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.     

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.     

光学显微镜测量胃食管反流病患者食管下段细胞间隙的临床价值

目的 通过光学显微镜（光镜）对糜烂性食管炎（ERD）、非糜烂性食管炎（NERD）、Barrett食管（BE）患者及正常对照组食管下段鳞状上皮细胞间隙宽度的测量,探讨胃食管反流病（GERD）患者各亚型尤其是BE食管下段细胞间隙的光镜下改变及其对临床诊断的意义.方法 顺次收集具有GERD症状且内镜和24 h食管pH监测证实为ERD 21例、NERD 21例;胃镜诊断为BE,并在病变处活检且经病理证实BE 13例;对照组为内镜检查及24 h食管pH监测均为阴性者,共20例.ERD组、NERD组及对照组在食管齿状线上2 cm取活检,经常规方法制成HE切片,在油镜下（×1000）观察细胞间隙增宽情况,并采集图像采用图像分析系统对鳞状上皮层基底上层细胞间隙宽度进行定量测量.每例样本测量10个细胞,每个细胞连续测量10个细胞间隙,即每例患者测量100个细胞间隙,求其均值后进行统计学分析.结果 光镜下正常对照组、BE、ERD及NERD组平均细胞间隙分别为0.59、0.99、1.29及1. 06μm.GERD各亚型的细胞间隙均较正常对照组显著增宽,ERD组平均、最大及最小细胞间隙均较NERD组和BE组显著增宽,差异有显著性意义（P=0.000）;NERD组和BE组平均、最大及最小细胞间隙差异无显著性意义（P＞0.05）.光镜下细胞间隙增宽诊断GERD的截断（cut-off）值为0.85 μm,联合临床症状、内镜表现及细胞间隙增宽大于此cut-off值,则光镜下细胞间隙增宽诊断ERD、NERD、BE的敏感度为89.1%,特异度为100.0%.结论 GERD各亚型食管下段均可见细胞间隙增宽的改变,光镜测量GERD患者食管下段鳞状上皮细胞间隙可作为ERD、NERD及BE诊断的一项辅助检查.     

Clinical characteristics of gastroesophageal reflux diseases and association with Helicobacter pylori infection]

BACKGROUND/AIMS: The prevalence of gastroesophageal reflux disease (GERD) in Korea was believed to be low until now. Korea is now believed to be on the evolving stage of GERD in its' prevalence. The aims of this study were to evaluate the epidemiologic and clinicopathologic characteristics among the subgroups of GERD i.e. non-erosive GERD (NERD), erosive GERD (ERD) and Barrett's esophagus (BE), and the role of Helicobacter pylori (H. pylori) infection in the pathogenesis of GERD. METHODS: A total of 253 patients with typical symptoms of GERD who underwent EGD were enrolled from October 2002 to January 2004. Patients were grouped as NERD, ERD or BE based on the symptoms and endoscopic findings. BE was histologically confirmed if necessary. Various clinical parameters including the status of H. pylori infection were analyzed. RESULTS: Among 253 patients, 106 patients were classified as NERD while 116 and 31 patients were classified as ERD and BE group respectively. BE and ERD group showed no gender predilection while NERD showed female preponderance (2.31:1, p < 0.05). NERD group were younger (49.57 y.o.) than BE (57.87 y.o.) and ERD (52.30 y.o.) group. About three quarters of the patients of erosive esophagitis were LA-A (74.2%) grade. This suggests the mild nature of erosive esophagitis in Korea. ERD showed significantly higher BMI (kg/m2) compared to NERD (p < 0.05). Hiatal hernia was frequently associated with BE and ERD (p < 0.05), but less frequently in NERD. Overall H. pylori positivity among GERD was significantly lower than the age and gender matched control group (p < 0.05). CONCLUSIONS: Subgroups of GERD in Korea showed different epidemiologic and clinical characteristics. Lower rate of H. pylori infection among GERD group may reflect the protective role of H. pylori infection regarding GERD prevalence in Korea.     

A comparison of the clinical, demographic and psychiatric profiles among patients with erosive and non-erosive reflux disease in a multi-ethnic Asian country

AIM: To examine the clinical spectrum of gastroesophageal reflux disease (GERD) and compare erosive (ERD) with non-erosive (NERD) in terms of clinical, demographic and psychiatric profiles. METHODS: Patients with reflux symptoms were enrolled and stratified to NERD and ERD after endoscopy (LA classification). Patients with ERD presenting with dyspepsia were included. Patients on proton pump inhibitors (PPI) or H2 receptor antagonists before endoscopy were excluded. Demographic data, Helicobacter pylori(H pylori) status and presence of minor psychiatric morbidity (based on General Health Questionnaire-28) were analyzed. RESULTS: Among 690 patients screened, 533 were eligible for analysis (male to female ratio: 3:2; Chinese: 75.4%; Malay: 9.8%; Indian: 14.8%). Clinical spectrum of GERD: N: 40.5%; A: 46%; B: 9.2%; C: 2.1%; D: 0.6%; Barrett's esophagus: 1.7%. Compared to patients with NERD, patients with ERD were significantly older (45 vs 39.4 years), more likely to be male (64.4% vs 53.7%), tended to smoke (19.6% vs 9.7%), less likely to have minor psychiatric morbidity (26.4 vs 46.7%) and were more likely to respond to PPI (79.7 vs 66.8%). There was also a trend towards a higher BMI (24.5 vs 23.5). Race, alcohol consumption and H pylori status were not significant. On multivariate analysis, age and presence of minor psychiatric morbidity remained with significant differences. CONCLUSION: The majority of patients who have typical symptoms of GERD have NERD or mild erosive reflux disease. Compared to patients with erosive reflux disease, patients with NERD were younger and had a higher prevalence of minor psychiatric morbidity.     

Prospective follow-up data from the ProGERD study suggest that GERD is not a categorial disease

OBJECTIVES: There is a controversy as to whether gastroesophageal reflux disease (GERD) exists as a spectrum of disease severity or as a categorial disease in three distinct groups: nonerosive (NERD) and erosive reflux disease (ERD) and Barrett's esophagus (BE). Aim of the study was to assess progression or regression of GERD over 2 yr in a large cohort of patients (N = 3,894) under routine clinical care in Germany, Austria, and Switzerland (ProGERD study). METHOD: Patients with predominant heartburn, with or without esophagitis, were recruited and classified according to endoscopic status at baseline, i.e., NERD, erosive reflux disease-Los Angeles (ERD-LA) grade A/B and ERD-LA grade C/D, and BE. After an initial treatment with esomeprazole, they were followed, regardless of their response. Medical therapy or endoscopy was initiated at the discretion of their primary care physician, in line with routine care. At 2 yr, endoscopy with biopsy was performed according to the protocol. RESULTS: After 2 yr, 25% of patients who had NERD at baseline progressed to LA A/B and 0.6% to LA C/D; 1.6% of patients who had LA A/B progressed to LA C/D and 61% regressed to NERD; 42% of patients who had LA C/D regressed to LA A/B and 50% regressed to NERD (all figures exclude patients with confirmed BE at baseline). At 2 yr, 22% of patients had been off medication for at least 3 months. Patients with ERD-LA grade C/D were at greatest risk of developing BE: 5.8% compared with 1.4% for ERD-LA grade A/B and 0.5% for NERD. CONCLUSION: GERD does not seem to be a categorial disease. Progression and regression between grades was observed in this large cohort of patients under routine clinical care.     

A prospective multicenter clinical and endoscopic follow-up study of patients with gastroesophageal reflux disease

BACKGROUND: Despite its high prevalence, data on the course of gastroesophageal reflux disease (GERD) are still sparse. There is also an ongoing debate on the natural history of its various manifestations, i.e., non-erosive reflux disease (NERD) vs. erosive reflux disease (ERD) vs. Barrett's esophagus (BE). PATIENTS AND METHODS: This study was conducted within the framework of a prospective multicenter study on the course and prevalence of intestinal metaplasia at the gastroesophageal junction. 1014 dyspeptic patients were screened by the means of upper GI endoscopy. Clinical data were recorded by the use of a questionnaire. At least 15 months after the initial examination, all patients were invited for follow-up (FU) examination. Patients were analyzed separately with respect to their clinical and endoscopic findings. For the latter, only patients without any treatment with proton-pump-inhibitors (PPI) prior to initial and follow-up examinations were included. Patients were categorized as GERD positive if typical symptoms were present and/or proton pump inhibitors were used. RESULTS: Sufficient clinical and/or endoscopic data were available in 590 GERD patients with heartburn at least once a week. Follow-up data could be obtained in 320 patients (clinical FU: n = 304; endoscopic FU: n = 52) after a mean follow-up period of 35 months (18-48 months). 96 of 144 previously asymptomatic patients (67%) remained asymptomatic at follow-up, the rest (n = 48) were symptomatic. 143 of 304 previously symptomatic patients (47%) were symptom-free at follow-up, and only 161 patients (53%) remained symptomatic or had concomitant therapy with proton-pump-inhibitors (PPI). For follow-up endoscopy in patients off PPI (n = 52), ERD was no longer confirmed in 7/12 ERD patients (58%), whereas progress to ERD was found in 3/34 patients (9%) in the NERD group. BE was newly diagnosed in two NERD patients but could no longer be detected in 2 of 6 patients with an initial diagnosis of BE. CONCLUSIONS: With respect to its clinical as well as its endoscopic manifestations, gastroesophageal reflux disease does not appear to be very stable over time. However, in most cases this is due to regression rather than progression of the disease.     

A critical assessment of the current status of non-erosive reflux disease

Non-erosive reflux disease (NERD) has assumed increasing prominence in studies of gastroesophageal reflux disease (GERD), but it remains a challenge to define NERD precisely and to define its place in the investigation and treatment of GERD. Most simply, NERD may be defined as GERD in an individual who has no evidence of erosions at endoscopy. Unfortunately, the characteristic symptoms of GERD--heartburn and regurgitation--are insufficient to identify all GERD patients and, hence, the diagnosis of NERD is hampered by the lack of clear criteria for the symptomatic diagnosis of GERD. The diagnosis of NERD is hampered further by limited interobserver agreement on the endoscopic diagnosis of erosive esophagitis and by the fact that endoscopy is often performed soon after patients have discontinued therapy. Improvements in endoscopic technology will increase the likelihood of identifying small erosions or other reflux-related lesions; however, this will increase the proportion of patients considered to have erosive esophagitis without defining precisely what constitutes NERD. It is important to recognize that NERD is but one manifestation of GERD and that it, like other manifestations of GERD, is associated with a marked diminution in patients' quality of life. However, this recognition apart, there seems to be little practical benefit or understanding to be gained in clinical practice or clinical research from considering NERD as a distinct entity or from studying NERD patients in isolation. Advances in understanding the pathogenesis of GERD and its symptoms may be better served by categorizing GERD with respect to the spectrum of its histologic, functional, endoscopic and symptomatic manifestations rather than by studying NERD, a manifestation that is characterized solely by the absence of esophageal erosions.     

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。