We have previously reported that SHR, an animal model of essential hypertension in human, was markedly less susceptible to stress-induced gastric ulcer compared with WKY. The heat shock protein 70 (HSP70) is part of a very sensitive and phylogenetically highly preserved defense mechanism. In the present study the mechanism of the different susceptibility to stress in gastric ulcer formation of SHR and WKY was investigated relating to HSP70 expression in the stomach. Methods: Male SHR and WKY from Charles River Japan Inc. were used at the age of 7-9 weeks. The blood pressure was measured by the tail cuff method. Rats were exposed to the restraint and water immersion stress (RWIS) for 7 hours at 23°C after a 17-hour fast. The expression of protein and mRNA for HSP70 in the stomach was analyzed 0, I, 4 and 7 hours after RWIS using Western-blot and in situ hybridization, respectively. Results: The blood pressure of the non-stressed SHR (l43:!::5 mm Hg) was significantly (p < 0.01) higher than that of the non-stressed WKY (121:!::3 mm Hg). The protein expression of HSP70 both in the corpus and the antrum of the non-stressed SHR were remarkably higher than those of the non-stressed WKY. RWIS induced gastric ulcer (erosive lesion) in WKY (52:!::7 mrrr') but less frequent in SHR (3:!:: I mrrr') (p < 0.00l). The protein expression of HSP70 in the corpus of WKY increased 1,4 and 7 hours after RWIS, whereas the protein expression of HSP70 in the corpus of SHR increased I hour, decreased 4 hours and increased 7 hours after RWIS, but remained higher in SHR than in WKY. In situ hybridization showed that the gastric expression of HSP70mRNA was localized to the cytoplasm of the mucosal epithelial cells both in the corpus and the antrum, with maximal expression in the proliferative zone and that the expression was often observed in the nuclei of the mucosal epithelial cells in the stomach of SHR. Conclusion: These results indicate that the genetically over expression of HSP70 in the stomach contribute to the less susceptible to stress-induced gastric ulcer formation.
HELICOBACTER PYLORI INFECTION IS A MAJOR RISK FACTOR IN THE DECREASE OF GASTRIC ACID SECRETION IN THE ELDERLY, Tomohiko Shimatani, Masaki Inoue, Yoko Horikawa, Yukinobu Kawai, Nobue Harada, Goro Kajiyama, Hiroshima Univ Sch of Med, Hiroshima, Japan. BACKGROUND AND AIMS: Until now, it has been commonly accepted that the decrease of gastric acid secretion in the elderly must be due to aging. However, since the discovery of Helicobacter pylori (HP), our understanding of the pathophysiology of the stomach has been completely renewed. We examined the relation between the decrease of gastric acid secretion in the elderly and HP infection. SUBJECTS AND METHODS: 33 patients in their twenties (18 HP-negative and 15 HP-positive) and 48 patients over 70 years old (18 HP-negative and 30 HP-positive) without any ulcerous or tumorous lesions participated in this experiment with informed consent. According to the extent of gastric mucosal atrophy, patients with HP infection were classified into three groups; mild, moderate and severe atrophy. The intragastric pH was measured for 24 hours without any treatment and the percentages of times with pH>3 (pH 3 holding time: pH3HT) were calculated. The serum pepsinogen (PG)-1 and -2 concentration were also measured by radioimmunoassay. RESULTS: (I) In patients without HP infection, gastric mucosal atrophy was not endoscopically observed at all in the young and even in the elderly. (2) In patients without HP infection, gastric acid secretion did not significantly decrease even in the elderly (pH3HT in the nighttime: 16.5:!:: 14.0% in the young, 22.0:!:: 10.3% in the elderly (mean:!::SD)). In patients with HP infection in the elderly, gastric acid secretion, especially nocturnal acid secretion, gradually decreased in proportion to the development of gastric mucosal atrophy (pH3HT in the nighttime: 46.5:!:: 16.3% in mild atrophy, 74.3:!:: 12.8% in moderate atrophy, 96.2:!::6.8% in severe atrophy). (3) In patients without HP infection, the PG 1/2 ratio in the elderly was not significantly lower than that in the young. In patients with HP infection, it significantly fell down in proportion to the development of gastric mucosal atrophy. CONCLUSION: The decrease of gastric acid secretion in the elderly is not due to aging, but gastric mucosal atrophy with long-term HP infection.