Acid and bile reflux in erosive reflux disease, non-erosive reflux disease and Barrett's esophagus

BACKGROUND/AIMS: Gastroesophageal reflux disease (GERD) may occur with acid, bile or in a mixed form. Endoscopic injury and mucosal metaplasia are a known sequlae to pathological GERD. The aim of the study was to determine the contribution of acid and duodenogastroesophageal reflux (DGER) to endoscopic severity in patients with GERD and Barrett's esophagus. METHODS: Ninety-one patients complaining of reflux symptoms were studied with upper gastrointestinal endoscopy and graded to non-erosive reflux disease (NERD), erosive reflux disease (ERD) and Barrett's esophagus (BE). Esophageal manometry and simultaneous ambulatory 24-h esophageal pH and bilirubin monitoring (Bilitec 2000) were done to all patients. RESULTS: Seventy one patients (78.0%) had ERD (Savary-Miller (grade I-III), 11 patients (12.1%) had NERD and 9 patients (9.9%) had BE suspected endoscopically and diagnosed by histological esophageal biopsy. Combined 24-h esophageal bilirubin and pH monitoring revealed that 39 patients (42.9%) had mixed acid and bile reflux, 16 (17.6%) had pathological acid reflux only, 18 (19.8%) had bile reflux only and 18 patients (19.8%) had no evidence of abnormal reflux. The percentage of the total time of bilirubin absorbance above 0.14, in 71 patients with ERD was (8.18 +/- 11.28%), and in 9 patients with BE was (15.48 +/- 30.48%) which was significantly greater than that in 11 patients with NERD (4.48 +/- 8.99%), p < 0.05 and p = 0.01 respectively. All BE patients had abnormal esophageal bile reflux (3 bile alone and 6 mixed bile and acid); 44 of 71 patients (61.97%) with ERD had abnormal esophageal bile reflux (13 bile alone and 31 mixed bile and acid); meanwhile 15 of them (21.2%) had abnormal acid exposure alone. Of the 11 patients with NERD, 4 patients (36.4%) had abnormal esophageal bile reflux, 2 of them mixed with acid. CONCLUSIONS: The Bilitec method reliably identifies the presence of bilirubin and quantitatively detects duodenogastroesophageal reflux of bile. Mixed reflux (acid and bile) is the chief pattern of reflux in GERD patients in this study. Bile reflux either alone or mixed with acid reflux contributes to the severity of erosive and non-erosive reflux disease as well as to Barrett's esophagus.     

Quantification of gastro-esophageal reflux in Barrett's esophagus

In the present paper we analyze the importance of gastro-oesophageal reflux in 20 patients with Barrett's oesophagus and in 20 patients with esophagitis without Barrett's mucosa; ten of this last group had mild esophagitis and ten severe inflammatory changes. In all the cases the oesophageal pH was measured during 24 hours; the results showed that although the reflux was more important in the group of patients with Barrett's esophagus than in the whole group of patients with esophagitis without Barrett's esophagus, figures were similar in the group with severe oesophagitis and the group with Barrett's oesophagus. We conclude that the pathogenesis of Barrett's esophagus includes factors other than gastroesophageal reflux.     

Duodenogastric reflux in patients with Barrett's esophagus

The role of duodenogastric reflux in the pathogenesis of gastroesophageal reflux disease is not clear. Using hepatobiliary scanning techniques, we found evidence of duodenogastric reflux in six of 13 patients with Barrett's esophagus. This compares with only two positive studies in 19 control subjects. This difference is statistically significant P=0.038, two-tailed Fisher's exact test). Three of nine patients who had gastroesophageal reflux without Barrett's esophagus had evidence of duodenogastric reflux, a frequency not significantly different from either of the other groups. Gastroesophageal reflux of bile and pancreatic enzymes, in addition to gastric acid may contribute to the greater esophageal damage often seen in Barrett's esophagus. The presence of duodenogastric reflux in these patients may have important pathophysiologic and therapeutic implications.     

Barrett's esophagus in patients with symptomatic reflux esophagitis

We evaluated the frequency with which Barrett's esophagus (BE) occurs in patients with symptomatic reflux esophagitis, and compared the clinical endoscopic and manometric features of patients with Barrett's esophagus with those of patients who had non-Barrett's esophagitis (NBE). The effect of 6 months' medical treatment on BE patients was reevaluated by repeating manometry, endoscopy, and biopsy. Esophageal manometry was performed by perfusion technique and endoscopic biopsies were obtained. There were 180 patients; 20 (11%) were found to have BE. The vast majority of BE patients were caucasians. BE patients had symptoms of gastroesophageal reflux for a longer time than did NBE patients. Mean lower esophageal sphincter pressure in BE patients was lower than that in NBE patients. On medical treatment, the severity of esophagitis as judged by endoscopic criteria in BE patients was reduced, but there was no increase in lower esophageal sphincter pressure and no regression of the columnar epithelium.     

Bacterial biota in reflux esophagitis and Barrett＇s esophagus

AIM: To identify the bacterial flora in conditions such as Barrett's esophagus and reflux esophagitis to determine if they are similar to normal esophageal flora. METHODS: Using broad-range 16S rDNA PCR, esophageal biopsies were examined from 24 patients [9 with normal esophageal mucosa, 12 with gastroesophageal reflux disease (GERD), and 3 with Barrett's esophagus]. Two separate broad-range PCR reactions were performed for each patient, and the resulting products were cloned. In one patient with Barrett's esophagus, 99 PCR clones were analyzed. RESULTS: Two separate clones were recovered from each patient (total = 48), representing 24 different species, with 14 species homologous to known bacteria, 5 homologous to unidentified bacteria, and 5 were not homologous (<97% identity) to any known bacterial 16S rDNA sequences. Seventeen species were found in the reflux esophagitis patients, 5 in the Barrett's esophagus patients, and 10 in normal esophagus patients. Further analysis concentrating on a single biopsy from an individual with Barrett's esophagus revealed the presence of 21 distinct bacterial species. Members of four phyla were represented, including Bacteroidetes, Firmicutes, Proteobacteria, and Actinobacteria. Microscopic examination of each biopsy demonstrated bacteria in intimate association with the distal esophageal epithelium, suggesting that the presence of these bacteria is not transitory. CONCLUSION: These findings provide evidence for a complex, residential bacterial population in esophageal reflux-related disorders. While much of this biota is present in the normal esophagus, more detailed comparisons may help identify potential disease associations.     

Increased acid and bile reflux in Barrett's esophagus compared to reflux esophagitis, and effect of proton pump inhibitor therapy

OBJECTIVES: Barrett's metaplasia is an acquired condition resulting from longstanding gastroesophageal reflux disease. Approximately 10% of esophagitis patients develop Barrett's esophagus. There is increasing evidence that duodenogastroesophageal reflux plays a role in the progression of disease. We further analyzed the correlation of acid and biliary reflux with reflux esophagitis and Barrett's esophagus and tested the effects of proton pump inhibitor therapy. METHODS: Patients with either reflux esophagitis (group 1) or Barrett's esophagus (group 2) prospectively underwent simultaneous 24-h esophageal pH and bile reflux testing without any therapy affecting acid secretion or GI motility. A total of 16 patients in group 1 and 18 patients in group 2 were tested again under proton pump inhibitor therapy. RESULTS: Acid and bile exposure were significantly increased in Barrett's patients (n = 23) compared to 20 esophagitis patients (median percentage of time that pH was <4 was 24.6% vs 12.4%, p = 0.01, median percentage of time that bilirubin absorbance was >0.2 was 34.7% vs 12.8%, p < 0.05). During therapy, both acid and bile reflux decreased significantly in both groups. Median percentage of time that pH was <4 and bilirubin absorbance was >0.2 before and during therapy was 18.2%/2.3% and 29.8%/0.7% (p = 0.001 and p = 0.001) in Barrett's esophagus patients versus 14.5%/3.6% and 21.5%/0.9% (p = 0.002 and p = 0.011) in esophagitis patients. There was no significant difference between the groups. In two esophagitis patients, bile reflux increased during therapy. CONCLUSIONS: There is a good correlation of the duration of esophageal exposure to acid and bile with the severity of pathological change in the esophagus. Both acid and bile reflux is significantly suppressed by proton pump inhibitor therapy with exceptions among individual esophagitis patients. The prolonged simultaneous attack of bile and acid may play a key role in the development of Barrett's metaplasia.     

Familial gastroesophageal reflux and development of Barrett's esophagus

The family of an elderly man with Barrett's esophagus was examined for gastroesophageal reflux and development of Barrett's esophagus. All five living children have gastroesophageal reflux or esophagitis, or both, and three have unequivocal Barrett's esophagus. Two third-generation descendents have gastroesophageal reflux. This pattern suggests autosomal dominant transmission of the gastroesophageal reflux trait. The family also has a high prevalence of cancer, which may represent the cancer family syndrome.     

Presence of acinar pancreas in reflux esophagitis and Barrett's esophagus

Pancreatic metaplasia in Barrett's esophagus was originally described by Krishnamurthy et al. They found that these focal clusters of cells resemble pancreatic acinar cells by immunohistochemistry and electron microscopy. Wang et al one year later, described these same cell clusters in normal and inflamed gastroesophageal junction. We studied 318 cases diagnosed as Barrett's esophagus (199 cases) and chronic esophagitis (119 cases) in the ABC Medical Center seen in 1996 and the first four months of 1997, to look for pancreatic acinar metaplasia. We found 14 cases of Barrett's esophagus and 11 cases of chronic esophagitis with pancreatic acinar metaplasia. By immunohistochemistry and electron microscopy that these cell clusters are actually acinar pancreatic cells. Our results are in keeping with those found by Krishnamurthy and Wang that the clusters represent pancreatic acinar cells and may be found in Barrett's esophagus and in chronic esophagitis. The significance of these findings remain to be elucidated.     

Barrett＇s esophagus and its correlation with gastroesophageal reflux in Chinese

AIM- To study the prevalence of Barrett‘s esophagus in Chinese and its correlation with gastroesophageal reflux. METHODS: This study was carded out in a large prospective series of 391 patients who had undergone upper endoscopy. The patients were divided into 3 groups according to the position of squamocolumnar junction (SC3). Reflux esophagitis (RE) and its degree were recorded. Intestinal metaplasia (IM) in biopsy specimen was typed according to histochemistry and HE and alcian blue (pH2.5) staining separately. Results correlating with clinical, endoscopic, and pathological data were analysed. RESULTS: The prevalence of IM endoscopically appearing Long-segment Barrett‘s Esophagus (LSBE) was 26.53%, Short-segment Barrett‘s Esophagus (SSBE) was 33.85% and gastroesophageal junction (GEJ) was 34.00%. IM increased with age of above 40 years old and no difference was found between male and female. Twelve were diagnosed as dysplasia (7 low -grade, 5 high-grade), 16 were diagnosed as cardiac adenocarcinoma and 1 as esophageal adenocarcinoma. The more far away the SCJ moved upward above GEJ, the higher the prevalence and the more severe the RE were. CONCLUSION: There was no difference of the prevalence of IM in different places of SCJ, and IM increased with age of above 40 years old. It is important to pay attention to dysplasia in the distal esophagus and gastro-esophageal junction, and adenocarcinoma is more common in cardia than in esophagus. BE is a consequence of gastroesophageal reflux disease.     

Tongue-like Barrett＇s esophagus is associated with gastroesophageal reflux disease

AIM： To test this hypothesis of barrett esophagus （BE） classified into two types and to further determine if there was any correlation between the shape of endoscopically suspected esophageal metaplasia （ESEM）, prevalence of reflux esophagitis （RE） and heartburn. METHODS： A total of 6504 Japanese who underwent endoscopy for their annual stomach check-up were enrolled in this study. BE was detected without histological confirmation that is ESEM. We originally classified cases of ESEM into 3 types based on its shape： Tongue-like （T type）, Dome-like （D type） and Wave-like （W type） ESEM. The respective subjects were prospectively asked to complete questionnaires concerning the symptoms of heartburn, dysphagia, and abdominal pain for a one-month period. RESULTS： ESEM was observed in 10.3% of 6504 subjects （ESEM 〈 1 cm, 9.4%; 1cm≤ESEM 〈 3 cm, 1.7%; ESEM≥3 cm, 0.5%）. The frequency of ESEM was significantly higher in males compared with female subjects. Statistical analysis showed that the prevalence of heartburn and RE were significantly higher in the T type ESEM than in the W type ESEM （P 〈 0.05）. CONCLUSION： The T type ESEM was strongly associated with reflux symptoms and RE whereas the W type ESEM was not associated with GERD.     

From reflux esophagitis to Barrett's esophagus and esophageal adenocarcinoma

The occurrence of gastroesophageal reflux disease is common in the human population.Almost all cases of esophageal adenocarcinoma are derived from Barrett's esophagus,which is a complication of esophageal adenocarcinoma precancerous lesions.Chronic exposure of the esophagus to gastroduodenal intestinal fluid is an important determinant factor in the development of Barrett's esophagus.The replacement of normal squamous epithelium with specific columnar epithelium in the lower esophagus induced by the chronic exposure to gastroduodenal fluid could lead to intestinal metaplasia,which is closely associated with the development of esophageal adenocarcinoma.However,the exact mechanism of injury is not completely understood.Various animal models of the developmental mechanisms of disease,and theoretical and clinical effects of drug treatment have been widely used in research.Recently,animal models employed in studies on gastroesophageal reflux injury have allowed significant progress.The advantage of using animal models lies in the ability to accurately control the experimental conditions for better evaluation of results.In this article,various modeling methods are reviewed,with discussion of the major findings on the developmental mechanism of Barrett's esophagus,which should help to develop better prevention and treatment strategies for Barrett's esophagus.     

Gene expression in Barrett＇s esophagus and reflux esophagitis induced by gastroduodenoesophageal reflux in rats

AIM: To investigate the difference of gene expression profiles between Barrett's esophagus and reflux esophagitis induced by gastroduodenoesophageal reflux in rats. METHODS: Eight-week-old Sprague-Dawley rats were treated esophagoduodenostomy to produce gastroduodenoesophageal reflux, and another group received sham operation as control. Esophageal epithelial tissues were dissected and frozen in liquid nitrogen immediately for pathology 40 wk after surgery. The expression profiles of 4 096 genes in reflux esophagitis and Barrett's esophagus tissues were compared with normal esophageal epithelium by cDNA microarray. RESULTS: Four hundred and forty-eight genes in Barrett's esophagus were more than three times different from those in normal esophageal epithelium, including 312 up-regulated and 136 down-regulated genes. Two hundred and thirty-two genes in RE were more than three times different from those in normal esophageal epithelium, 90 up-regulated and 142 down-regulated genes. Compared to reflux esophagitis, there were 214 up-regulated and 142 down-regulated genes in Barrett's esophagus. CONCLUSION: Esophageal epithelium exposed excessively to harmful ingredients of duodenal and gastric reflux can develop esophagitis and Barrett's esophagus gradually. The gene expression level is different between reflux esophagitis and Barrett's esophagus and the differentially expressed genes might be related to the occurrence and development of Barrett's esophagus and the promotion or progression in adenocarcinoma.     

The role of obesity in gastroesophageal reflux disease and Barrett's esophagus

The prevalence of gastroesophageal reflux disease (GERD) and related disorders has been increasing worldwide, particularly in Western populations where a parallel rise in obesity prevalence has been reported. As weight gain often overlaps with the GERD-related symptoms, several recent studies investigated the significance of this correlation, mainly using meta-analyses. Here, we discuss the large amount of evidence linking obesity and GERD-related symptoms, providing potential mechanisms for their co-occurrence. Particular attention is given also to the association between obesity, Barrett's esophagus and esophageal adenocarcinoma development.     

Free radicals and antioxidant systems in reflux esophagitis and Barrett＇s esophagus

AIM: Experimental studies suggest that free radicals are involved in acid and pepsin-induced damage of esophageal mucosa. The profile and balance between free radicals and antioxidant systems in human esophagitis are unknown. METHODS: Superoxide anion and its powerful oxidant reaction with nitric oxide (peroxynitrite) generation were determined in esophageal mucosal biopsies from 101 patients with different gastro-esophageal reflux diseases and 28 controls. Activity of both superoxide dismutase (SOD) and catalase, and reduced glutathione (GSH) levels, were also assessed. Expression of Cu,ZnSOD, MnSOD and tyrosine-nitrated MnSOD were analyzed by Western blot and/or immunohistochemistry. RESULTS: The highest levels of superoxide anion generation were found in patients with severe lesions of esophagitis. Peroxynitrite generation was intense in Barrett's biopsies, weaker in esophagitis and absent/weak in normal mucosa. Expression of Cu,ZnSOD and MnSOD isoforms were present in normal mucosa and increased according to the severity of the lesion, reaching the highest level in Barrett's esophagus. However, SOD mucosal activity significantly decreased in patients with esophagitis and Barrett's esophagus, which was, at least in part, due to nitration of its tyrosine residues. Catalase activity and GSH levels were significantly increased in mucosal specimens from patients with esophagitis and/or Barrett's esophagus. CONCLUSION: A decrease in SOD antioxidant activity leading to increased mucosal levels of superoxide anion and peroxynitrite radicals may contribute to the development of esophageal damage and Barrett's esophagus in patients with gastroesophageal reflux. Administration of SOD may be a therapeutic target in the treatment of patients with esophagitis and Barrett's esophagus.     

Gastroesophageal reflux and Barrett's esophagus in adults born with esophageal atresia

OBJECTIVE: Postoperative morbidity after correction of esophageal atresia is partly determined by gastroesophageal reflux disease, which has been proven to affect from one-half to two-thirds of patients during childhood. We conducted a follow-up study to test our hypothesis that, if former patients still show gastroesophageal reflux at adult age, they are at high risk for developing Barrett's esophagus, which is considered to be premalignant. METHODS: Of 69 patients born between 1971 and 1978, all having undergone a primary anastomosis, 24 had died, five of them because of aspiration. Of the 45 survivors, 39 could be traced; they all completed a questionnaire inquiring after symptoms related to the esophagus. Of these patients, 34 underwent an additional esophagogastrocopy. RESULTS: Only nine of the 39 patients had no symptoms at all; 30 had mild to severe dysphagia symptoms, and 13 had mild to severe reflux symptoms. Esophagogastrocopy in 34 patients revealed that the anastomosis was still recognizable in all cases, but stenoses were not found. Six patients showed a small hiatal hernia, and one a large one. The incidences of reflux symptoms (13/39, p < 0.01), reflux esophagitis (9/34, p < 0.01) and Barrett's esophagus (2/34, p < 0.001) were significantly higher than in the normal population. CONCLUSIONS: This group seems to be at risk for developing Barrett's esophagus. As this is the first follow-up study of a consecutive group of adult esophageal atresia patients, we think it is advisable to perform an esophagogastroscopy in all patients at adulthood until more long term follow-up data are available.     

Barrett's esophagus in Latinos undergoing endoscopy for gastroesophageal reflux disease symptoms

Previous studies comparing the prevalence of Barrett's esophagus in Latinos and non‐Latino whites are inconsistent. The aim of the study is to compare the prevalence of Barrett's esophagus in Latinos and non‐Latino whites and to determine risk factors associated with Barrett's esophagus. Between March 2005 and January 2009, consecutive Latino and non‐Latino white patients who underwent endoscopy for primary indication for symptoms of gastroesophageal reflux disease were identified by examining the internal endoscopy database at Los Angeles County + USC Medical Center. Barrett's esophagus was defined by columnar‐lined distal esophagus on endoscopy confirmed by intestinal metaplasia on histology. Clinical features and endoscopic findings were retrospectively reviewed. The mean age of the 663 patients was 50 ± 12 years, 30% were male, and 92% were Latino. Compared with non‐Latino whites, Latinos had more females (72% vs. 46%; P = 0.0001) and more Helicobacter pylori infection (53% vs. 24%; P = 0.003) but less tobacco use (7% vs. 17%; P = 0.01). Overall, 10% (68/663) of all patients had Barrett's esophagus whereas the prevalence was 10% (62/611) among the Latinos and 12% (6/52) among the non‐Latino whites (OR 0.9, 95% CI 0.4–2.1; P = 0.75). One patient in the Latino group had high‐grade dysplasia. On multivariate analysis, male gender (AOR 2.3, 95% CI 1.4–4.1; P = 0.002), diabetes (AOR 2.2, 95% CI 1.1–4.5; P = 0.03), and age ≥55 years (AOR 2.2, 95% CI 1.3–3.8; P = 0.006) were independently associated with Barrett's esophagus; Latino ethnicity remained nonsignificant (AOR 1.1, 95% CI 0.4–2.7; P = 0.88). In Latinos undergoing endoscopy for gastroesophageal reflux disease symptoms, the prevalence of Barrett's esophagus was 10%, comparable with non‐Latino white controls as well as the prevalence previously reported among Caucasians. In addition to established risk factors, diabetes was associated with Barrett's esophagus.