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Gastroesophageal reflux disease poorly responsive to single-dose proton pump inhibitors in patients without Barrett's esophagus: acid reflux, bile reflux, or both?

OBJECTIVES: Studies using ambulatory pH and esophageal bile reflux monitoring (Bilitec) have shown that both acid reflux and duodeno-gastro-esophageal reflux (DGER) frequently occur in patients with gastroesophageal reflux disease (GERD). A subset of patients with GERD has persistent reflux symptoms in spite of standard doses of proton pump inhibitors (PPIs). The aim of the present study was to investigate the role of acid and DGER in patients with reflux disease poorly responsive to PPIs. METHODS: Sixty-five patients (32 men, 44 +/- 2 yr) without Barrett's esophagus and with persistent heartburn or regurgitation during standard PPI doses were studied. They underwent upper gastrointestinal endoscopy and simultaneous 24-h ambulatory pH and Bilitec monitoring while PPIs were continued. RESULTS: Thirty-three patients (51%) had persistent esophagitis. Seven patients (11%) had only pathological acid exposure, 25 (38%) had only pathological DGER exposure, and 17 (26%) had pathological exposure to both acid and DGER. Acid exposure under PPI was positive in only 37%, but adding Bilitec increased the diagnoses of persistent reflux to 75%. Patients with persistent esophagitis had similar acid exposure, but significantly higher DGER exposure than those without esophagitis. The highest prevalence of esophagitis was found in patients with pathological exposure to both acid and DGER; symptoms did not differ according to the type of reflux. CONCLUSIONS: Combined pH and Bilitec monitoring is superior to pH monitoring alone in demonstrating ongoing pathological reflux in patients with medically poorly responsive reflux disease.

Adult↗

Bile reflux gastritis.

Bile reflux gastritis is a disabling postgastrectomy condition characterized by abdominal pain, bilious vomiting, and weight loss. The syndrome appears to be caused by free enterogastric reflux of bile and other proximal small bowel constituents. Endoscopic confirmation of bile reflux and documentation of gastritis support the diagnosis but are not specific for it. Results of medical therapy with chelating agents or drugs that promote gastric motility have been disappointing. Diet and antacids frequently aggravate symptoms. The only effective treatment is surgical diversion of bile away from the gastric mucosa. During a recent seven-year period, 15 patients had diversionary operation for bile reflux gastritis diagnosed by history and endoscopic findings. Before operation, medical management had failed to yield improvement in any case. After operation, all patients showed improvement, and pain was relieved in 85%. Based on our experience, we conclude that current medical therapy may alter but not cure symptoms of bile reflux gastritis; Roux-en-Y diversion is the treatment of choice in patients with persistent symptoms; and delayed gastric emptying is a common complication after the Roux-en-Y procedure, but in our series, the incidence was reduced by using the Tanner 19 modification. New cytoprotective agents that may offer an alternative to operation are currently being studied.

Adult↗

Endoscopical and histological features in bile reflux gastritis.

Bile reflux gastritis is due to an excessive reflux of duodenal contents into the stomach. The increased enterogastric reflux may provide the basis for increased mucosal injury. Bile reflux gastritis can appear in two circumstances: gastric resection with ablation of pylorus and primary biliary reflux due to the failure of pylorus. The aim of the study was to evaluate the endoscopical and histological changes caused by duodenal reflux on the gastric mucosa. The mucosal features were correlated with the risk factors involved in the development of bile reflux gastritis. Our study included 230 patients with alkaline reflux gastritis admitted in Medical Clinic no. 1, Emergency County Hospital Craiova. In all cases we performed an upper gastrointestinal endoscopy. Multiple biopsies were taken from gastric mucosa in 89 patients and the histological features were scored in accordance with the Sydney system. The average age of the patients with bile reflux gastritis was 58.387 years and the incidence of alkaline reflux gastritis was higher between 51 and 80 years. Reflux gastritis was noted to 138 males lpar;60%rpar; and 92 females (40%), ratio males/females was 1.5/1. The most frequent risk factors for bile reflux gastritis were gastric and biliary surgery. Alkaline reflux gastritis was observed in 167 cases (72.6%) after gastric surgery, consisting in gastric resection, pyloroplasty and gastroenteric-anastomosis. Gastroduodenal reflux after biliary surgery was noted in 17 cases (7.39%), 13 cases (5.69%) with cholecystectomy and four cases (1.73%) with biliary anastomosis. The average time interval from original operation to the discovery of the alkaline reflux gastritis was 14.91 years after gastric surgery and 15.29 years after biliary surgery. The commonest endoscopic alterations were: erythema of the gastric mucosa in 139 cases (64.43%), the presence of bile into the stomach in 133 cases (57.83%), the thicken of gastric folds in 22 cases (9.55%), erosions in 12 cases (5.22%), gastric atrophy in 12 cases (5.22%), petechiaes in five cases (2.17%), intestinal metaplasia one case (0.43%) and gastric polyp one case (0.43%). The histologic alterations observed from tissues collected during endoscopic examination were: chronic inflammation in 75 cases (84.06%), foveolar hyperplasia in 36 cases (40.44%), intestinal metaplasia in 31 cases (34.83%), acute inflammation in 16 cases (16.08%), Helicobacter pylori infection in 16 cases (16.08%), chronic atrophic gastritis in 12 cases (13.46%), gastric polyps in 12 cases (13.46%), dysplasia in 10 cases (11.23%), benign ulcerations in seven cases (3.04%), edema in six cases (6.74%) and neoplasia two cases (2.24%). Conclusions. Bile reflux gastritis was more frequent to male gender. The most frequent risk factors for alkaline reflux gastritis were gastric and biliary surgery. Reflux gastritis after gastric resection, pyloroplasty and gastroenteric-anastomosis were more frequent to male gender, while cholecystectomy and biliary anastomosis were predominantly to female gender. The average time interval from original operation to the discovery of the bile reflux gastritis was similar after gastric and biliary surgery. The commonest endoscopic alterations were: erythema of the gastric mucosa, the presence of bile into the stomach, thickens of gastric folds, erosions, gastric atrophy, petechiaes, intestinal metaplasia and gastric polyp. Acute inflammation, Helicobacter pylori infection, gastric polyps and benign ulcerations were more frequent in patients with bile reflux gastritis after gastric surgery, while edema and dysplasia were increased after biliary surgery.

Adult↗

The clinical significance of bile reflux.

Although bile reflux into the stomach has been a subject of major interest during the last 15 years, its role in gastric pathology is not fully understood. The simple technique of sampling gastric contents and measuring bile acids is probably the most useful and reliable method available. Whether the reflux always precedes ulceration or is caused in some way by the gastritis remains unresolved, for bile reflux is common in many clinical situations where gastritis is present. After gastric surgery bile has been blamed for the gastritis which occurs as well as symptoms of post prandial epigastric discomfort, heartburn and bile vomiting. This is probably the only clinical situation where further procedures have been examined which specifically divert bile away from the stomach with good results. Bile reflux is also very common in patients with heartburn suggesting that bile and acid are both necessary to produce oesophagitis and heartburn. This is borne out by clinical observations and experimental work in animals. With the exception of those patients who have had gastric surgery, we have little or no evidence of the consequences of bile exclusion from the stomach in other pathological situations.

Bile Acids and Salts↗

Gallbladder function and fasting enterogastric bile reflux.

The relationship between gallbladder function and duodenogastric reflux of bile has been investigated in the fasting phase by 99Tcm-EHIDA biliary scintigraphy in 370 patients with abdominal pain. This isotope is cleared from the blood-pool by hepatocellular function and is excreted into the biliary tract. Obstruction of the common bile duct was found in 79 patients, leaving 291 who were evaluable for duodenogastric bile reflux. Gallblader function was present in 169 and absent in 122 patients. Duodenogastric reflux of bile was observed in 82 patients, 10 of whom had had previous gastric surgery. Only 298 of 169 (17%) patients with a functioning gallbladder showed evidence of enterogastric bile reflux compared to 43 of 122 (35%) with absent gallbladder function (p less than 0.005 by Chi Square). These results suggest that continuous bile flow into the duodenum in the absence of a functioning gallbladder facilitates duodenogastric reflux.

Adult↗

Persistent acid and bile reflux in asymptomatic patients with Barrett esophagus receiving proton pump inhibitor therapy.

HYPOTHESIS: Symptom control does not reflect elimination of abnormal acid reflux or abnormal bile reflux in patients with long-segment Barrett esophagus receiving proton pump inhibitors (PPIs). DESIGN: Prospective survey. SETTING: University hospital. PATIENTS: Thirty-two patients with long-segment Barrett esophagus who were asymptomatic with PPIs. MAIN OUTCOME MEASURES: Twenty-four-hour ambulatory pH and bile reflux monitoring while continuing PPIs. RESULTS: Abnormal acid reflux (pH <4 for 11.9% [interquartile range, 6.8%-19.6%) of 24 hours] persisted in 15 patients (47%) who could not be distinguished from those with normal acid reflux (pH <4 for <4.5% of 24 hours) by any endoscopic, manometric, or therapeutic characteristic. Abnormal bile reflux (absorbance >0.14 for 8.7% [interquartile range, 3.9%-8.7%] of 24 hours) was detected in 11 (48%) of 23 patients, such that both normal bile reflux (absorbance >0.14 for <1.8% of 24 hours) and normal acid reflux were observed in only 8 patients (35%). There was no association between abnormal acid reflux and abnormal bile reflux. CONCLUSIONS: Despite symptom control with PPIs, both acid reflux and bile reflux were controlled in only one third of patients. Posttherapeutic monitoring of acid and bile reflux is recommended in future clinical trials of PPI treatment vs laparoscopic antireflux surgery.

2-Pyridinylmethylsulfinylbenzimidazoles↗

[Clinical characteristics of bile reflux gastritis].

Thirty patients with bile reflux gastritis, proven by gastroscopy and Milk 99mTc-EHIDA Test, were studied and their clinical features were compared with those of patients with non-bile reflux gastritis. The symptoms were similar in both groups of patients, whereas histologically in bile reflux gastritis there were more hyperemia of mucosa, more obvious edema in lamina propria and more polymorphonuclear infiltration. Furthermore, in bile reflux gastritis the histological changes were more severe in the antrum and decreased in severity toward the cardia. Acid secretion was significantly lower in patients with bile reflux gastritis than in patients with non-bile reflux gastritis while the serum gastrin level was significantly higher in the former than in the latter group. The authors suggest that there may be a vicious cycle among duodenogastric reflux, low level of gastric acidity and high level of serum gastrin. When duodenogastric reflux occurs, not only the bile salts damage the gastric mucosa and subsequently cause the back diffusion of hydrogen ion but also the alkaline duodenal juice neutralizes the gastric acid, resulting in decrease of gastric acidity. The bile salts and low acidity can stimulate the release of serum gastrin which antagonizes the effects of cholecystokinin and secretin on pyloric tone and aggravates the duodenogastric reflux.

Adult↗

[An experimental study on the effect of vagotomy on stress ulcer and the influence of bile reflux].

I investigated the significance of bile reflux, when vagotomy was done to stress ulcer, by means of measuring gastric ulcer index, gastric pH and serum gastrin levels of rats. And in order to examine influence of alkali factor of bile, I measured gastric acid output and serum gastrin levels after alkali or acid solution was infused into the untreated rat's stomach. Results were summarized as follows: 1. When I infused alkali solution into the untreated stomach, there was no significant change in serum gastrin level but gastric acid output was significantly accelerated, as compared with infusing acid solution. On the other hand, when I infused alkali solution into the vagotomized stomach, serum gastrin level increased significantly and gastric acid output was significantly accelerated, as compared with infusing acid solution, so, acceleration of acid output observed when I infused alkali solution into the untreated stomach was not suppressed in spite of vagotomy operation. 2. In the vagotomized group, gastric acid output was significantly suppressed and serum gastrin level increased significantly as compared with the untreated group. But, when bile was led into the stomach in the vagotomized group, acid output was accelerated and serum gastrin level also showed a tendency to increase as compared with the group of vagotomy alone. 3. When mild stress was inflicted, stress ulcer formation was significantly prevented in the bile reflux group (vagotomy + pyloroplasty) as well as in the non-bile reflux group (vagotomy + pyloric ligation + gastroileostomy) if vagotomy was done. But, when severe stress was inflicted, stress ulcer formation was significantly prevented in the non-bile reflux group, but not prevented in the bile reflux group. As mentioned above, it was proved that stress ulcer formation was not prevented under a severe stress, if bile reflux existed, even though vagotomy was done. So, if we do vagotomy operation, we need to choose the operation method not to induce bile reflux as much as possible.

Animals↗

Spontaneous bile reflux in the elderly.

Duodenogastric bile reflux is common in postoperative stomach but has been reported in intact stomachs. Spontaneous bile reflux in the elderly has not been studied before. This has been assessed in dyspeptic elderly and young patients. Total bile acid (TBA) levels and pH were measured in the samples of fasting gastric juice. Antral biopsies were taken for histological examination including Helicobacter pylori identification. TBA levels were significantly higher in elderly patients with gastritis in comparison to elderly and young normal groups. Only 10% of elderly patients with gastritis and 7% with gastric ulcer has abnormal TBA (> 1 mmol/l). There was some correlation between the pH and TBA but a significant proportion of elderly patients has pH > 4 with a normal TBA. TBA levels were not significantly different in H. pylori +ve and H. pylori -ve patients. Nineteen elderly patients had evidence of reactive gastritis. Five of these patients had raised TBA levels with severe H. pylori infection. The remaining 15 patients had normal TBA. These patients were on NSAIDs and 4 of them had H. pylori infection. We conclude that spontaneous bile reflux in the elderly is uncommon. Hypochlorhydria which is observed in the elderly is not caused by alkaline bile reflux. The main cause of reactive gastritis in the elderly is NSAIDs ingestion.

Adult↗

The relationship between acid and bile reflux and symptoms in gastro-oesophageal reflux disease.

BACKGROUND: The role of bile in the genesis of oesophageal symptoms and disease is incompletely understood. A new method of ambulatory bile monitoring may help to define this role. AIMS: To establish the relationship between symptom events and acid and bile reflux episodes. PATIENTS: 59 consecutive patients presenting for further investigation of gastro-oesophageal reflux disease. METHODS: All patients underwent combined ambulatory pH and bile monitoring. For each patient, a symptom index (SI) was calculated in relation to both acid reflux and bile reflux episodes. RESULTS: Patients were divided into those without (group 1, n = 21) and those with (group 2, n = 38) acid reflux. A total of 394 symptoms were identified in 59 patients. In group 1, there were fewer symptom events per patient (mean 4.1) than group 2 (mean 8.1). Twenty three per cent of symptom events were associated with acid reflux in group 1 and 41% in group 2. Only 6% of symptom events in both groups were related to bile reflux. In group 1 both the acid and bile related SI score were low. In group 2 the bile related SI score was low, but the acid related SI score was high. CONCLUSIONS: Symptoms are much more often related to acid reflux than bile reflux. Bile reflux does not seem to be a major factor in producing oesophageal symptoms.

Adult↗

Gastric pathology in cholecystectomy patients: role of Helicobacter pylori and bile reflux.

The data regarding the role of Helicobacter pylori infection in patients with bile reflux are conflicting. Bile reflux is often observed after cholecystectomy. This study focuses on the role of H. pylori in gastric pathology of patients who had undergone cholecystectomy. Eighty-seven consecutive patients were included in the study. An upper gastrointestinal endoscopy was performed, and biopsy specimens were taken in the antrum, incisura angularis, and in the gastric body. The presence of bile reflux in gastric fluid at endoscopic examination was recorded. The overall H. pylori infection rate was 62%, with no difference between patients with (59.7%) and without (64%) endoscopic bile reflux (p = 0.67). The intestinal metaplasia rate in gastric mucosa was significantly higher in patients with both H. pylori and bile reflux than in patients without infection and bile reflux (36.4% vs. 5.6%, p = 0.02). Moreover, the mean number of years after cholecystectomy in patients with intestinal metaplasia was significantly higher than in those without metaplasia (21.1 +/- 7 vs. 11.5 +/- 8 years, p < 0.0001), whereas mean age did not differ significantly between groups (60.3 +/- 12 vs. 55.8 +/- 11 years, p = 0.14). Furthermore, we found four cases of gastric cancer, three with H. pylori infection. The mean number of years after cholecystectomy was significantly higher in patients with gastric cancer than in other patients (21.8 +/- 4 vs. 12.2 +/- 8 years, p = 0.009). This study found that H. pylori infection is frequent in cholecystectomized patients, also in the presence of endoscopic bile reflux. Bile reflux seems to act synergistically with H. pylori infection on gastric pathology.

Adult↗

Healthy controls have as much bile reflux as gastric ulcer patients.

Data on duodenogastric reflux of bile in gastric ulcer are conflicting. We therefore measured intragastric bile acid concentration and its composition from individual bile acids, duodenogastric bile acid reflux rate, gastric emptying rate, and secretion rates of volume and acid in 30 patients with gastric ulcer and in 66 healthy controls, both in the fasting state and after feeding a liquid meal. Patients had higher gastric bile acid concentrations (p less than 0.05) than controls in the fasting state, but the overlap between the groups was considerable. In fasting patients with corpus ulcer, gastric secretion rates were significantly decreased when compared with controls. There was no difference between patients and controls with respect to gastric emptying rate, bile acid reflux rate, intragastric amount of bile acids, and bile acid composition in the fasting state. Postprandially, all parameters tested were similar in patients and controls. Controls showed high reflux rates with similar frequency as did ulcer patients. We conclude that increased gastric bile acid concentrations in the fasting stomach of patients with gastric ulcer are the result of gastric hyposecretion and not of increased reflux. They probably are pathogenetically irrelevant.

Adult↗

Bile reflux gastritis and Barrett's oesophagus: further evidence of a role for duodenogastro-oesophageal reflux?

BACKGROUND: There is increasing evidence that reflux of bile plays a part in the pathogenesis of Barrett's oesophagus. Bile injury to the gastric mucosa results in a "chemical" gastritis in which oedema and intestinal metaplasia are prominent. AIM: To determine if patients with Barrett's oesophagus have more bile related changes in antral mucosa than patients with uncomplicated gastro-oesophageal reflux disease (GORD) or non-ulcer dyspepsia (NUD). PATIENTS AND METHODS: Patients were identified by a retrospective search of pathology records and those with a clinically confirmed diagnosis of either Barrett's oesophagus or reflux oesophagitis who had oesophageal and gastric biopsies taken at the same endoscopy and had no evidence of Helicobacter pylori infection entered the study. Control biopsies were taken from H pylori negative NUD patients. Antral biopsies were examined "blind" to clinical group and graded for a series of histological features from which the "reflux gastritis score" (RGS) and "bile reflux index" (BRI) could be calculated. The reproducibility of these histological scores was tested by a second pathologist. RESULTS: There were 100 patients with Barrett's, 61 with GORD, and 50 with NUD. The RGSs did not differ between groups. BRI values in the Barrett's group were significantly higher than those in GORD subjects (p=0.014) which in turn were higher than those in NUD patients (p=0.037). Similarly, the frequency of high BRI values (>14) was significantly greater in the Barrett's group (29/100; 29%) than in the GORD (9/61; 14.8%) or NUD (4/50; 8%) group. However, agreement on BRI values was "poor", indicating limited applicability of this approach. CONCLUSION: Patients with Barrett's oesophagus have more evidence of bile related gastritis than subjects with uncomplicated GORD or NUD. The presence of bile in the refluxate could be a factor in both the development of "specialised" intestinal metaplasia and malignancy in the oesophagus.

Adult↗

[The role of detecting bile reflux in the diagnosis of gastroesophageal reflux disease].

OBJECTIVE: To investigate the incidence of esophageal bile reflux and its relationship with acid or alkaline reflux and to evaluate the significance of detecting bile reflux in the diagnosis of gastroesophageal reflux disease (GERD). METHODS: Using ambulatory 24-hour pH monitoring and bilirubin monitoring technique, the changes of 24-hour intraesophageal pH and bile reflux in 34 subjects (including healthy subjects, patients with reflux esophagitis and patients after gastrectomy) were simultaneously assessed. RESULTS: The time of esophageal acid exposure for reflux esophagitis (RE) patients was significantly longer than that in the controls and the patients after gastrectomy, but there was no difference between postgastrectomized patients and healthy controls. Total percent time of pH > 8 in each group was similar and were very low. Bile reflux [duodenogastroesophageal reflux (DGER)], represented by total time percentage of bilirubin absorbance >or=0.14, was greatest in postgastrectomized patients, and next in the patients with RE, but the value in both groups was significantly higher than that in the controls. There was a close association between DGER and total time percentage of pH < 4 (r = 0.75, P < 0.05) but a poor relationship (r = 0.17) with total time percentage pH > 8. 63.6% of the patients with RE had acid and bile reflux simultaneously. CONCLUSION: DGER is common in GERD and postgastrectomized patients. It can occur with acid reflux and may play a role in the development of GERD. It is very important to monitor acid and bile reflux at the same time in the diagnosis of GERD.

Adult↗

The significance of gastric bile reflux seen at endoscopy.

We evaluated the significance of bile seen in the stomach at the time of endoscopy. Twenty-three percent of 110 consecutive patients undergoing elective panendoscopy were found to have bile in their stomachs. Gastric biopsies were obtained from these patients. To assess the significance of bile reflux, the patients underwent a quantitative gastric bile analysis on two separate days. On day 1, gastric juice was aspirated by nasogastric suction, and bile acid concentrations were measured. On day 2, bile reflux into the stomach was quantitated by scintiscan measurement of gastric nucleotide after intravenous administration of 99mTc-DISIDA. Approximately half the patients with bile reflux showed histologic evidence of mucosal injury. However, fewer than half with histologic injury had significant bile reflux when measured by quantitative methods. There was no correlation among the gastric bile acid concentration, degree of histologic injury, or severity of endoscopic changes. We conclude that finding bile reflux at endoscopy is probably of no clinical significance.

Bile Reflux↗

Ursodeoxycholic acid treatment of bile reflux gastritis.

Intractable epigastric pain associated with nausea and bilious vomiting often follows gastric surgery and has been attributed to reflux of bile and the irritating effects of endogenous bile acids on the gastric remnant. To test the effect of changing bile acid composition of the refluxed material on the symptoms and gastric mucosal histology, 12 patients with symptomatic alkaline reflux gastritis were treated for 1 mo with placebo and for 1 mo with ursodeoxycholic acid, 1000 mg/day. Before treatment, all patients were symptomatic and manifested epigastric pain, nausea, and bilious vomiting. The gastric mucosa was erythematous, friable, and bile stained, and the histology revealed chronic inflammation. No significant change in symptoms was noted during administration of placebo. In contrast, ursodeoxycholic acid treatment resulted in a profound decrease in the intensity and frequency of pain and almost abolished nausea and vomiting. During bile acid therapy the proportion of ursodeoxycholic acid in gastric bile rose to 50% of total bile acids, whereas cholic and deoxycholic acids decreased and chenodeoxycholic acid remained unchanged. The macroscopic and microscopic appearance of the gastric mucosa, however, did not change after 1 mo of ursodeoxycholic acid treatment. These results suggest that increasing the proportion of ursodeoxycholic acid in refluxed gastric bile reduces the pain and frequency of symptoms associated with bile reflux.

Adult↗

Primary bile reflux gastritis: diagnosis and surgical treatment.

Bile reflux gastritis has been recognized since the first successful gastric operations and has persisted for more than a century. Diagnosis has been difficult and non-operative therapy largely ineffective. Early attempts at surgical correction resulted in stomal ulceration and it was not until the advent of flexible endoscopy and other techniques that diagnosis became more secure. Operative attempts at correction have included the Roux-en-Y procedure, the Braun enteroenterostomy, and Henley jejunal interposition. None of the procedures has been uniformly successful, and the Roux-en-Y has resulted in a disabling stasis syndrome in most patients. The diagnosis of bile reflux without previous gastric surgery has been even more elusive and seems to be associated with previous cholecystectomy. Thirty-one patients diagnosed with primary bile reflux, having typical symptoms of epigastric pain, nausea, and bilious vomiting have been treated by diverting bile flow through a Roux-en-Y choledochojejunostomy without accompanying gastric resection or vagotomy. There were no operative deaths and no long-term problems, such as anastomotic stricture. Two patients had self-limited bile leaks. Twenty-seven of the 31 patients (87%) have achieved complete relief of symptoms and have no gastrointestinal complaints. Serial gastric emptying has demonstrated no alteration in 9 of 12 patients who were normal before operation, and improvement in 12 of the 19 (63%) patients with abnormal preoperative studies.

Anastomosis, Roux-en-Y↗