Nonerosive reflux disease

Nonerosive reflux disease (NERD) is the most common phenotype of gastroesophageal reflux disease. By definition, patients with NERD have typical reflux symptoms caused by the intraesophageal reflux of gastric contents but have no visible esophageal mucosal injury. This is in contrast to patients with erosive reflux disease (ERD) or Barrett's esophagus (BE) who have obvious esophageal mucosal injury on endosco-py. Only 50% of patients with NERD have pathologic esophageal acid exposure as detected on 24-h pH monitoring. NERD patients with physiologic esophageal acid exposure and good temporal correlation of symptoms with reflux events are considered to have esophageal hypersensitivity, while patients with no symptom-reflux correlation are considered to have functional heartburn. It is possible yet uncommon for NERD to progress to severe ERD (i.e. LA Grade C or D) or BE. Patients with NERD and pathologic esophageal acid exposure have motor dysfunction and acid reflux abnormalities that are similar to patients with ERD and BE, whereas NERD patients with physiologic esophageal acid exposure have minimal abnormalities and are not much different than healthy controls. The pathological feature most indicative of NERD is the presence of dilated intercellular spaces within squamous epithelium, an ultrastructural abnormality readily identified on transmission electron microscopy but also on light microscopy. A symptomatic response to an empiric trial of high-dose proton pump inhibitor (PPI) therapy is a simple and useful strategy to establish the diagnosis of NERD, although histology and pH monitoring may be useful in confirming the diagnosis. Patients with NERD suffer similar decrements in quality of life as do patients with erosive esophagitis. Therapy is aimed at eliminating or reducing symptoms and improving quality of life. PPIs are the most effective agents for the treatment of NERD although they are less effective in providing symptom relief than in patients with erosive esophagitis. Laparoscopic antireflux surgery is an effective therapy for selected patients with NERD and outcomes are better when performed in high volume centers.     

Gastro-esophageal reflux disease: the recent trend in Japan

Gastro-esophageal reflux disease (GERD) has increased in Japan, as in other countries. This is probably due to increased acid secretion among Japanese due to Westernized foods and lifestyle as well as decreased prevalence of Helicobacter pylori infection. Proton pump inhibitor (PPI) is mainly used for treatment of this condition. PPI has recently been approved for treatment of nonerosive reflux disease (NERD) in Japan. NERD is known to have different characteristics to GERD, and effectiveness of PPI in NERD patients is lower than that in reflux esophagitis patients. Regarding therapeutic benefit of treatment, a recent study showed that PPI improved quality of life (QOL) of GERD patients also in Japan. For diagnosis of reflux esophagitis in Japan, we use a unique classification, a modified Los Angeles (LA) classification, which includes minimal change (grade M esophagitis) as one distinct criteria. However, recent studies from Japan showed poor interobserver agreement in diagnosis of grade M, although excess acid reflux in minimal change was shown in another study. Our definition of Barrett’s esophagus is also different from that in the West. Nationwide consensus on diagnosis of reflux esophagitis and Barrett’s esophagus should be achieved in Japan, preferably consistent with world standard.     

Functional heartburn,nonerosive reflux disease,and reflux esophagitis are all distinct conditions—A debate: Pro

Opinion statement Gastroesophageal reflux disease (GERD) traditionally has been approached as a spectrum-continuum, suggesting that patients may progress over time and develop a more severe esophageal mucosal involvement. The spectrum-continuum conceptual model had a profound impact on the research priorities in GERD, as well as on proposed diagnostic algorithms and therapeutic strategies. Natural course studies in GERD are almost always retrospective and commonly afflicted with a plethora of shortcomings. Factors that affect quality of natural course studies in GERD include the following: index endoscopy results are taken at face value; antireflux treatment is consumed until index endoscopy and/or offered during the follow-up phase; pathophysiologic, anatomic, and genetic factors are overlooked; and lack of confirmation of the durability of the new esophageal mucosal finding. Functional heartburn is common and likely to affect a large subset of patients presenting with heartburn. Evidence to support progression of functional heartburn to nonerosive reflux disease (NERD), erosive esophagitis, or Barrett’s esophagus is very scarce. The largest population-based or longest-duration natural course studies report that only 10% of patients progress from NERD to erosive esophagitis over time. The other GERD patients remained within their respective phenotypic presentations of GERD.     

Barrett食管、糜烂性食管炎和非糜烂性反流病食管酸暴露及食管动力学分析

目的分析胃食管反流病(GERD)三种亚型Barrett食管(BE)、糜烂性食管炎(EE)和非糜烂性反流病(NERD)患者食管24 h pH监测与高分辨率食管测压结果,探讨不同亚型胃食管反流病食管酸暴露及动力学变化特点。 方法收集2015年12月至2017年12月,新疆维吾尔自治区人民医院接受住院治疗的90例GERD患者的临床资料,其中BE组28例、EE组35例、NERD组27例,通过食管24 h pH监测结果评价患食管酸暴露及反流特点,高分辨率食管测压检查评价食管动力学特点。 结果3组患者年龄及身体质量指数(BMI)等一般资料比较,差异无统计学意义(P>0.05);EE组患者24 h食管pH监测中pH≤4(酸反流)、40.05);3组Demeester评分比较,差异无统计学意义(P>0.05);LES长度3组无明显差异,BE组LES静息压及残余压较EE组和NERD组稍高,但差异无统计学意义(P均>0.05);3组在食管远端收缩积分比较,差异无统计学意义(P>0.05)。 结论食管测酸检查在GERD临床亚型的鉴别方面并无显著差别;Barrett食管、糜烂性食管炎、非糜烂性反流病均存在抗反流屏障功能减退,但不同程度的食管粘膜损伤对食管动力学的影响并无差异。     

Functional heartburn, nonerosive reflux disease, and reflux esophagitis are all distinct conditions—A debate: Con

Opinion statement Gastroesophageal reflux disease (GERD) is currently defined as a condition that develops when the reflux of stomach contents causes recurrent symptoms and/or complications. The clinical presentation of GERD has been recognized to be much broader than before, when the typical symptoms of heartburn and acid regurgitation were considered as the main clinical presentation. However, now it is recognized that GERD can present with various other mainly extraesophageal symptoms, abdominal pain, and even sleep disturbance. Moreover, there is an important overlap with functional gastrointestinal disorders such as functional dyspepsia and irritable bowel syndrome. The morphologic spectrum of esophageal involvement in GERD encompasses erosive (erosive reflux disease [ERD]), Barrett’s esophagus (BE), and nonerosive reflux disease (NERD). However, there is still no consensus on whether GERD represents one disease that can progress from NERD to ERD and BE, or whether it is a spectrum of different conditions with its own clinical, pathophysiologic, and endoscopic characteristics. Recently published data suggest that mild erosive esophagitis behaves in a way similar to NERD and that there is considerable movement between these categories. But follow-up data also show that after 2 years, some patients with NERD or GERD Los Angeles A or B went on to develop severe GERD or even BE. A practical approach is to categorize patients with reflux symptoms into “functional heartburn” (ie, reflux symptoms and negative endoscopy and absent objective evidence of acid reflux into the esophagus), NERD (negative endoscopy but positive documentation of acid reflux into the esophagus), and ERD (erosions documented endoscopically). In conclusion, it appears that GERD is a disease with a spectrum of clinical and endoscopic manifestations, with characteristics that make it a continuum and not a categorical condition with separate entities. It is difficult to clearly delineate the spectrum of GERD based on the clinical, endoscopic, and pathophysiologic characteristics, but therapeutic trials and follow-up studies suggest that GERD is not composed of different conditions.     

Pharmacologic management of gastroesophageal reflux disease

The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short-and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.     

不同亚型胃食管反流病食管黏膜下层炎症因子变化特点研究

目的分析3种亚型胃食管反流病患者与对照组食管黏膜的组织变化和局部IL-4、IL- 6表达,探讨Th2型炎症因子在胃食管反流病发生发展中的作用。 方法选取2016年12月至2017年12月新疆维吾尔自治区人民医院69例患者临床资料,根据Gerd Q评分和内镜结果将所有入选研究者分为Barrett食管（BE）、糜烂性食管炎（EE）、非糜烂性反流病（NERD）和对照4组,利用食管24 h pH监测法评价胃食管反流病（GERD）患者食管酸暴露及反流特点;通过食管组织HE染色进行组织病理学评分,使用免疫组化法和酶联免疫吸附剂测定法检测食管局部及血清中IL-4、IL-6表达情况。 结果食管24 h pH监测结果中,3亚组间DeMeester指数、弱酸反流次数、反流总事件数比较,差异均无统计学意义（P均>0.05）,NERD组酸反流次数较其余2组低,差异有统计学意义（P均<0.05）;4组样本食管黏膜组织病理学评分中发现,BE组、EE组与其余2组相比均明显升高,差异有统计学意义（P均<0.05）,BE组与EE组评分之间亦有显著差异（P<0.05）,NERD组与对照组间差异不明显;IL-4在4组食管标本中均有不同程度表达,但4组间IL-4阳性率的比较并无显著差异（P均>0.05）;IL-6在NERD组和对照组表达量较低甚至不表达,EE组IL-6阳性率明显高于对照组（P<0.05 ）,但与NERD组间无显著差异,BE组阳性率与对照组和NERD组之间均有明显差异（P均<0.05 ）。 结论GERD食管黏膜上皮组织学炎症等级随食管炎的恶化而升高,其中NERD的食管组织学已出现炎性化趋势,但尚不足以与正常食管区别;IL-4在不同亚型GERD食管黏膜组织中的表达差异不及IL-6显著。     

Pharmacologic management of gastroesophageal reflux disease

Opinion statement The burden of gastroesophageal reflux disease (GERD) results from its widespread prevalence and the unfavorable impact of its symptoms on well-being and quality of life. Whereas abnormalities of the antireflux barrier (lower esophageal sphincter) are important in the pathophysiology of GERD, pharmacologic therapy for GERD is based on suppression of acid, which is responsible for the majority of the symptoms and for epithelial damage. Proton pump inhibitors (PPIs) are the agents of choice for achieving the goals of medical therapy in GERD, which include symptom relief, improvement in quality of life, and healing and prevention of mucosal injury. As a class, these drugs are extremely safe. The newest PPI, esomeprazole, brings a statistically significant increase in healing of mucosal injury and symptom relief in patients with erosive esophagitis, compared with omeprazole and lansoprazole. This article reviews the role of medical therapy in the short- and long-term management of symptomatic patients with or without erosive esophagitis, including extraesophageal presentations, GERD during pregnancy, and Barrett’s esophagus. Management of refractory patients is addressed.     

Transepithelial Leak in Barrett’s Esophagus

Using orally administered sucrose as a probe of gastrointestinal permeability, this study focused on determining whether Barrett’s metaplasia exhibits a paracellular transepithelial leak to small nonelectrolytes. Subjects in five separate classes (nonendoscoped, asymptomatic controls; endoscoped, asymptomatic controls; gastroesophageal reflux disease without mucosal complications; grossly visible esophagitis; and Barrett’s esophagus) consumed a sucrose solution at bedtime and collected all overnight urine. Urine volume was measured and sucrose concentration was determined by high-performance liquid chromatography. Patients with Barrett’s were observed to exhibit a transepithelial leak to sucrose whose mean value was threefold greater than that seen in healthy control subjects or patients with reflux but without any mucosal defect. A parallel study of claudin tight junction proteins in endoscopy biopsy samples showed that whereas Barrett’s metaplasia contains dramatically more claudin-2 and claudin-3 than is found in normal esophageal mucosa, it is markedly lower in claudins 1 and 5, indicating very different tight junction barriers. Support by the Cancer Research and Prevention Foundation, the Sharpe-Strumia Foundation, and the Mary L. Smith Foundation.     

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.     

Gastroesophageal reflux disease and Barrett��s esophagus

Gastroesophageal reflux disease is the most common gastrointestinal diagnosis recorded during visits to outpatient clinics. The spectrum of injury includes esophagitis, stricture, the development of columnar metaplasia in place of the normal squamous epithelium (Barrett’s esophagus), and adenocarcinoma. Barrett’s esophagus is a premalignant lesion detected in the majority of patients with esophageal and gastroesophageal adenocarcinoma. The incidence of these cancers has been increasing in the United States and they are associated with a low rate of survival (5-year survival rate, 15–20%). When symptoms of gastroesophageal reflux disease are typical and the patient responds to therapy, no diagnostic tests are necessary to verify the diagnosis. Endoscopy is the primary test in patients whose condition is resistant to empirical therapy but its yield in this setting is low because of the poor correlation between symptoms attributed to the condition and endoscopic features of the disease. Clinical experience suggests that lifestyle modifications may be beneficial for gastroesophageal reflux disease although trials of the clinical efficacy of dietary or behavioral changes are lacking. Abundant data from randomized trials show benefits of inhibiting gastric acid secretion and suggest that proton-pump inhibitors are superior to H2-blockers and that both are superior to placebo. In patients with Barrett’s esophagus, antireflux interventions are intended to control symptoms of reflux and promote healing of the esophageal mucosa. If a patient has symptoms refractory to proton-pump inhibitors or cannot tolerate such therapy, antireflux surgery, most commonly Nissen fundoplication, may be an alternative management approach. In patients with high-grade dysplasia, endoscopic therapies or surgical resection must be considered.     

Relevance of ineffective esophageal motility and hyperactive acid sensitization in patients with gastroesophageal reflux

BACKGROUND AND AIM: Esophageal motor abnormalities including ineffective esophageal motility (IEM) and visceral hypersensitivity have been frequently observed in patients with gastroesophageal reflux. The aim of this study was to observe the incidences of hypersensitivity to acid infusion and motor abnormalities in non-erosive reflux disease (NERD) compared with erosive esophagitis. METHODS: We performed upper GI endoscopy, an acid perfusion test and esophageal manometry on 113 NERD patients and 37 erosive esophagitis patients. RESULTS: The frequency of acid sensitization was 69.9% in NERD and 67.6% in erosive esophagitis. The frequency of esophageal motor abnormality in patients with erosive esophagitis (48.6%) was higher than in patients with NERD (25.7%, P = 0.014). The most frequent esophageal motor abnormality was IEM. The frequency of IEM was 15.9% in NERD patients, 42.9% in Los Angeles grade A, 53.8% in Los Angeles grade B and 66.7% in Los Angeles grade C esophagitis (chi(2) = 16.67, P < 0.0001). CONCLUSION: Our results suggest that no difference exists between visceral hypersensitivity in patients with NERD and those with erosive esophagitis, and that IEM occurs in NERD as well as erosive esophagitis patients. The occurrence of IEM is associated with the endoscopic severity of gastroesophageal reflux disease.     

Role of gastric acid secretion in the pathogenesis of Barrett’s esophageal cancer in a Japanese population

The acidity of the refluxate into the esophagus is an important factor not only for reflux esophagitis, but also for Barrett’s esophagus and the development of Barrett’s esophageal cancer. On the other hand, H. pylori infection is thought to prevent reflux esophagitis and Barrett’s esophagus by causing atrophic gastritis, which in turn decreases gastric acid secretion. Moreover, the preservation of gastric acid secretion may be important for the development of gastroesophageal junction cancer, including Barrett’s esophageal cancer, irrespective of the H. pylori infection status. An increase in gastric acid secretion in Japanese populations has been predicted based on a decreasing rate of H. pylori infection and the westernization of eating habits in Japan; this, in turn, may lead to an increase in the prevalence of Barrett’s esophageal cancer in Japan in the future.     

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.     

On-demand PPI therapy in GERD

Opinion statement Considerable clinical experience with proton pump inhibitors (PPIs) attests to their efficacy and safety in short-and long-term therapy for gastroesophageal reflux disease (GERD) in erosive esophagitis and endoscopy-negative (NERD) patients. One alternative to continuous PPI maintenance is PPI therapy administered noncontinuously (eg, “on demand”). Qualities of good PPI therapy for such a modality should include fast and sustained acid suppression. The newer-generation PPI esomeprazole has provided greater acid inhibition. Randomized controlled clinical trials comparing ondemand PPI versus placebo or versus continuous PPI therapy in GERD patients have shown that on-demand therapy with currently available PPIs (esomeprazole in particular) appears to be effective in the long-term management of patients with NERD or mild esophagitis and uninvestigated forms of GERD, who make up the overwhelming majority of patients with GERD. This is because it is safe and provides adequate symptom control and sustains quality of life. However, it is not indicated in patients with severe erosive esophagitis or with complicated esophagitis (ie, Barrett’s esophagus or stricture). On-demand PPI therapy is important for economic reasons, as it may save up to two thirds of daily doses of the drugs, with a considerable containment of drug expenses. For a long-term disease whose treatment is aimed primarily at symptom control, it is a sensible and cost-effective approach.     

Endoscopic ablation of Barrett’s esophagus

Barrett’s esophagus is a premalignant lesion of the esophagus that arises as an abnormal tissue response to epithelial injury from gastroesophageal reflux. Barrett’s esophagus has previously been considered an irreversible lesion that required life-long surveillance to prevent malignant transformation. Recently, combination therapy with pharmacologic or surgical control of acid reflux combined with endoscopic delivery of a mucosal injury appears to have the capability of reversing superficial Barrett’s tissue, and perhaps deeper tissue as well. Whether Barrett’s esophagus is cured and cancer/dysplasia prevented by these techniques will require long-term follow-up of these patients.     

Comparison of esophageal acid exposure distribution along the esophagus among the different gastroesophageal reflux disease (GERD) groups

BACKGROUND: Patients with nonerosive reflux disease (NERD) have the lowest esophageal acid exposure profile compared with the other gastroesophageal reflux disease (GERD) groups. AIM: To compare lower esophageal acid exposure recordings 1 cm above the lower esophageal sphincter (LES) with those 6 cm above the LES as well as to determine the characteristics of esophageal acid exposure along the esophagus among the different GERD groups. METHODS: Patients with classic heartburn symptoms were enrolled into the study. Patients were evaluated by a demographics questionnaire and the validated GERD Symptom Checklist. Upper endoscopy was performed to evaluate the presence of esophageal erosions and Barrett's esophagus (BE). Ambulatory pH testing was performed using a commercially available 4-sensor pH probe with sensors located 5 cm apart. The distal sensor was placed 1 cm above the LES. RESULTS: Sixty-four patients completed the study. Of those, 21 patients had NERD, 20 had erosive esophagitis (EE), and 23 had BE. All patient groups demonstrated greater esophageal acid exposure 1 cm above the LES than 6 cm above the LES. In NERD and EE, this phenomenon was primarily a result of a higher mean percentage of upright time with pH <4. Unlike patients with EE and BE, those with NERD had very little variation in esophageal acid exposure throughout the esophagus (total and supine). CONCLUSIONS: ALL GERD groups demonstrated significant greater esophageal acid exposure at the very distal portion of the esophagus, primarily as a result of short upright reflux events. Unlike erosive esophagitis and BE, NERD patients demonstrate a more homogenous acid distribution along the esophagus.     

Barrett’s esophagus: A molecular perspective

Carcinogenesis in Barrett’s esophagus involves the accumulation of DNA abnormalities that enable cells to 1) provide their own growth signals; 2) ignore growthinhibitory signals; 3) avoid apoptosis; 4) replicate without limit; 5) sustain angiogenesis; and 6) invade and proliferate in unnatural locations. This report reviews recent publications describing molecular abnormalities in Barrett’s esophagus that could lead to the acquisition of these key physiologic hallmarks of malignancy. Some recent reports suggest that the gastroesophageal reflux of acid and bile can activate molecular pathways that promote proliferation and interfere with apoptosis in Barrett’s metaplastic cells. Inactivation of the p16 and p53 tumor suppressor genes through promoter methylation, gene mutation, or loss of heterozygosity appears to be important for carcinogenesis in Barrett’s esophagus. Finally, this report discusses recent data regarding the role of the Cdx2 gene in the development of esophageal intestinal metaplasia.