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。     

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内脏高敏感性与食管下括约肌局部降钙素基因相关肽阳性神经纤维的关系

背景：食管内脏高敏感性是非糜烂性反流病（NERD）最重要的病理生理特征之一，但引起食管内脏感觉过敏的确切机制仍不甚清楚。目的：通过测定NERD患者食管对机械扩张刺激和对酸刺激的敏感性变化和降钙素基因相关肽（CGRP）在食管下括约肌（LES）局部组织中的表达，探讨食管感知阈值与LES局部黏膜CGRP表达之间的关系。方法：采用Synectics内脏刺激器／电子气压泵行食管气囊扩张术以检测食管对机械扩张刺激的敏感性；采用食管酸灌注试验（betastein test）检测食管对酸的敏感性；采用免疫组化法和罔像分析技术观察LES局部组织中CGRP的表达。结果：根据对酸刺激和（或）机械扩张刺激的感知过敏，NERD患者可分为感知过敏组（21例）和感知正常组（10例）。感知过敏组患者食管对气囊扩张刺激的初始感知闽值和最大耐受疼痛阈值较感知正常组和正常对照组显著降低（P〈0．05）。感觉过敏组LES黏膜中CGRP阳性纤维数和平均吸光度（A）值较感知正常组和正常对照组显著增高（P〈0．05）。LES局部组织中CGRP阳性产物A值与食管初始感知阈值和最大耐受疼痛阈值呈直线负相关（r分别为-0．68和-0．79．P〈0．03）。结论：多数NERD患者存在对食管机械扩张刺激和（或）对食管酸刺激感知过敏；感知过敏的NERD患者其LES局部黏膜中CGRP表达增加，提示LES肽能神经的改变可能与食管内脏高敏感性有关。     

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。     

肠易激综合征患者直肠扩张后脑诱发电位的研究

目的 通过比较直肠扩张后脑诱发电位(CEP)的改变,探讨肠易激综合征(IBS)患者内脏高敏感性的发生机制,旨在进一步获得IBS感觉传入通路异常的客观依据。方法 根据罗马Ⅱ标准选择女性IBS患者10例,其中腹泻型6例,便秘型2例,腹泻-便秘交替型2例,另设7例女性健康志愿者为对照组,对其进行直肠气囊扩张,首先测出每例受试者感觉阈值,用1.5倍该阈值空气体积作为刺激(频率1Hz,连续100次,休息10分钟,重复一次),启动并记录两组受试者CEP的变化。结果 直肠节律性机械扩张引出可识别、可复制的CEP。与健康对照者相比,IBS患者N_1,P_1,N_2潜伏期明显缩短(P<0.05),同时,峰间波幅有增大趋势,但无统计学意义(P>0.05)。结论 IBS患者经直肠扩张后产生的CEP的改变证实了其内脏高敏感性及内脏传入通路的异常。     

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。     

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.     

肠易激综合征患者饮冰水及直肠扩张脑诱发电位的研究

目的　通过记录并比较直肠扩张脑诱发电位 (CEP)的特征及饮冰水后CEP的改变 ,探讨肠易激综合征 (IBS)患者内脏高敏感性的发生机制 ,旨在进一步获得IBS感觉传入通路异常的客观依据。方法　根据罗马Ⅱ标准选择女性IBS患者 2 0例 ,其中腹泻型 10例 ,便秘型 6例 ,腹泻 便秘交替型4例 ,另设 12例女性健康志愿者为对照组 ,对其进行快速直肠气囊扩张 ,首先测出每例受试者感觉阈值 ,用该阈值空气体积作为刺激 (频率 1Hz,连续 10 0次 ,休息 10min ,重复 1次 ) ,启动并记录两组受试者CEP的变化。随后 ,每例受试者饮 4℃冰水 2 2 0ml,2 0min后重复上述步骤。结果　直肠节律性机械扩张引出可识别、复制的CEP。与健康对照者 [(87± 17)ms,(14 0± 2 3)ms ,(198± 31)ms]相比 ,IBS患者N1、P1、N2 潜伏期 [(6 9± 15 )ms,(12 1± 2 1)ms,(177± 2 4 )ms) ]明显缩短 (P <0 .0 5 ) ;腹泻型较便秘型IBS患者CEP潜伏期明显缩短 (P <0 .0 5 ) ;饮冰水后 ,IBS患者N1、P1、N2 潜伏期缩短 ,与饮冰水前相比差异有显著性 [分别为 (5 4± 16 )ms,(10 8± 2 0 )ms,(16 1± 2 4 )ms比 (6 9± 15 )ms,(12 1± 2 1)ms,(177± 2 4 )ms;P <0 .0 5 ],而健康对照组饮冰水后CEP无明显变化 ,两组CEP波幅无明显改变。结论　IBS患者经直肠节律性     

非心源性胸痛病人食管扩张诱发的大脑电位

除胃食管返流和食管动力异常外,食管刺激的痛阈降低也被认为是非心源性胸痛的病理生理因素,而对食管气囊扩张的敏感性增高是其表现之一。已证明电或机械刺激人食管可诱发持续的大脑电位。作者通过测量大脑诱发电位来研究食管感觉信息向大胸皮层     

氟哌噻吨美利曲辛治疗胃食管反流病的疗效观察

<正>胃食管反流病(GERD)是指胃、十二指肠内容物反流入食管引起的以烧心、反酸为主要特征的临床综合征,为消化内科的常见病、多发病。GERD根据内镜检查食管是否有明显破坏分为反流性食管炎(RE)和非糜烂性胃食管反流病(NERD)。大量研究表明,GERD的致病因素除胃内容物反流外,还有内脏感觉敏感性增高。中枢5-羟色胺     

Alterations in cerebral potentials evoked by rectal distention and drinking ice water in patients with irritable bowel syndrome

AIM: Visceral hypersensitivity has been found to be present in irritable bowel syndrome (IBS). The current study sought to study visceral afferent hypersensitivity in IBS patients and obtain further objective evidence of alterations in intestinal afferent pathways in IBS patients by cerebral evoked potentials (CEP). METHOD: We studied 30 female IBS patients and 12 female healthy subjects. Rectal perception thresholds to balloon distention were measured and CEP was recorded in response to rhythmic rectal distention (two distention series, each of 100 repetitions at a frequency of 1 Hz) at the volume of perception thresholds. All subjects were then asked to drink 220 mL 4 degrees C ice water and the above steps were repeated 20 min later. RESULTS: Rectal distention led to recognizable and reproducible CEP. Compared to healthy subjects, IBS patients demonstrated significantly shorter N1, P1 and N2 latencies (P < 0.05). After drinking ice water, IBS patients exhibited further shortened N1, P1 and N2 latencies (P < 0.05), but drinking did not alter the latencies of healthy controls and the amplitudes of both IBS patients and healthy controls. CONCLUSION: The shorter latency of cerebral potentials evoked by rectal distention and ice water stimulation in IBS patients provided further objective evidence for defective visceral afferent transmission in IBS patients.     

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.     

Neurophysiologic assessment of esophageal sensory processing in noncardiac chest pain

BACKGROUND & AIMS: Esophageal hypersensitivity is thought to be important in the generation and maintenance of symptoms in noncardiac chest pain (NCCP). In this study, we explored the neurophysiologic basis of esophageal hypersensitivity in a cohort of NCCP patients. METHODS: We studied 12 healthy controls (9 women; mean age, 37.1 +/- 8.7 y) and 32 NCCP patients (23 women; mean age, 47.2 +/- 10 y). All had esophageal manometry, esophageal evoked potentials to electrical stimulation, and NCCP patients had 24-hour ambulatory pH testing. RESULTS: The NCCP patients had reduced pain thresholds (PT) (72.1 +/- 19.4 vs 54.2 +/- 23.6, P = .02) and increased P1 latencies (P1 = 105.5 +/- 11.1 vs 118.1 +/- 23.4, P = .02). Subanalysis showed that the NCCP group could be divided into 3 distinct phenotypic classifications. Group 1 had reduced pain thresholds in conjunction with normal/reduced latency P1 latencies (n = 9). Group 2 had reduced pain thresholds in conjunction with increased (>2.5 SD) P1 latencies (n = 7), and group 3 had normal pain thresholds in conjunction with either normal (n = 10) or increased (>2.5 SD, n = 3) P1 latencies. CONCLUSIONS: Normal esophageal evoked potential latencies with reduced PT, as seen in group 1 patients, is indicative of enhanced afferent transmission and therefore increased esophageal afferent pathway sensitivity. Increased esophageal evoked potential latencies with reduced PT in group 2 patients implies normal afferent transmission to the cortex but heightened secondary cortical processing of this information, most likely owing to psychologic factors such as hypervigilance. This study shows that NCCP patients with esophageal hypersensitivity may be subclassified into distinct phenotypic subclasses based on sensory responsiveness and objective neurophysiologic profiles.     

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.     

Somatosensory evoked potentials in hepatic encephalopathy

Median nerve somatosensory evoked potentials were recorded from 33 patients with various degrees of hepatic failure and from 10 age-matched controls. Within 20 ms poststimulation, one negative peak (N13) could be recorded from the middle of the back of the patient's neck at the C2 vertebral level. Within 150 ms, three negative and three positive peaks, sequentially designated as N1, P1, N2, P2, N3, and P3, could be recorded from the scalp over the contralateral sensory cortex. There was a progressive prolongation of peaks and interpeak latencies correlating with the severity of hepatic encephalopathy. In 10 patients with hepatic failure but no clinical evidence of hepatic encephalopathy, latencies of peak N3 and P3 were delayed and N1-N3 interpeak latencies were prolonged. Thirteen patients with grade 1 or 2 hepatic encephalopathy showed further delayed latencies of peaks P2, N3, and P3, further prolonged N1-N3, N1-P2 interpeak latencies, and distortion of waveforms. Peaks N2, P2, N3, and P3 were further delayed, and even disappeared in 10 patients with grade 3 or 4 hepatic encephalopathy. However, central conduction time (N13-N1 interpeak latency) was not prolonged in all stages of hepatic failure. In addition, serial somatosensory evoked potential studies correlated well with the clinical course. The present data suggest that somatosensory evoked potential recording is a reliable objective method in the early assessment and monitoring of hepatic encephalopathy.