Capsaicin receptor (TRPV1) and non-erosive reflux disease

BACKGROUND/AIM: Non-erosive reflux disease (NERD) is a common and heterogeneous disorder. We hypothesized that changes in peripheral innervation may lead to hyperalgesia and contribute to the development of the disorder. METHODS: Patients referred for evaluation of reflux symptoms with wireless pH monitoring were asked to provide demographic and clinical data and complete a survey related to severity of reflux symptoms. Endoscopies were performed to rule out macroscopic abnormalities of the esophageal mucosa. Biopsies obtained 2 cm above the gastroesophageal junction were stained for protein gene product 9.5 (PGP 9.5; general neuronal marker) and TRPV1 (capsaicin receptor) immunoreactivity. The density of immunoreactive fibers in the esophageal mucosa was determined morphometrically. RESULTS: A total of 39 patients without evidence of Barrett's metaplasia, erosive or ulcerative esophagitis were enrolled. Most patients had daily symptoms. The total esophageal acid exposure time was 5.6+/-0.6%, with 16 patients (41%) having increased acid reflux. Immunoreactivity for PGP 9.5 or TRPV1 was detected in papillary structures as well as within the epithelium (free intra-epithelial endings). Total acid-exposure time, but not symptom score or duration correlated significantly with density of PGP 9.5 immunoreactivity and TRPV1 positive fibers. CONCLUSION: Even in the absence of macroscopic injury, esophageal acid exposure is associated with changes in mucosal innervation of the esophagus, thus potentially further enhancing symptoms in patients with gastroesophageal reflux.     

Epidemiology of non-erosive reflux disease

Non-erosive reflux disease (NERD) is a relatively new entity, the definition of which has been evolving and involves the use of symptoms, endoscopy, and objective evidence of reflux or reflux-related damage. The closest entity to NERD that is examined by available epidemiologic studies is defined by the presence of gastroesophageal reflux disease (GERD) symptoms in the absence of esophageal erosions or Barrett's esophagus. In this review, I identified two population-based studies, one non-community study, and several endoscopy-based studies that provided information on several aspects of NERD. Most of GERD is NERD (50-85%), and therefore one can estimate 11-12% of the general population and considerably higher proportions of patients presenting to endoscopy (37-87%) may have NERD. Risk factors for NERD including absence of hiatus hernia, low BMI, and presence of Helicobacter pylori indicate that it is a 'milder' part of the GERD spectrum. Other associations of NERD include younger age, female sex, and psychological comorbidities that resemble those of functional gut disorders. The temporal trends in NERD are unclear, and are probably increasing because GERD symptom prevalence has increased.     

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.     

Functional heartburn and non-erosive reflux disease

Gastroesophageal reflux disease (GERD) is a common disorder in Western countries. For many years our attention has been focused on patients with erosive esophagitis, but in recent times we have realized that endoscopy-negative reflux disease is the most common presentation of this illness, affecting up to 70% of these individuals. Patients with the non-erosive form (NERD) are a heterogeneous group including various subpopulations with different mechanisms for their main symptom of heartburn: reflux of acidic and non-acidic gastric contents, mucosal hypersensitivity, intraesophageal distension by gas, intraduodenal infusion of fat, muscle contractions and psychological abnormalities. As to esophageal acid exposure, patients with NERD can be subdivided into those with abnormal and normal pH testing. The latter group includes patients with a positive correlation between symptoms and reflux events, in whom heartburn can be controlled by proton pump inhibitor (PPI) therapy. According to the recent Rome III criteria, they are still in the realm of GERD. An additional group is called functional heartburn, because this typical symptom is associated neither with an abnormal pH test nor with a positive symptom index. Their response to PPIs is very disappointing. Therefore, there is an increasing consensus on the fact that they do not have GERD and should be treated with drugs other than PPIs.     

Pathophysiology and pharmacological treatment of gastroesophageal reflux disease

Gastroesophageal reflux disease (GERD) is one of the most common diagnoses in a gastroenterologist's practice. Gastroesophageal reflux describes the retrograde movement of gastric contents through the lower esophageal sphincter (LES) to the esophagus. It is a common, normal phenomenon which may occur with or without accompanying symptoms. Symptoms associated with GERD include heartburn, acid regurgitation, noncardiac chest pain, dysphagia, globus pharyngitis, chronic cough, asthma, hoarseness, laryngitis, chronic sinusitis and dental erosions. The introduction of fiberoptic instruments and ambulatory devices for continuous monitoring of esophageal pH (24-hour pH monitoring) has led to great improvement in the ability to diagnose reflux disease and reflux-associated complications. The development of pathological reflux and GERD can be attributed to many factors. Pathophysiology of GERD includes incompetent LES because of a decreased LES pressure, transient lower esophageal sphincter relaxations (TLESRs) and deficient or delayed esophageal acid clearance. Uncomplicated GER may be treated by modification of life style and eating habits in an early stage of GERD. The various agents currently used for treatment of GERD include mucoprotective substances, antacids, H(2) blockers, prokinetics and proton pump inhibitors. Although these drugs are effective, they do not necessarily influence the underlying causes of the disease by improving the esophageal clearance, increasing the LESP or reducing the frequency of TLESRs. The following article gives an overview regarding current concepts of the pathophysiology and pharmacological treatment of GERD.     

非糜烂性胃食管反流病患者的反流事件研究

[目的]研究非糜烂性胃食管反流病(NERD)患者的胃食管反流事件,为进一步探讨NERD发病机制和有效治疗提供临床依据。[方法]68例NERD患者进行食管阻抗-pH监测,根据监测结果、症状指数,分为病理性酸反流(PAR)组、功能性烧心(FH)组、高敏性食管(HE)组,比较3组间反流事件的差异,研究反流与症状之间的相关性。[结果]PAR组总反流次数、酸反流次数、混合反流次数均高于FH组、HE组;HE组总反流次数、弱酸反流次数、混合反流次数、非酸反流次数均高于FH组;各组近段反流次数比较差异无统计学意义。68例中35例(51.5%)SI和(或)SAP呈阳性,其中50%的症状与弱酸反流相关,40%的症状与酸反流相关,少部分症状与非酸反流相关。[结论]PAR、FH、HE患者的食管阻抗-pH监测结果存在差异,可为临床鉴别诊断和治疗提供一定的依据。     

Image-enhanced endoscopy is specific for the diagnosis of non-erosive gastroesophageal reflux disease

Objectives: We assessed the performance characteristics of image-enhanced endoscopy with i-Scan or narrow band imaging (NBI) in patients with non-erosive gastroesophageal reflux disease (GERD) compared to controls without heartburn.

Material and methods: Image-enhanced endoscopic findings of vascularity at the squamocolumnar junction, distal esophageal micro-erosions, and non-round pit pattern at the squamocolumnar junction were assessed in cases (heartburn not responsive to PPIs, positive results on validated GERD questionnaire, no esophageal erosions, esophageal biopsies with histologic evidence of GERD (basal cell hyperplasia, elongation of papillae and dilation of intercellular spaces all required)) and in controls (no GERD symptoms or esophageal erosions).

Results: Twenty cases and 60 controls were compared. The pre-defined features were more common in cases vs. controls: vascularity RR?=?4.9 (95% CI: 2.4–10.0), specificity?=?86.7%; micro-erosions RR?=?9.7 (3.6–26.5), specificity?=?93.3%; non-round pit pattern RR?=?2.4 (1.7–3.3), specificity?=?60.0%; combination of vascularity and micro-erosions RR?=?30.0 (4.1–220), specificity?=?98.3%. These differences were consistent with both i-Scan and NBI.

Conclusions: Image-enhanced endoscopic findings of vascularity and micro-erosions were very specific for non-erosive GERD. Image-enhanced endoscopy may be useful in real-time diagnosis of non-erosive GERD when patients undergo upper endoscopy for heartburn. The relative utility of image-enhanced endoscopy vs. pH-impedance monitoring, based on efficacy, cost and patient acceptance, requires additional study.     

Erosive esophagitis and nonerosive reflux disease (NERD): comparison of epidemiologic, physiologic, and therapeutic characteristics

Nonerosive reflux disease (NERD) and erosive esophagitis are the main presentations of gastroesophageal reflux disease. However, NERD is the most common presentation of gastroesophageal reflux disease in community-based patients. Patients with NERD differ in demographic characteristics from patients with erosive esophagitis, primarily in sex distribution, weight/body mass index, and prevalence of hiatal hernia. Physiologically, patients with NERD tend to have normal lower esophageal sphincter resting pressure, minimal esophageal body motility abnormalities, low esophageal acid exposure profile and minimal nighttime esophageal acid exposure. Patients with NERD have a lower symptom response rate to proton pump inhibitor once daily than patients with erosive esophagitis. Additionally, NERD patients demonstrate a longer lag-time for symptom resolution and lack of difference in symptom response rate between half to full dose proton pump inhibitor as compared with patients with erosive esophagitis.     

Pathophysiology of gastro-oesophageal reflux disease

Gastro-oesophageal reflux disease (GERD), defined as symptoms or mucosal damage caused by reflux of gastric contents into the esophageal body, is a multifactorial disorder. Malfunctioning of the anti-reflux barrier at the esophagogastric junction, consisting of the right diaphragmatic crus and the lower esophageal sphincter (LES), is the pivotal abnormality. Other factors such as impaired esophageal clearance, decreased resistance of the esophageal mucosa and delayed gastric emptying, may contribute.     

Pathophysiology of gastroesophageal reflux disease

The gastroesophageal junction is structurally complex and functionally designed to ensure the acid secreted by the most proximal gastric mucosa flows towards the stomach and not up onto the oesophageal squamous mucosa. The pattern and mechanism of reflux vary with the severity of reflux disease and this probably represents different ends of a spectrum rather than distinct pathophysiological mechanisms. Nearly all patients with severe reflux disease have hiatus hernia, however, a substantial proportion of patients with mild reflux disease do not, and this may be a result of intermittent or partial hiatus hernia undetectable by current available tools. The acid pocket is an area of post-prandial unbuffered gastric acidity immediately distal to the gastroesophageal junction and which is enlarged in patients with hiatus hernia. The acid pocket provides a reservoir of acid available to reflux when the intrinsic sphincter fails. Central obesity is an important factor in the aetiology of reflux and does this by the increased abdomino-thoracic pressure gradient inducing hiatus hernia and increasing the rate of flow of reflux when sphincter opens. Central obesity also induces short segment intrasphincteric reflux and thereby columnar metaplasia of the most distal oesophagus.     

Pathophysiology of gastroesophageal reflux disease

The pathophysiology of gastroesophageal reflux disease remains incompletely understood. Its hallmark symptom is "heartburn" and, on the basis of endoscopy, those with heartburn are subdivided into nonerosive reflux disease and erosive esophagitis. Although subjects with nonerosive reflux disease have no gross damage on endoscopy, a characteristic histopathologic feature of this disease is present on endoscopic biopsy. This lesion is known as "dilated intercellular spaces," a finding present within squamous epithelium. This report details how acid in contact with a damaged esophageal epithelium leads to heartburn and to the progression of nonerosive reflux disease to erosive esophagitis. It also addresses the fact that esophageal pH monitoring may be normal in a significant number of subjects with heartburn, particularly with nonerosive reflux disease, and details how this observation suggests that in addition to defects in the antireflux barrier, for example, transient lower esophageal sphincter relaxations and low lower esophageal sphincter pressure, defects in tissue resistance created by contact with ingested products may also be etiologic in some subjects with gastroesophageal reflux disease.     

Precise role of acid in non-erosive reflux disease

The fundamental abnormality in gastroesophageal reflux disease is exposure of the esophageal epithelium to acidic gastric contents, resulting in histopathologic injury and/or symptoms. With increasing understanding of gastroesophageal reflux disease, non-erosive reflux disease (NERD) is found to account for >50% of cases involving gastroesophageal reflux. There is a good correlation between esophageal acid exposure (EAE) and endoscopic changes. Duration of EAE correlates with severity of erosive esophagitis (EE), and the number of prolonged acid reflux episodes and esophageal exposure to acid and pepsin is increased in more severe reflux. However, there is no convincing evidence to support a significant difference in the acid secretory capacity between patients with NERD or EE. Although acid reflux gives rise to similar symptoms in both NERD and EE patients, the underlying mechanism of acid injury may be different. Dilated intercellular spaces may be responsible for the enhanced perception of proximal acid reflux and dilated intercellular spaces are a feature of NERD patients, irrespective of EAE, and can be considered an objective, structural marker of reflux symptoms. Three different mechanisms have been proposed to explain the occurrence of heartburn in endoscopy-negative patients: esophageal visceral hypersensitivity, sustained esophageal contractions, and abnormal tissue resistance. Impaired esophageal mucosal resistance or increased sensitivity, even to small amounts of acid reflux, plays a key role in the pathophysiology of NERD. Moreover, hyperalgesia may be a predominant mechanism in eliciting symptoms in NERD patients. Increasingly seen are patients with a poor response to acid suppression treatment. Moreover, even double proton pump inhibitor dosing does not completely inhibit gastric acid secretion and relieve all symptoms. Thus, current definitions of acid reflux require review to increase the sensitivity to determine the frequency and implication of short periods of acidity in the esophagus. Analysis such as analysis of the area under the H(+) activity time curve is one alternative approach for evaluating acid secretion. The precise role of acid in NERD needs further clarification.     

文拉法辛对伴抑郁焦虑的非糜烂性胃食管反流病的作用

目的: 探讨文拉法辛对伴有抑郁和/或焦虑的非糜烂性胃食管反流病的治疗效果.方法: 56例伴有抑郁和/或焦虑的非糜烂性胃食管反流病患者双盲随机分为对照组和治疗组, 所有患者使用埃索美拉唑(20 mg qd)联合莫沙必利分散片(5 mg tid)治疗4 wk;治疗组另加用文拉法辛(25-50 mg tid)治疗4 wk.观察烧心、反流、抑郁和焦虑等症状, 并用症状积分及有效率评价疗效.结果: 与治疗前比较, 2组患者治疗后烧心、反流积分均改善, 差异有统计学意义(P<0.01);治疗后治疗组与对照组比较, 患者烧心、反流积分均改善, 差异有统计学意义(P<0.01),HAMD及HAMA积分均改善, 差异有统计学意义(P<0.05);治疗组总有效率高于对照组(96.1% vs 79.1%, P<0.05).结论: 对伴有抑郁和/或焦虑的非糜烂性胃食管反流病文拉法辛和埃索美拉唑及莫沙必利联用有较好的疗效.     

Symptom- versus endoscopy-based diagnosis and treatment of gastroesophageal reflux disease (GERD)

The current guidelines of the German Society for Digestive Diseases (DGVS) endoscopy recommends for patients representing with reflux symptoms. In daily routine as well as in Guidelines from other countries and international guidelines, however, a symptom-based strategy for the management of patients with reflux disease is favoured. Since either strategies is dependent on specific clinical findings, neither can be recommended. The preference for one or the other strategy depends on the prevalence of so-called alarm symptoms, risk factors for a reflux carcinoma or Barrett's metaplasia, demographic factors, e. g., age and gender, patient's wish and initial response to empirical therapy with proton pump inhibitors (PPI). However, most patients with characteristic reflux symptoms without any alarm symptoms and/or other risk factors can be safely managed with a symptom-based strategy in acute and long-term care.     

Functional dyspepsia and non-erosive reflux disease. A review

Functional, or non-ulcer, dyspepsia (FD) and non-erosive reflux disease (NERD), or endoscopy negative reflux disease are common reasons for referral to both the primary care physician and the gastroenterologist. Their aetiology remains largely obscure but both clinical and basic research have revealed much to suggest that these two disease entities are inextricably linked and may represent part of the same disease process. Several theories have been proposed to explain the pathophysiology of functional dyspepsia, including visceral hypersensitivity, delayed gastric emptying, impaired gastric fundus accommodation, Helicobacter pylori infection and psychosocial factors. Recent work suggests that NERD is also a heterogeneous disorder, with some demonstrating abnormal acid exposure and/or sensitivity and others entirely normal 24-h pH studies (functional heartburn). It would appear that the overlap of these two conditions is most apparent between FD and those NERD patients with normal pH studies.