The influence of reflux of bile and pancreatic juice on gastric carcinogenesis in rats

The effect of reflux of the duodenal contents on the development of gastric stump carcinoma without carcinogen in rats was studied. At the first experiment, seventy male Wistar rats were subjected to gastrojejunostomy for the diversion of duodenal contents into the resected stomach through the afferent and the efferent loops. The incidence of adenocarcinoma in the afferent anastomosis were 0/8 (0%) at the 10th week, 3/16 (18.8%) at the 20th week and 7/20 (35%) at the 40th week, so the incidence was apt to rise in parallel to the time. In the second experiment, ninety rats were divided into 4 groups: Group I received the same operation as the first experiment, group II received the operation with Braun's anastomosis, group III received the operation for reflux of bile alone to the remnant stomach, and group IV received the operation for reflux of pancreatic juice alone. Animals surviving after surgery were sacrificed at the 40th week. The incidence were 33.3% in group I, 0% in group II, 0% in group III, and 8.3% in group IV, respectively. These findings suggest that reflux of duodenal contents (both bile and pancreatic juice) is an important factor in the gastric stump carcinogenesis.     

Relative contribution of bile and pancreatic juice duodenogastric reflux in gastric ulcer disease and cholelithiasis

Bile acid concentrations, phospholipase A2 activity and pH in the stomach were measured in the fasting state and for 2 h after a fat-containing test meal in patients with an active gastric ulcer (GU), in patients with gallstones before and after cholecystectomy and in normal subjects. Fasting and peak postprandial bile acid concentrations in the stomach were low in all normal controls. Although high concentrations were found in many patients with GU (P less than 0.01), similar concentrations were found in many patients with radiologically non-functioning gallbladders containing gallstones (NFG) (P less than 0.01) and also after cholecystectomy (AC) (P less than 0.01). Fasting intragastric phospholipase A2 activities were similar, and very high in GU and NFG patients compared with control subjects (P less than 0.01). High values were not found after cholecystectomy. There was no difference in pH profile or in postprandial phospholipase A2 between patient groups. Since patients with cholelithiasis or after cholecystectomy are not known to have an increased incidence of gastric ulceration, the significance of duodenogastric reflux in the aetiology of gastric ulcers must be questioned. If reflux does produce ulcers in GU patients then factors in addition to bile acid are probably involved. However, neither patterns of phospholipase A2 reflux nor pH profiles can explain the absence of gastric ulceration in those patients with gallstones who reflux large quantities of bile acid.     

Promoting effect of bile acids on gastric carcinogenesis induced by MNNG in rats

The promoting effect of bile acids on the development of gastric carcinoma was examined in rats treated with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). At the first experiment, two hundred and fifteen male Wistar rats were divided into 5 groups; after oral administration MNNG (120 micrograms/ml) for 24 weeks, group 1 received tap water, group 2 administered of chenodeoxycholic acid (CDCA) solution, group 3 had deoxycholic acid (DCA) solution for the next 12 weeks. Group 4 received CDCA solution and group 5 received DCA solution for 36 weeks without MNNG. At the second experiment, fifty one rats were divided into 3 groups; for the first 12 weeks, group 1 received tap water, group 2 CDCA and group 3 DCA. These 3 groups received MNNG for the next 24 weeks followed by tap water for 12 weeks. The incidence of gastric adenocarcinoma in MNNG-treated rats was significantly higher in group 3 (63.6%) as compared with that in group 1 (36.7%) in the first experiment. No carcinoma lesions was found in groups 4 and 5. In the second experiment, no significant changes was observed among 3 groups. Undifferentiated adenocarcinomas were identified in groups 2 and 3, especially treated with MNNG plus bile acids. The result suggested a promoting effect of bile acids, especially DCA, in stomach carcinogenesis.     

Intestinal intussusception valve for postgastrectomy bile reflux and/or dumping

The short-term results of a new surgical procedure for prevention of duodenogastric reflux and rapid gastric emptying after partial gastric resection are reported. A jejunal segment provided with an intussusception valve was interposed between the gastric remnant and the duodenum in six patients with severe postgastrectomy symptoms. Duodenogastric reflux, determined with an isotope derivative method, was found to be completely eliminated after the remedial operation. Gastric emptying of a glucose solution showed no significant delay. Previous gastroscopic findings of "gastritis" could not be recognized at postoperative examination. The histologic mucosal changes showed no remission, however. No patient became completely free from gastric symptoms after the remedial operation. The residual symptoms possibly were caused by impaired emptying of the gastric remnant. Gastric mycosis was found occasionally in all the patients during follow-up. The jejunal intussusception valve effectively prevented bile reflux and seemed to have a beneficial effect on dumping symptoms.     

Effects of duodenogastric bile reflux on gastric mucosal hexosamine concentrations after selective proximal vagotomy or extended distal gastrectomy for duodenal ulcer

Effects of duodenogastric reflux (DGR) of bile on hexosamine concentrations in gastric mucosa were studied in 17 healthy controls and 133 patients with duodenal ulcer patients before and after surgery. Total bile acid concentration in gastric juice was measured using enzyme method to estimate DGR. Mucosal hexosamine concentration of the biopsy specimens taken from the gastric corpus and antrum was measured according to Boas's method. The operative procedures included selective proximal vagotomy (SPV) with or without pyloroplasty, and extended distal gastrectomy with Billroth I(BI) or II(BII) anastomosis. The rate of DGR were significantly higher in cases after gastrectomy, especially in BII cases than in cases after SPV. In the early postoperative period after SPV with or without pyloroplasty, DGR was increased significantly. However, the reflux rate was decreased gradually to the preoperative level thereafter, suggesting that normal function of gastric emptying might be recovered with time. The hexosamine concentration of the antral mucosa showed clearly an inverse relationship to the changes in DGR rate. These results suggested that SPV could be the more physiological procedure than gastrectomy from the point of DGR.     

Incidence of bile reflux in gastric ulcer and after partial gastrectomy

Duodenogastric bile reflux (DGBR) is reported to be increased in patients with gastric ulcer (GU) and following Billroth I partial gastrectomy (BIPG). pH, total bacterial counts, and total and free bile acids were measured in gastric juice aspirated hourly for 24 h in 6 patients with GU, 7 patients with a BIPG performed for GU and in 8 healthy normal controls. Intragastric pH was significantly higher in the BIPG group during the day (P less than 0.001) and at night (P less than 0.001) compared with normals and the GU group. There were no differences between GUs and normal patients. Bile acid concentrations in the gastric juice were not significantly different between GU and control groups over the 24 h. Median and range values were 0.14 (0.06-0.52) mmol l-1 in GU patients and 0.14 (0.05-0.67) mmol l-1 in the normals. However total bile acid concentrations were significantly greater in the BIPG group (0.23, 0.04-0.84) compared with GU or controls. (P = 0.04, P = 0.02). Our data do not support the role of DGBR in the pathogenesis of GU, but deoxycholic acid was detected in significantly greater amounts in BIPG subjects than controls (chi 2 = 12.94, P less than 0.001) or GU subjects (none detected) and may be important in the pathogenesis of gastric stump cancer.     

The effect of reflux of bile juice on the development of residual stomach cancer

An experimental study was performed using an organ culture method to evaluate the effect of a duodenal juice reflux on the development of cancer in the residual stomach. The following results were as follows. An intracellular DNA levels to combine with carcinogenic agents was significantly increased in the mucosa of the residual stomach compared to the parietal mucosa in the whole stomach (control group). In the human gastric mucosa exposed to the bile acid, the intracellular DNA level to combined with carcinogenic agents was increased, and thus the effect of the bile acid as a surfactant on the experimental development of gastric cancer was suggested. An atrophic change was main feature of the residual stomach. Autoradiographic findings revealed that the proliferative zone was extended and a number of immature cells appeared which became to be target cells. Therefore, the residual stomach might provide a situation where the cancer would easily develop.     

Free and conjugated catecholamines in gastric and bile juice during surgical operations

From 40 patients under surgical operation, gastric or bile juice was obtained to determine the possible excretion of free and conjugated catecholamine (CA) into the two kinds of juice. The patients were divided into normal renal function group and chronic renal failure group and former group was further divided into the dopamine (DA)-administered group and the non-DA-administered group. In the non-DA group with normal renal function, the gastric juice contained 0.30 +/- 0.11ng.ml-1 of free and 0.12 +/- 0.06ng.ml-1 of conjugated norepinephrine (NE) and also 0.09 +/- 0.07ng.ml-1 of free and 0.40 +/- 0.10ng.ml-1 of conjugated DA. In DA group, the gastric juice contained 2.01 +/- 0.41ng.ml-1 of free and 3.66 +/- 0.84ng.ml-1 of conjugated DA respectively. Significant differences in DA were observed between two groups. In the bile juice, the conjugated NE increased significantly from 0.15 +/- 0.05 ng.ml-1 to 1.24 +/- 0.34ng.ml-1 and also the conjugated DA increased significantly from 2.17 +/- 0.77ng.ml-1 to 21.33 +/- 5.23ng.ml-1 by infusion of DA at the rate of 2 micrograms.kg-1.min-1 for 197 +/- 48min. In chronic renal failure group, the conjugated NE and DA increased significantly to 1.04 +/- 0.27ng.ml-1 and 1.64 +/- 0.61ng.ml-1 respectively compared to that of normal renal group. It was confirmed that gastric juice and bile juice contain the free and conjugated CA during surgical operation and by the infusion of DA, free and conjugated DA are excreted into gastric juice and bile juice and also conjugated CA in the gastric juice from chronic renal failure group is increased.     

Effect of bile acid gavage or vagotomy and pyloroplasty on gastrointestinal carcinogenesis

Possible promotion of MNNG-induced gastrointestinal carcinogenicity was evaluated in male Wistar rats exposed to unconjugated bile acid given as gavage or as obtained through truncal vagotomy plus pyloroplasty. No significant difference was found compared with the relevant control groups. Even though gastroduodenal erosions were found more frequently in the bile acid gavage and MNNG groups than in MNNG-treated controls, secondary deconjugated bile acids apparently did not reach optimal promoting concentrations. In contrast to partial gastrectomy, vagotomy and pyloroplasty does not increase the tumor yield in the rat.     

胃手术后的胆汁反流与残胃粘膜病变的研究

为了解胃手术方式对胆汁反流及残胃粘膜的影响，作者观察了６５例残胃患者［毕氏１式１７例，毕氏Ⅱ式２０例，选择性迷走神经切断加胃窦部切除１６例，高选择性迷走神经切断（ＨＳＶ）１２例］及１５例溃疡病患者胃液胆酸浓度、ｐＨ及胃内细菌变化，并对残胃粘膜进行组织学检查。发现各种胃手术组胃液胆酸浓度均高于溃疡病组（对照组），其中Ｂ－Ⅱ组胃液胆酸浓度、ｐＨ及菌量升高最明显，而ＨＳＶ组则显著低于其他各手术组（Ｐ＜０．０１），残胃粘膜组织学异常改变的程度亦显著低于其他手术组（Ｐ＜０．０５，Ｐ＜０．０１）。结果表明：胃手术方式对胆汁反流可产生重要影响，残胃粘膜组织学异常改变与胃液胆酸浓度、ｐＨ的升高以及胃内菌量的增多有关。作者认为，选用保留幽门及生理功能的术式，能减少肠胃反流的发生，对预防残胃粘膜出现癌前病变及癌变有重要意义。     

Effects of fecal bile acids on experimental colon carcinogenesis]

Because of the in a controversial way held discussion on an possibly existing connection between bile acid metabolism and the development of colonic carcinomas experimental researches on this problems were carried out with Wistar rats. Two test series with altogether 130 animals manifested independently from each other the result of a provable connection. During model tests small bowel resections and colon exclusion operations were realized. The carcinoma protection was accomplished by 1.2 dimethylhydrazine administered for 14 weeks in a doses of 20 mg/kg body weight. The carcinoma was proved after a 32-weeks-period. It was shown that in case of shortening the ileum more than in case of reduction of the jejunum on the left-side colon adenocarcinomas develop and the amount of the excreted fecal bile acids is the highest one. In bypassing the left-side section of the colon carcinomas develop also on the left side of the colon. But their number is significantly lower than of those on the right side. The test results indicate a causal connection.     

Effect of pyloric drainage procedures on gastric passage and bile reflux after esophagectomy with gastric conduit reconstruction

BACKGROUND AND AIMS: Controversy still exists about the need for pyloric drainage procedures (pyloroplasty or pyloromyotomy) after esophagectomy with esophagogastrostomy and vagotomy. Although pyloric drainage may prevent postoperative delayed gastric emptying, it may also promote bile reflux into the oesophagus. We analysed pyloric drainage methods for their potential effect on gastric outlet obstruction and bile reflux in patients undergoing esophagectomy. MATERIALS AND METHODS: One hundred and ninety-eight patients with esophageal carcinoma were treated by transthoracal esophagectomy with gastric conduit reconstruction either with pyloromyotomy (group II, n = 118), pyloroplasty (group III, n = 34) or without pyloric drainage (group I, n = 46) between January 2000 and December 2004. The postoperative gastrointestinal passage by radiological investigation, anastomotic leakage rate, mortality and incidence of gastroesophageal reflux by endoscopy within the first postoperative year were retrospectively analysed. RESULTS: Patient demographics and the types of surgical procedures did not differ between the three groups. There was no difference in hospital mortality, anastomotic leakage rate, gastrointestinal passage and postoperative hospital stay between the three groups. However, more patients with pyloric drainage showed bile reflux (I = 0% vs II+III=14.9%, p = 0.069) and reflux esophagitis (I = 10.3% vs II+III = 34.5%, p < 0.05) compared to patients without pyloric drainage. On the multivariate analysis, pyloric drainage and the anastomotic height were independent and were significant risk factors associated with postoperative reflux esophagitis. CONCLUSION: Pyloric drainage after esophagectomy with gastric conduit reconstruction should be omitted because it does not improve gastric emptying and may favour biliary reflux esophagitis.     

The extent of bile reflux and development of gastric cancer after resections in rat

Authors performed gastric resections (Billroth II, Billroth I, Billroth II+, Braun anastomosis and Roux Y reconstruction) and laparotomies in five groups, of 110 Wistar male rats. Thirty-eight weeks postoperatively the surviving 91 animals were sacrificed, and histological study was made of the frequency of gastric stump cancer in the individual groups and the extent of bile reflux characteristic of the individual GEA types was measured. Based on their results, the risk of stump cancer was higher in operation types associated with considerable bile reflux (a cancer incidence rate of 50% after Billroth II, 28.5% after Billroth I). Following gastric resections accompanied by insignificant bile reflux (Billroth II + Braun, Roux Y) the risk of gastric stump cancer was significantly lower.     

Experimental study of the effect of bile juice on the remnant gastric cancer development

Experimental studies were performed to investigate the role, if any, of bile reflux in cancer development in the stomach. A 20% solution of human bile juice and 50 micrograms/ml of the known carcinogenic MNNG were given perorally and heterochronically to male Wistar rat, and the incidence of carcinoma in the gastric gland of the rat was studied. The animals were divided into 4 groups: Group I, to which only MNNG was given. Group II, to which human bile juice and then MNNG were administered. Group III, to which MNNG and then human bile juice were administered. And Group IV, to which only human bile juice was given. The incidence of cancer was 37.5% (3/8) in Group II, 25% (2/8) in Group III, and 0% in Group I (0/12) and IV (0/12). The gastric gland mucosa was histologically examined at various times and also by microautoradiography using 3H-TdR. The results suggested that a reverse flow of bile juice to the human remnant stomach may induce an increase in proliferative cells in the lacunar epithelia of the stomach mucosa and that a predisposed site would then be available for cancer development.     

Suppression of gastric acid secretion in patients with gastroesophageal reflux disease results in gastric bacterial overgrowth and deconjugation of bile acids

The aim of this study was to test the hypothesis that gastric bacterial overgrowth is a side effect of acid suppression therapy in patients with gastroesophageal reflux disease (GERD) and that the bacteria-contaminated gastric milieu is responsible for an increased amount of deconjugated bile acids. Thirty patients with GERD who were treated with 40 mg of omeprazole for at least 3 months and 10 patients with GERD who were off medication for at least 2 weeks were studied. At the time of upper endoscopy, 10 ml of gastric fluid was aspirated and analyzed for bacterial growth and bile acids. Bacterial over-growth was defined by the presence of more than 1000 bacteria/ml. Bile acids were quantified via high-performance liquid chromatography. Eleven of the 30 patients taking omeprazole had bacterial over-growth compared to one of the 10 control patients. The median pH in the bacteria-positive patients was 5.3 compared to 2.6 in those who were free of bacteria and 3.5 in the control patients who were off medication. Bacterial overgrowth only occurred when the pH was >3.8. The ratio of conjugated to unconjugated bile acids changed from 4:1 in the patients without bacterial overgrowth to 1:3 in those with bacterial growth greater than 1000/ml. Proton pump inhibitor therapy in patients with GERD results in a high prevalence of gastric bacterial overgrowth. The presence of bacterial overgrowth markedly increases the concentration of unconjugated bile acids. These findings may have implications in the pathophysiology of gastroesophageal mucosal injury.     

Maximal gastric secretion and duodenogastric reflux in patients with gastric or duodenal ulcer and in control subjects

Maximal gastric secretion was studied in 41 unoperated patients with gastric ulcer, 201 patients with duodenal ulcer, and 122 control subjects. The patients with a gastric ulcer were divided into high, body and prepyloric, according to the site of the ulcer. Both high and body gastric ulcers secreted significantly less than the controls, and the duodenal ulcer patients secreted significantly more. However, the patients with gastric ulcer were older and lighter than the controls and, since these factors are known to influence maximal gastric secretion, the controls and patients with duodenal ulcer were standardized to the mean weight (and age, for the controls) of the gastric ulcer group. After this standardization, there was no significant difference in secretion between the patients with body ulcers and normal controls. Pyloric loss was a similar percentage of maximal gastric secretion in all groups, but duodenogastric reflux was higher in the gastric ulcer group compared to the controls. The mean volume of duodenogastric reflux was greatest in the patients with a prepyloric gastric ulcer. It is commonly accepted that hyposecretion in patients with a gastric ulcer is due to gastritis consequent upon increased duodenogastric reflux. However, in this study, no gastric hyposecretion was evident in the body and prepyloric gastric ulcer groups, both of whom had greater than normal levels of duodenogastric reflux.