非糜烂性反流病患者食管感觉特征分析

目的研究非糜烂性反流病(NERD)患者对食管气囊扩张的机械性刺激和食管滴酸化学性刺激的感觉反应,以明确内脏高敏感在 NERD 中的作用。方法 10例健康对照者、31例经反流性疾病诊断问卷(RDQ)和内镜诊断为 NERD 的患者参与试验。采用 Synectics 内脏刺激器/电子气压泵行食管气囊扩张,测定其机械性感觉阈值,以气囊充气容积表示;行食管酸灌注试验测定其化学性感觉阈值,以触发症状时间和酸相关症状积分表示。结果 NERD 患者食管对气囊扩张刺激的初始感知阈值、疼痛阈值分别为(9.6±4.8)ml 和(12.3±3.2)mI,对照组为(1 3.2±7.5)ml 和(21.6±5.7)ml(P<0.01),70.9%的 NERD 患者酸灌注试验阳性(P<0.01),平均症状诱发时间为(4.8±2.1)min,对酸和(或)机械性刺激过敏的 NERD 患者总计占74.2%;对照组仅1例酸灌注试验阳性。结论 NERD 患者对食管机械扩张刺激、酸刺激的感觉阈值均降低,内脏高敏感性在 NERD 的发生机制中起重要作用。     

应用功能性磁共振成像技术研究非糜烂性反流病患者食管酸灌注时大脑功能活动模式的变化

背景：血氧水平依赖性功能性磁共振成像（BOLD-fMRI）技术近来被广泛应用于人体内脏感觉的研究，而非糜烂性反流病（NERD）的发生与内脏感觉高敏有密切关系。目的：应用BOLD-fmRI技术，通过研究食管酸灌注时NERD患者大脑功能活动模式的改变，探讨NERD患者食管内脏高敏感的中枢机制。方法：对31例NERD、13例反流性食管炎（RE）和12名健康志愿者在食管酸灌注时行fMRI；根据食管内球囊扩张和酸灌注试验结果将NERD患者分为两组：感觉高敏（NERD-H）组和感觉正常（NERD-N）组；对三组受试者大脑的兴奋情况进行统计学分析。结果：食管酸灌注刺激在NERD内脏高敏的患者中激活范围较广泛，包括单侧或双侧第Ⅱ躯体感觉皮质（SⅡ）、第Ⅰ躯体感觉皮质（SI）、前额叶皮质（右侧为主）、眶额回皮质、岛叶皮质、运动区、辅助运动区、前扣带回、后扣带回、楔前叶、杏仁体、腹侧纹状体、丘脑、小脑等，其中双侧SⅡ、右前额叶皮质、运动区、辅助运动区、岛叶皮质、杏仁体、腹侧纹状体和小脑的最大信号增加幅度显著高于NERD-N组和对照组（P〈0．01）。内脏高敏的NERD患者fMRI功能初始信号呈现时间、达峰值时间较NERD-N组和对照组显著缩短（P〈0．01）。结论：食管酸灌注时产生的fMRI参数改变为揭示NERD患者中枢神经系统整合、处理食管感觉传入信息功能异常提供了依据。     

非糜烂性反流病患者食管黏膜SP和CGRP的表达

目的 观察非糜烂性反流病(NERD)和反流性食管炎(RE)患者食管黏膜内P物质(SP)和降钙素基因相关肽(CGRP)免疫反应阳性产物的表达,探讨其在NERD发病中的作用.方法 选择有典型胃食管反流症状并经反流性疾病诊断问卷(RDQ)调查、PPI试验、胃镜检查及食管24h pH检测诊断为GERD患者51例,其中RE组21例,NERD酸反流阳性组(NERD+组)12例,NERD酸反流阴性组(NERD-组)18例,采用免疫组化方法 在显微镜下观察NERD、RE患者食管黏膜内SP、CGRP的表达,应用彩色病理图像分析软件,分析计算SP、CGRP免疫反应的阳性指数(PI),并与正常对照组10例比较.结果 NERD-组食管黏膜内SP、CGRP的Pl值为96.77±31.74和24.76±29.15,明显高于NERD+组(73.64±31.38、9.78±10.30)、RE组(67.56±34.62、9.61±6.20)及正常对照组(59.82±46.15、8.64±12.12)(P均<0.05).结论 SP、CGRP在NERD-的患者食管黏膜内有明显表达,可能在食管内脏感觉中发挥着重要的作用.     

非糜烂性胃食管反流病食管黏膜肥大细胞的改变

目的探讨在非糜烂性胃食管反流病（non erosive reflux disease，NERD）患者中食管黏膜肥大细胞的改变。方法选择14例NERD患者（NERD组）与10例正常健康志愿者（对照组），取食管黏膜组织，行免疫组化法染色观察并计数肥大细胞，电镜下观察肥大细胞超微结构。结果NERD组患者食管黏膜肥大细胞数量显著高于对照组（P〈0．01）；黏膜脱颗粒肥大细胞比率显著高于对照组（P〈0．01）；电镜观察到NERD组患者肥大细胞内高尔基体、线粒体及内质网较多，有特异性分泌颗粒，存在较多脱颗粒后留下的空泡。结论NERD患者食管黏膜肥大细胞数增多，功能活跃，可能在NERD的发病机制中具有一定作用。     

反流性食管炎和非糜烂性反流病患者酸暴露与食管压力监测结果分析

目的通过对胃食管反流病（GERD）患者的酸暴露情况、食管下括约肌（LES）压力、食管体部压力、幽门螺杆菌（Hp）感染结果的比较，探讨反流性食管炎（RE）、非糜烂性反流病（NERD）的不同状况，为临床治疗提供科学依据。方法2001年10月至2005年7月，具有反流症状（烧心、反酸）的患者80例，胃镜检出RE31例，NERD45例，Barrett食管（BE）4例。行食管24hpH动态监测，并以De—Meester积分均值将GERD分为轻、中、重度，检测LES、食管体部即LES上方5cm、7cm、13cm（简记为L5、L7、L12）和食管上括约肌（UES）下方1cm、6cm、8cm（简记为U1、U6、U8）压力指标，并进行Hp感染的检查。结果RE、NERD两组患者食管24hpH酸暴露各指标的差异，无统计学意义（P〉0．05），De-Meester积分均值亦无统计学意义（P〉0．05）；轻、中、重度GERD患者食管24hpH监测指标具有统计学意义（P〈0．01）。RE、NERD两组患者LES压力、食管体部的L5、L7、L12、U6和u8压力监测指标无统计学意义（P〉0．05），只有RE组U1压力低于NERD组，差异有统计学意义（P〈0．05）；轻、中、重度GERD患者LES压力和食管体部的压力监测指标差异无统计学意义（P〉0．05）。RE和NERD组患者Hp感染率分别为16．1％和22．2％，其差异无统计学意义（P〉0．05），OR为1．309，95％C10．364～4．705。结论RE和NERD患者酸暴露、LES压力和食管体部压力等相应指标无明显差异；NERD在发病机制中，酸反流的强弱没有起到决定性作用。     

非糜烂性胃食管反流病患者大脑皮质诱发电位的研究

目的通过比较食管扩张刺激-脑诱发电位(OD-CEP)的改变,探讨非糜烂性胃食管反流病(NERD)患者食管内脏高敏感性的发生机制,旨在进一步获得NERD患者食管-中枢内脏感觉传导通路失调的客观依据。方法10例正常健康自愿者和21例NERD患者参与试验;采用Synectics内脏刺激器/电子气压泵和带有低顺应性气囊的导管给食管以时相性扩张刺激;利用食管气囊扩张术检测受试者食管最大耐受痛阈,用75%最大疼痛耐受容积作为诱发刺激的强度(刺激频率为12次/分,连续64次);采用OD-CEP系列技术记录并分析NERD患者和正常人CEP的变化。结果食管气囊扩张刺激能诱发出可识别、可重复的、多峰的CEP波形,以NP型为主。与正常对照者比较,NERD患者CEP波形变异性大,其N1、P1、N2波潜伏期明显缩短(P值分别为0·016,0·003,0·031),且NERD患者CEP的P1-N2峰间波幅明显增加(P=0·03)。结论NERD患者经食管时相性扩张后产生的特征性CEP改变证实其食管内脏高敏感性及食管-中枢内脏感觉传导通路的失调。     

非糜烂性反流病内脏高敏感的外周与中枢机制研究

目的研究非糜烂性反流病(NERD)患者食管腔内气囊扩张刺激-脑诱发电位(ED-CEP)的特征及其食管黏膜中降钙素基因相关肽(CGRP)、P物质(SP)表达的改变,探讨NERD内脏高敏的机制。方法收集第二军医大学长海医院消化内科2004-10—2005-03NERD患者26例和健康对照者12名,采用ED-CEP技术记录分析CEP的变化,并观察远端食管黏膜组织中CGRP、SP免疫反应阳性产物的分布和表达。结果NERD患者CEP波形变异性大,其N1、P1、N2波潜伏期明显缩短(P<0·05),CEP的P1-N2峰间波幅也明显增加[(7·8±3·2)μV对(6·2±1·9)μV,P=0·03]。其远端食管黏膜的CGRP、SP阳性产物OD值分别较对照组升高[(0·46±0·16)对(0·23±0·10),(0·42±0·12)对(0·29±0·05)](P<0·05)。结论NERD患者ED-CEP和食管黏膜中CGRP、SP的表达与对照组存在差异,提示NERD患者的食管-中枢内脏感觉传导通路存在一定的异常改变。     

非糜烂性反流病患者食管动力特征分析

背景：食管动力障碍在胃食管反流病（GERD）的发生中起重要作用。目的：探讨不同类型非糜烂性反流病（NERD）的食管动力特征。方法：选取161例具有典型胃食管反流症状者和20名健康体检者,分别行上消化道内镜检查、24 h食管pH监测和食管测压。纳入内镜检查未见Barrett食管和食管黏膜破损、症状指数≥50%的NERD患者,根据其是否存在病理性酸反流分为异常酸反流组和食管酸高敏组,比较反流组（28例）、高敏组（13例）和对照组（15例）的食管测压结果。结果：反流组下食管括约肌（LES）长度较对照组显著缩短（P〈0.05）,LES压力显著降低（P〈0.05）,高敏组与对照组间则无明显差异。反流组和高敏组食管体部动力障碍均以食管远段为主,表现为收缩波幅降低、蠕动波传导速度减慢和非传导性收缩波比例增加,反流组改变更为明显。结论：不同类型NERD的食管动力特征存在差异。异常酸反流亚型NERD患者存在LES长度和压力异常,食管远段动力障碍更为明显。     

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。     

非糜烂性胃食管反流病患者酸灌注及食管扩张脑诱发电位的研究

目的研究非糜烂性胃食管反流病(NERD)患者和正常人食管扩张刺激(OD)-脑诱发电位(CEP)的特征及食管酸灌注后 CEP 的改变,探讨 NERD 患者食管内脏高敏感性的发生机制。方法10例健康志愿者和21例 NERD 患者参与试验;采用 Synectics 内脏刺激器/电子气压泵和带有低顺应性气囊及多个灌注式压力通道的导管给食管以时相性扩张刺激和酸灌注;利用食管气囊扩张术检测受试者食管最大耐受痛阈,用75%最大疼痛耐受容积作为诱发刺激的强度(刺激频率为12次/min,连续64次);采用 OD-CEP 系列技术记录并分析食管酸灌注前后 NERD 患者和正常人 CEP 的变化。组间比较采用 t 检验,多组间比较采用单因素方差分析。结果食管时相性机械扩张刺激诱发出可识别、可重复、多峰的 CEP 波形,以 NP 型为主。正常对照者 N1、P1、N2波潜伏期分别为(246±77)、(388±84)和(502±78)ms,NERD 患者 CEP 波形变异性大,其 N1、P1、N2波潜伏期分别为(192±46)、(293±76)和(440±79)ms,较对照组明显缩短(P 值均<0.05);P1-N2峰间波幅明显增加[(6.2±1.9)μV 比(7.8±3.2)μV,P<0.05]。食管酸灌注能明显缩短 NERD 患者 N1、P1、N2波潜伏期,与酸灌注前相比差异有统计学意义(P 值均<0.05),且酸灌注后 NERD 患者 P1-N2皮层波幅值较酸灌注前显著增加(p<0.05),健康对照组除 CEP 的 N1波潜伏期较对应基线值显著降低(P=0.05)外,其余 CEP 参数均无明显改变。结论 NERD 患者存在食管对机械和酸刺激的高敏感性及食管-中枢内脏感觉传导通路失凋。     

High Expression of Calcitonin Gene-Related Peptide and Substance P in Esophageal Mucosa of Patients with Non-Erosive Reflux Disease

Background

Visceral hypersensitivity is an important etiology of non-erosive reflux disease (NERD). Calcitonin gene-related peptide (CGRP) and substance P (SP) are involved in the sensitization of afferent neuronal pathways.

Aim

The objectives of this study were to evaluate visceral hypersensitivity in NERD patients, investigate the association between visceral hypersensitivity and mucosal expression of SP and CGRP, and assess their involvement in the pathogenesis of NERD.

Methods

Twenty-six NERD patients and 12 healthy volunteers were recruited. Intraesophageal balloon distention was performed, and initial perception threshold (IPT) and threshold of discomfort (ToD) were determined. Immunohistochemical staining was used to measure the optical density (OD) of CGRP and SP-reactive levels in esophageal mucosa, and the numbers of CGRP and SP-reactive neural fibers.

Results

IPT and ToD were 9.6 ± 4.8 and 12.3 ± 3.2 ml, respectively, in NERD patients, significantly lower than for controls (13.2 ± 7.5 and 21.6 ± 5.7 ml, P < 0.05 and P < 0.01, respectively). Mean OD values for CGRP and SP staining were significantly higher in NERD than for controls (both P < 0.05) and, in NERD, were negatively correlated with IPT and ToD (all P < 0.01). Numbers of CGRP and SP-reactive neural fibers in esophageal submucosa of NERD patients were significantly increased (both P < 0.05).

Conclusions

Expression of esophageal epithelial CGRP and SP is increased, and correlates negatively with perception thresholds in NERD. These findings may aid understanding of peripheral visceral hypersensitivity and the development of new therapeutic approaches for management of NERD.     

Role of Nociceptors/Neuropeptides in the Pathogenesis of Visceral Hypersensitivity of Nonerosive Reflux Disease

Background and Aims

Esophageal visceral hypersensitivity has been proposed to be a pathogenesis of heartburn in nonerosive reflux disease (NERD), but its further mechanisms are unclear. Recently, it has been suggested that nociceptors and neuropeptides control sensory and pain mechanisms. Therefore, the objective of the present study was to estimate expression of acid-sensitive nociceptors such as transient receptor potential vanilloid 1 (TRPV1) and acid-sensing ion channel 3, protease-activated receptor 2 (PAR2), neuropeptides such as substance P and calcitonin-gene-related peptide, and their receptors such as neurokinin 1 receptor (NK1R) and receptor activity-modifying protein 1 in the esophageal mucosa of NERD patients.

Methods

Biopsy samples were taken from NERD patients and healthy control subjects without heartburn. The expression level of nociceptors, neuropeptides, and their receptors were assessed by real-time RT-PCR and enzyme immunoassay. Localization of substance P and CGRP in the esophageal mucosa was determined by immunohistochemical staining.

Results

Expression of mRNA for TRPV1 and PAR2 was significantly elevated in the esophageal mucosa of NERD patients. Substance P protein level and its receptor NK1R mRNA also increased in NERD patients. A positive correlation between the substance P protein level and reflux symptoms was observed. Immunohistochemical study revealed the presence of substance P-positive nerves in the lamina propria of the esophagus.

Conclusions

These findings suggest that visceral hypersensitivity in NERD patients is involved in neurogenic inflammation showing the increase in both substance P release and NK1R expression, which may be associated with the activation of TRPV1 and PAR2.     

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.     

食管扩张刺激后兔食管内脏感觉改变及其中枢机制的实验研究

目的 探讨食管扩张刺激后兔食管内脏感觉改变及P物质(SP)、降钙素基因相关肽(CGRP)、5-羟色胺(5-HT)、Fos蛋白在中枢神经系统的作用.方法 新西兰白兔20只分为三组:食管扩张组(A组,n=8)和对照组(B组,n=6),分别给予0.9cm食管球囊扩张及假手术刺激,每次持续30 s,每日2次,共14 d,以及空白对照组(C组,n=6).采用动物行为学评分评价食管内脏感觉改变,免疫组化法观察幼兔食管下段黏膜、脊髓和脑组织中神经递质CGRP、SP、5-HT及Fos蛋白的表达.结果 动物食管机械扩张后,在行为学评分为1、2、3分时,A组球囊直径较B、C组明显减小(P＜0.05);A组食管、脊髓和延髓孤束核(NTS)的SP表达明显高于B、C组(P＜0.05),而B、C组间差异无统计学意义(P＞0.05);A组食管黏膜、脊髓、NTS、中脑导水管周围灰质(PAG)、丘脑的CGRP、Fos阳性细胞数较B、C组明显增多(P＜0.05);在食管和脊髓,A组5-HT的表达较B、C组显著升高(食管:27.67±3.27比11.00±1.79和11.17±1.33;脊髓24.00±5.22比11.33±2.94和11.83±2.48,P＜0.01),而在PAG,B组(17.67±2.07)和C组(16.83±2.32)5-HT的表达较A组(13.17±2.04)增多(P＜0.05).在脊髓,CGRP与Fos、SP与Fos、CGRP与SP有明显的相关性(相关系数分别为0.813、0.779、0.772,P值分别为0.025、0.034、0.036).结论 持续的食管扩张可引起食管内脏敏感性增高,食管的机械扩张刺激通过脊髓、NTS、PAG、丘脑传导,且SP、CGRP、5-HT等在食管内脏感觉发生中发挥着重要作用.     

Esophageal and Lower Response to Balloon Distention in Patients with Achalasia Esophageal Sphincter

Achalasia is characterized by absent orincomplete lower esophageal sphincter (LES) relaxationand aperistalsis in the smooth muscle esophageal body inresponse to swallowing. The esophageal and LES response to distention has not previously been studied.I aimed to characterize the responses to esophagealballoon distention in achalasia patients in comparisonto controls. Sixteen consecutive achalasia patients and 11 healthy volunteers underwent standardesophageal manometry followed by graded midesophagealballoon distention during which LES (as measured by theDent sleeve) and esophageal body pressures were monitored. Subject perception of distention wasalso recorded using a standardized scoring system. TheLES relaxation response to esophageal balloon distentionwas markedly impaired in achalasia patients, irrespective of whether the patient hadradiological evidence of a dilated or nondilatedesophagus. However, phasic contractions proximal to thedistending balloon were preserved. The esophageal bodyresponses below the balloon were inconsistent in bothgroups, and not significantly different from oneanother. Pain-sensation scores were significantly lowerin achalasia patients at the highest distending volumes, but this difference was attributable to thesubgroup of patients with a dilated esophagus.Distention-induced LES relaxation is markedly impairedin achalasia patients in keeping with loss of intrinsic inhibitory innervation. Preservation of theproximal excitation suggests that extrinsic vagalreflexes are intact.