Esophageal diseases: gastroesophageal reflux disease, Barrett's esophagus and eosinophilic esophagitis

Interesting advances are always reported in Digestive Disease Week. This year's studies on gastroesophageal reflux disease (GERD) stressed the role of weight gain and psychological factors in both symptom production and lack of treatment response. In Barrett's esophagus, radiofrequency ablation has become the treatment of choice in cases associated with dysplasia or neoplasms in situ. Finally, notable studies of eosinophilic esophagitis highlighted the difficulty of distinguishing between this entity and GERD. Topical steroids and exclusion diets are effective therapeutic alternatives.     

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.     

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.     

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.     

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.     

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.     

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.     

Barrett's食管、糜烂性食管炎及非糜烂性反流病发生机制的比较

目的:比较糜烂性食管炎(EE)、非糜烂性反流病(NERD)及Barrett's食管(BE)患者反流发生特点,探讨不同类型GERD的可能发病机制.方法:105例GERD患者根据胃镜及病理情况分为:EE组(35例)、BE组(34例)及NERD组(36例),对照组30例为健康志愿者.比较4组受检者食管测压与24 h食管pHT及胆汁反流同步监测结果的差异.结果:与对照组相比,GERD各组LES静息压均有不同程度减低,以EE组最明显(P<0.05).EE与BE组患者远段食管收缩波幅及有效蠕动百分比明显低于NERD组与对照组(均P<0.05).DeMeester评分等酸反流指标在EE组最高.BE组Abs>0.14时间百分比等长时间胆汁反流指标最高.NERD患者中仅52.8%存在病理性反流.各组中混合反流类型占各组病理性反流总人数的比例分别为68.57%(EE组)、84.38%(BE组)及63.15%(NERD组).结论:胃酸与胆汁的混合反流是GERD患者中最常见病理性反流类型,且对食管黏膜的损害较单纯酸或胆汁反流为重,胆汁反流在BE的发病机制中占有重要地位.     

Colonization with cagA-positive Helicobacter pylori strains inversely associated with reflux esophagitis and Barrett's esophagus

AIM: The hypothesis that colonization with cagA(+) Helicobacter pylori strains protects against the development of gastroesophageal reflux disease (GERD) and its complications is tested. METHODS: Patients with reflux esophagitis and Barrett's esophagus were studied. Antral biopsy specimens were obtained for detection of H. pylori. A serum sample was obtained for determination of IgG antibodies to H. pylori and to the CagA protein. RESULTS: 736 patients were studied. 118 patients had reflux esophagitis, 36 had Barrett's esophagus, 108 had hiatal hernia without signs of inflammation (the reflux group), and 20 patients had esophageal or stomach cancer. The remaining 454 patients had no signs of GERD. The 262 patients with reflux disease had a significantly lower prevalence of H. pylori (34.9%) than the 454 controls (54.6%; p<0. 001). Among 310 H. pylori-positive patients from whom serum was available, colonization with cagA(+) strains was detected in 59% in the control group versus 35% in the reflux group (p<0.001). Conclusion: Patients with reflux esophagitis and Barrett's esophagus have a significantly lower prevalence of H. pylori colonization than controls, in particular of the cagA(+) type. These data suggest that colonization with cagA(+) H. pylori strains may be protective against the development of GERD Copyright 2000 S. Karger AG, Basel.     

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.     

Is Barrett's esophagus characterized by more pronounced acid reflux than severe esophagitis?

Objective: Barrett's esophagus is related to gastroesophageal reflux disease (GERD). However, only a small fraction of patients with GERD develop Barrett's esophagus. We evaluated whether gastroesophageal acid reflux is more pronounced in Barrett's patients than in patients with moderate or severe endoscopic esophagitis.
Methods: Retrospective evaluation of results of esophageal manometry and 24 hour ambulatory pH monitoring performed between 1990 and 1996 at the Leiden University Medical Center in those patients who also underwent endoscopy ≤3 months before pH-metry. Included were 51 patients with Barrett's esophagus, 30 patients with severe esophagitis, 45 patients with moderate esophagitis, and 24 healthy control subjects.
Results: Patients with Barrett's esophagus had significantly increased acid reflux time (   p < 0.01  –0.05) compared to patients with moderate, but not compared to patients with severe esophagitis. Distal esophageal body motility and LES pressure were significantly (   p < 0.01  –0.05) reduced in patients with Barrett's esophagus compared to patients with moderate esophagitis but not compared to those with severe esophagitis.
Conclusion: Although acid reflux is increased in patients with Barrett's esophagus and esophageal motility is impaired, other factors apart from acid exposure and motility contribute to the development of Barrett's esophagus.     

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.     

Increased expression of endothelin‐1 and endothelin receptor A in reflux esophagitis and Barrett's esophagus

Barrett's esophagus (BE) is considered a complication of the inflammation provoked by acid and bile reflux. Endothelin‐1 (ET‐1) expresses in various cells during inflammatory process. However, the role of ET‐1 in human inflamed and uninflamed esophageal tissue is unknown. The present study aimed to examine the expression of ET‐1 and its receptors in human reflux esophagitis (RE) and BE. Endoscopic biopsies of normal squamous epithelium (NSE) (n = 20), RE (n = 22), and long segment BE (n = 14) were obtained. The segmental degree of endoscopic and histopathological inflammation was graded, and immunohistochemistry and real‐time quantitative polymerase chain reaction were used to determine the expression of ET‐1 and endothelin receptor A (ET(A)R) and endothelin receptor B (ET(B)R). ET‐1 and ET(A)R messenger RNA (mRNA) levels were higher in RE than in NSE (3.25 ± 1.78 vs. 1.10 ± 0.71, P = 0.000; 2.13 ± 1.06 vs. 1.12 ± 0.64, P = 0.001, respectively). In BE, relative ET‐1 mRNA levels in the proximal segment were higher than in the distal segment (3.03 ± 1.83 vs. 1.16 ± 0.70, P = 0.004) and in normal esophageal epithelium (P = 0.002). There was no significantly difference of ET(A)R mRNA levels between the proximal segment and the distal segment (1.99 ± 1.28 vs. 1.14 ± 0.67, P = 0.072). ET(B)R mRNA expression was unaltered between the groups. Furthermore, immunohistochemistry demonstrated that ET‐1 expression increased significantly in RE (51.18 ± 30.14) compared with those in NSE (21.10 ± 18.17, P = 0.000) and in distal BE segment (28.02 ± 24.92, P = 0.022). There were more ET‐1 positive cells in proximal BE segment (50.07 ± 25.88) than in distal BE segment (P = 0.030) and in NSE (P = 0.001). ET‐1 expression increased in a stepwise manner with the growing degree of inflammation, and there were significant differences between mild, moderate, and marked degree esophagitis (36.08 ± 27.84, 65.86 ± 11.82, 98.00 ± 8.49, P = 0.003, respectively). However, expression of receptors remained unchanged. This study demonstrates that over‐expression of ET‐1 and ET(A)R in esophagitis may be related to the inflammatory process. ET‐1 may play a significant role in the progression of Barrett's metaplasia.     

Importance of bile reflux in Barrett's esophagus

Barrett's esophagus (BE) is an acquired condition in which the squamous epithelial lining of the lower esophagus is replaced by a columnar epithelium due to chronic gastroesophageal reflux. The role of acid and bile in the development of esophageal mucosal injury and the formation of BE is controversial. Acid and pepsin are unquestionably important in causing mucosal damage and BE formation in both animal models and humans. Animal studies suggest the potential for synergistic damage from conjugated bile acids and gastric acid, as well as from unconjugated bile acids and trypsin in more neutral pH settings. Evidence of the involvement of bile and its constituents in humans has been less conclusive; however, the advent of better technology to detect bile reflux is beginning to clarify the role of these constituents. Human studies show that the reflux of bile parallels acid reflux and increases with the severity of gastroesophageal reflux disease, being most marked in BE. However, recent ex vivo studies suggest that pulses of acid reflux may be more important than bile salts in the development of dysplasia or adenocarcinoma in Barrett's epithelium. Nevertheless, antireflux surgery and aggressive acid suppression with proton pump inhibitors will decrease both acid and bile refluxes, and eliminate the synergism between these two duodenogastric constituents.     

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.     

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.     

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.