Gastroesophageal reflux: clinical presentations,diagnosis and management.

Symptomatic gastroesophageal reflux occurs daily in an estimated 7% of adults and weekly or monthly in 29%. Untreated it can lead to esophageal erosions, ulceration and stricture formation. The pathogenesis is often multifactorial: defects in the function of the lower esophageal sphincter, esophageal clearance mechanisms and gastric emptying combine to produce frequent lengthy periods during which the lower esophagus is bathed in regurgitated acid. In most patients reflux disease is easily recognized as recurrent heartburn, regurgitation or dysphagia, or a combination. When acute chest pain or respiratory illness is the primary presenting complaint the patient needs particularly careful investigation to determine whether the symptoms are due to a primary cardiac or respiratory condition, are secondary to gastroesophageal reflux alone or represent a combination of disorders. Endoscopy with biopsy and long-term pH monitoring are the most reliable ways of determining whether reflux disease is present. Additional investigations, such as exercise testing, cardiac catheterization or inhalation challenge, may be needed in patients with cardiac or respiratory symptoms. Treatment should follow a stepped-care approach and in most patients should begin with changes in lifestyle, including dietary manipulation, reducing alcohol and cigarette consumption, and raising the head of the bed, together with appropriate use of antacids or alginate-antacid combinations. H2-receptor antagonists and agents to improve both gastric emptying and the tone of the lower esophageal sphincter may be added in sequence. Most patients will respond well to this regimen. Surgery should be considered only for those with intractable symptoms or with complications (e.g., stricture formation, bleeding, development of dysplastic epithelium in those with Barrett''s esophagus, or secondary pulmonary disease that does not respond to medical management). It is successful in 85% of well-selected patients and has few complications.     

Effects of feeding on luminal pH and morphology of the gastroesophageal junction of snakes

At the gastroesophageal junction, most vertebrates possess a functional lower esophageal sphincter (LES) which may serve to regulate the passage of liquids and food into the stomach and prevent the reflux of gastric contents into the esophagus. Snakes seemingly lack an LES and consume meals large enough to extend anteriorly from the stomach into the esophagus thereby providing the opportunity for the reflux of gastric juices. To explore whether snakes experience or can prevent gastric reflux, we examined post-feeding changes of luminal pH of the distal esophagus and stomach, the fine scale luminal pH profile at the gastroesophageal junction, and the morphology of the gastroesophageal junction for the Burmese python (Python molurus), the African brown house snake (Lamprophis fuliginosus), and the diamondback water snake (Nerodia rhombifer). For each species fasted, there was no distension of the gastroesophageal junction and only modest changes in luminal pH from the distal esophagus into the stomach. Feeding resulted in marked distension and changes in tissue morphology of the gastroesophageal junction. Simultaneously, there was a significant decrease in luminal pH of the distal esophagus for pythons and house snakes, and for all three species a steep gradient in luminal pH decreasing across a 3-cm span from the distal edge of the esophagus into the proximal edge of the stomach. The moderate acidification of the distalmost portion of the esophagus for pythons and house snakes suggests that there is some anterior movement of gastric juices across the gastroesophageal junction. Given that this modest reflux of gastric fluid is localized to the most distal region of the esophagus, snakes are apparently able to prevent and protect against acid reflux in the absence of a functional LES.     

Surgical Models of Gastroesophageal Reflux with Mice

Multiple surgical procedures have been reported to induce gastroesophageal reflux in animals. Herein, we report three surgical models with mice aiming to induce reflux of gastric contents, duodenal contents or mixed contents. Surgical procedures and general principles have been described in detail. A researcher with surgical experience should be able to grasp the technique after a short period of practice. After surgery, most mice can survive and develop reflux esophagitis similar to that in humans. However, it should be noted that histological differences between mouse and human esophagus are the inherent limitations of these surgical models. If used for research on Barrett’s esophagus and adenocarcinoma, these procedures may need to be combined with genetic modifications.     

pH, healing rate, and symptom relief in patients with GERD

Gastroesophageal reflux symptoms are common and occur in all of us from time to time. In others, reflux may be associated with ulcerative esophagitis. The symptoms may be aggravated by large meals, coffee, smoking and position. Physiological and pathological reflux can be separated by the frequency and duration of the exposure of the lower esophagus to acid. Pathological reflux results in symptoms and also esophagitis and ulceration in some patients. Although gastroesophageal reflux disease (GERD) is considered to result from a disorder of motility in the esophagus, gastric acid and peptic activity are deemed pivotal to the initiation and continuation of the esophageal damage and the development of symptoms. Acid exposure in the esophagus is normally less than 4 percent of the 24 hours with a pH below 4. An increase over 4 percent of the time with a pH less than 4 is considered pathological. Hence, antisecretory drugs have become the principle approach to the treatment of reflux symptoms and esophagitis since they reduce the acidity, of gastric juice and the activity of pepsin. Importantly, they also reduce the volume of gastric juice available for reflux into the esophagus. There is a clear relationship between the degree and duration of acid suppression and the relief of heartburn and healing of esophagitis. Pharmacodynamic studies with different dose regimens of the H2-receptor antagonists and the proton pump inhibitors show a difference in the degree and duration of the antisecretory effect, and this correlates closely with the results of clinical trials with respect to the healing of esophagitis and the relief of symptoms. Proton pump inhibitors achieve healing rates by week four, which are not achieved by H2-receptor antagonists even after 12 weeks of treatment. The advantage of proton pump inhibitors over H2-receptor antagonists is due to the greater degree, longer duration of effect and more complete inhibition of acid secretion that maintains intragastric pH above 4 for a maximal duration. Although there is no significant difference between proton pump inhibitors with respect to healing of esophagitis, symptom relief occurs earlier with lansoprazole than omeprazole, and this is probably due to the greater oral bioavailability and faster onset of action of lansoprazole when compared to omeprazole.     

Pulmonary responses to tracheal or esophageal acidification in guinea pigs with airway inflammation.

The association between asthma and gastroesophageal reflux has been attributed to microaspiration of gastric contents and/or vagally mediated reflex bronchoconstriction. In previous experimental studies concerning the pulmonary effects of tracheal or esophageal acid infusion, only animals without airway inflammation have been studied. We assessed the effects of esophageal and tracheal administration of hydrochloric acid (HCl) on normal guinea pigs (GP) and GP with airway inflammation induced by repeated ovalbumin exposures. These GP were anesthetized (pentobarbital sodium) and received 1) 20 microl of either 0.2 N HCl or saline into the trachea, or 2) 1 ml of either 1 N HCl or saline into the esophagus. Intratracheal HCl resulted in a significant increase in both respiratory system elastance and resistance (P < 0.001). There were no significant changes in respiratory mechanics when HCl was infused into the esophagus. In conclusion, we observed that infusion of large volumes of HCl into the esophagus did not change pulmonary mechanics significantly, even in guinea pigs with chronic allergen-induced airway inflammation. In contrast, intratracheal administration of small amounts of acid had substantial effects in normal GP and GP with airway inflammation.     

Eicosanoids and the esophagus

Eicosanoids are products of arachidonic acid metabolism. Among the products produced are the prostaglandins and leukotrienes, products which are known to play important roles in health and disease of many gastrointestinal tissues. Here, we review current knowledge about eicosanoids in the esophagus, including production in healthy and diseased tissues and potential physiologic and pathophysiologic effects in two important esophageal mucosal disorders, reflux esophagitis and esophageal cancer.     

Does Helicobacter pylori infection contribute to gastroesophageal reflux disease?

Helicobacter pylori organisms that infect the stomach conceivably could contribute to esophageal inflammation in patients with gastroesophageal reflux disease (GERD) through any of at least three potential mechanisms: 1) by causing an increase in gastric acid secretion; 2) by spreading to infect the gastric-type columnar epithelium that occasionally can line the distal esophagus; and/or 3) by secreting noxious bacterial products into the gastric juice. Studies regarding these potential mechanisms are discussed in this report. Most investigations have found no apparent association between H. pylori infection and reflux esophagitis. Presently, infection with H. pylori does not appear to play an important role in the pathogenesis of GERD.     

Helicobacter pylori, ethnicity, and the gastroesophageal reflux disease spectrum: a study from the East

BACKGROUND: Ethnic differences in gastroesophageal reflux disease (GERD) and its complications as well as racial variations in the prevalence of Helicobacter pylori infection are well documented. Nevertheless, the association between reflux disease, H. pylori, and race has not been adequately explored. AIMS: We estimated the strength of the association between H. pylori, ethnicity, and the gastroesophageal reflux disease (GERD) spectrum, including Barrett's esophagus, in Asian patients presenting for endoscopy in a tertiary referral center. METHODS: Prospectively, we studied 188 consecutive patients with GERD, short- and long-segment Barrett's esophagus, and controls. All patients underwent gastroscopy with gastric biopsies to assess H. pylori, gastritis, and atrophy. CagA status and H. pylori infection were determined by immunoblot assay. RESULTS: The overall prevalence of H. pylori infection was 52.1% (of which 77.6% were cagA(+)) and was lowest in the long-segment Barrett's esophagus group (36.7%) (p = .048). When Barrett's esophagus was present, the length of abnormality was 44.8% shorter in the presence of H. pylori (p = .015). Indians had the highest prevalence of H. pylori (75%) and Malays the lowest (19.6%) (p < .001). In Indians, increased prevalence of H. pylori and cagA-positive strains was associated with reduced severity of GERD (p < .004 and p < .001, respectively), a trend not apparent in the other races. Corpus atrophy, which was almost exclusively associated with H. pylori, was highest in Indians as compared to the other races (p = .013). CONCLUSIONS: Presence of H. pylori was associated with a reduced severity of GERD spectrum disease in Asians, especially Indians. H. pylori infection may protect against complicated reflux disease via induction of corpus atrophy.     

Tissue engineering interventions for esophageal disorders — Promises and challenges

The diseases of the esophagus include congenital defects like atresia, tracheoesophageal fistula as well as others such as gastro-esophageal reflux disease (GERD), Barrett's esophagus, carcinoma and strictures. All esophageal disorders require surgical intervention and reconstruction with appropriate substitutes. Primary anastomosis is used to treat most cases but treatment of long gap atresia still remains a clinical challenge. Autologous graft therapies using tissues from colon, and small and large intestine or gastric transplantations have been attempted but have constraints like leakage, infection and stenosis at the implanted site, which leads to severe morbidity and mortality. An alternative for autologous grafts are allogenic and xenogenic grafts, which have better availability but disease transmission and immunogenicity limit their applications. Use of biodegradable and biocompatible scaffolds to engineer the esophagus promises to be an effective regenerative strategy for treatment of esophageal disorders. Nanotopography of the fibrous scaffolds mimics the natural extracellular matrix (ECM) of the tissue and incorporation of chemical cues and tailoring mechanical properties provide the right microenvironment for co-culture of different cell types. Scaffolds cultured with esophageal cells (epithelial cells, fibroblast and smooth muscle cells) might show enhancement of the biofunctionality in vivo. This review attempts to address the various strategies and challenges involved in successful tissue engineering of the esophagus.     

Migration of the ductular elements of gut-associated glands gives clues to the histogenesis of structures associated with responses to acid hypersecretory state: the origins of "gastric metaplasia" in the duodenum of the specialized mucosa of barrett's esophagus and of pseudopyloric metaplasia.

This article suggests that cell lineages of defined phenotype arise within gastrointestinal epithelia exposed to acid hypersecretion-the ulcer-associated cell lineage (UACL), "gastric metaplasia" and that of Barrett''s esophagus. Detailed study of both the histogenesis and secretory peptide phenotype of the UACL and gastric metaplasia reveal an origin from newly-formed ducts and Brunner''s gland ducts, respectively. It is suggested that Barrett''s epithelium arises directly from the epithelium of the cardiac esophageal glands, and that these three ductal epithelia are the origins of these three important adaptive phenomena to gastric hypersecretion.     

Liquid in the gastroesophageal segment promotes reflux, but compliance does not: a mathematical modeling study

The mechanical force relationships that distinguish normal from chronic reflux at sphincter opening are poorly understood and difficult to measure in vivo. Our aim was to apply physics-based computer simulations to determine mechanical pathogenesis of gastroesophageal reflux. A mathematical model of the gastroesophageal segment (GES) was developed, incorporating the primary anatomical and physiomechanical elements that drive GES opening and reflux. In vivo data were used to quantify muscle stiffness, sphincter tone, and gastric pressure. The liquid lining the mucosa was modeled as an "effective liquid film" between the mucosa and a manometric catheter. Newton's second law was solved mathematically, and the space-time details of opening and reflux were predicted for systematic variations in gastric pressure increase, film thickness, muscle stiffness, and tone. "Reflux" was defined as "2 ml of refluxate entering the esophagus within 1 s." GES opening and reflux were different events. Both were sensitive to changes in gastric pressure and sphincter tone. Reflux initiation was extremely sensitive to the liquid film thickness; the protective function of the sphincter was destroyed with only 0.4 mm of liquid in the GES. Compliance had no effect on reflux initiation, but affected reflux volume. The presence of abnormal levels of liquid within the collapsed GES can greatly increase the probability for reflux, suggesting a mechanical mechanism that may differentiate normal reflux from gastroesophageal reflux disease. Compliance does not affect the probability for reflux, but affects reflux volume once it occurs. Opening without reflux suggests the existence of "gastroesophageal pooling" in the distal esophagus, with clinical implications.     

Review: Helicobacter pylori and non‐malignant upper gastrointestinal diseases

This review covers recent publications investigating the relationship between Helicobacter pylori infection and gastroesophageal reflux disease, Barrett's esophagus, eosinophilic esophagitis, peptic ulcer disease (PUD), H pylori gastritis, and functional dyspepsia. In the area of gastroesophageal reflux disease, new data suggest that reflux may have a role in the transmission of H pylori infection. In addition to several observational studies, data on alterations in esophageal physiology in patients with H pylori infection are presented. Further evidence for the inverse relationship between H pylori infection and Barrett's esophagus is available in the form of a meta‐analysis from the North American Barrett's and Esophageal Carcinoma Consortium. The relationship between H pylori infection and eosinophilic esophagitis remains uncertain. Although new data do not indicate a significantly lower prevalence of H pylori among patients with eosinophilic esophagitis, a meta‐analysis showed a 37% reduced risk of eosinophilic esophagitis among H pylori‐infected patients. Novel data are presented on the genetic variability of bacterial virulence factors and their relationship with PUD. We also report data on plasma biomarkers, which may detect progression to gastric cancer in H pylori‐associated PUD. A new meta‐analysis was published, which assessed the risk of PUD in low‐dose aspirin users with H pylori infection. Finally, we report on the ongoing attempts to stratify patients with gastritis using endoscopic methods when compared to standard biopsy examination.     

Pharmacologic modulation of motility

Etiologically, gastroesophageal reflux disease (GERD) can be regarded as motility disorder: Although blocking acid is effective in the treatment of GERD, it does not overcome the underlying pathologic factors that allow acid, pepsin, and bile to reflux into the esophagus. Prokinetic agents address the upper gastrointestinal motility disturbances contributing to GERD and, thus, have an important role in the short- and long-term medical management of reflux esophagitis. This paper discusses the rationale for the effectiveness of pharmacologic modulation by reviewing current concepts and postulated theories about the mechanisms underlying the neuromuscular abnormalities. The multifactorial aspects of GERD are addressed and the potential for tailoring medical therapy also emphasized.     

Helicobacter pylori in Barrett's esophagus.

Barrett's esophagus is an anatomicoclinical state in which, due to the prolonged action of gastroesophageal reflux, the squamous epithelium is replaced by columnar epithelium. Helicobacter pylori has been implicated in the pathogenesis of various gastrointestinal disorders and has occasionally been observed in Barrett's esophagus. The aim of this study is to determine the incidence of H. pylori in Barrett's esophagus and try to establish its role in the pathogenesis of this disorder. H. pylori was observed in 31 biopsies (44.3%) of the 70 studied, mainly when the epithelium is of the gastric atrophic-fundic type (p less than 0.01). Its presence shows no relation to the degree of inflammatory activity and does not seem, therefore, to play an important role in the pathogenesis of the lesion.     

胃食管反流病的治疗进展

胃食管反流病(gastroesophaeal reflux disease,GERD)是医疗实践中的最常见的疾病之一,其发病率在世界范围内呈逐年上升趋势,且随年龄增长而增加,40-60岁为高发年龄[1]。GERD是一种由胃、十二指肠内容物反流入食管引起不适症状和(或)并发症的疾病,GERD在临床上大致可分为:糜烂性食管炎(EE)(反流性食管炎(RE))和非糜烂性食管炎(NERD)。其中NERD最多见,约占60%。GERD远期危害较小,但其病情漫长且极易复发,严重影响了生活质量。主要表现为食管症状(包括典型的烧心和反流)和食管外症状(包括咽部异物感、咳嗽、声嘶、哮喘、咽喉炎等表现),还有增加发展为Barrett食管及食管癌的危险[2,3]。GERD的治疗目的是愈合食管炎,快速缓解症状、减少复发、提高生活质量,治疗方法主要包括以下4个方面:一般治疗,药物治疗,内镜下治疗和外科治疗。近年来已成为国内外研究的热点,本文就近年来对GERD的治疗进展做一综述。     

Intestinal pathophysiology in autism

Autism is a life-long developmental disorder affecting as many as 1 in 500 children. The causes for this profound disorder are largely unknown. Recent research has uncovered pathology in the gastrointestinal tract of autistic children. The pathology, reported to extend from the esophagus to the colon, is described here along with other studies pointing to a connection between diet and the severity of symptoms expressed in autism. The evidence that there is impaired intestinal permeability in autism is reviewed, and various theories are discussed by which a leaky gut could develop. Lastly, some possible ways in which impaired gastrointestinal function might influence brain function are discussed.     

Management of refractory and complicated reflux esophagitis.

Simple intermittent heartburn with minor or no esophagitis can be treated with simple measures including lifestyle changes and antacids as needed, or H2 receptor antagonists (H2RA), and has a good outcome. Problematic reflux includes resistance to therapy, stricture, Barrett''s esophagus and aspiration. Severe reflux esophagitis, often resistant to H2RA therapy, requires more potent treatment with potent acid suppression using proton pump inhibitors, often indefinitely. When complicated by stricture, dilatations with potent acid suppression are needed. Barrett''s esophagus is subject to esophagitis, which is no more difficult to treat than other cases of esophagitis. Reflux in Barrett''s esophagus should be treated on its own merits without regard to the presence of Barrett''s epithelium. Dysplasia leading to adenocarcinoma is a different problem, apparently not influenced by reduced exposure to acid. Indications for antireflux surgery are quite limited and should be carefully analyzed as a cost/risk/benefit problem.