【作者】 张艳丽；

【导师】 柯美云； 冯逢； 方秀才；

【作者基本信息】 中国协和医科大学 ， 内科学， 2007， 博士

【摘要】 摘要一RE和NERD患者症状谱、生活质量及精神心理状态的调查背景与目的胃食管反流病(GERD)是消化科门诊常见的慢性病,其临床症状多样、患者生活质量明显受损,并且可见精神心理因素与GERD症状相关。目前将GERD根据内镜下表现分为反流性食管炎(RE)、非糜烂性反流病(NERD)和Barrett食管(BE)。NERD和RE患者可能有不同的发病机制,对质子泵抑制剂(PPI)的疗效不同。本研究目的:通过GERD症状问卷调查,全面分析比较RE和NERD患者的人口学特征和临床特点,为进一步探讨发病机制和有效治疗提供临床依据。对象和方法对北京协和医院消化内科门诊2006年3月至2007年5月的278名经内镜证实为NERD或RE的患者连续入组进行问卷调查。入组标准:年龄18—75岁;有反酸、反食、烧心、或合并有胸骨后疼痛等症状,反流症状评分≥6分;无其它消化系统疾病、手术病史和可引起反流症状的全身系统性疾病。问卷调查的内容包括一般人口学特征;胃食管反流及相关症状谱,食管外症状,重叠症状;生活质量;精神心理状态等。结果1、278名GERD患者(男性107名、平均48.42岁,女性165名、平均51.35岁),NERD和RE患者的比例分别为60.8%和37.1%。2、NERD组患者的女性比例明显高于RE组(68.4 vs 47.8,p＜0.05),平均年龄较RE组年轻(48.54±11.74 vs 52.39±14.28,p＜0.05),Hp感染率高于RE患者(50.9%vs 24.6%,p＜0.05),其他人口学特征方面则无差异。3、反流症状评分在两组患者间无显著差异,NERD患者烧心发作频次多于RE患者(p＜0.05),胸骨后疼痛较RE患者更突出(p＜0.05),但RE患者的反食症状重于NERD患者(p＜0.05)。4、两组患者的食管外症状、重叠症状发生率无显著差别(p＞0.05)。5、与RE组患者比,NERD患者生活质量更差,合并精神心理异常、尤其是抑郁状态的比例更高(p＜0.05)。6、NERD患者精神心理异常与生活质量下降显著相关(R=0.36,p=0.001),而反流症状评分与精神心理异常、生活质量下降均无相关性(p＞0.05)。结论本研究调查显示:NERD患者较多见,约GERD占61%,比RE患者的年龄更轻、女性比例更高、Hp感染率更高。NERD和RE患者临床反流及相关症状谱差别不大,但生活质量下降、合并精神心理异常可能是NERD患者不同于RE患者的重要特征,提示NERD和RE发病机制不同。摘要二非糜烂性反流病患者内脏高敏及相关因素的探讨背景与目的NERD和RE患者的反流症状差别不大,但与RE相比,NERD食管酸反流监测阳性率低,易合并精神心理异常。食管内脏高敏感性可能是NERD病生机制的重要方面。本研究目的:观察NERD对食管酸灌注的反应性,并探讨其相关因素。对象和方法20名HS(男11名,平均40.9岁)、11名RE(男6名,平均49.3岁)和31名NERD(男9名,平均45.3岁)患者纳入本研究。RE和NERD患者的反流症状、生活质量和精神心理评价在第一部分研究中已经完成。对NERD患者进行食管24h pH监测。对三组进行食管滴酸试验(APT),即食管内依次滴入生理盐水3min、0.1N的盐酸10min和生理盐水10min(滴速均为10ml/min)。滴酸过程中受试者出现烧心等不适症状时定义为APT阳性。阳性时记录酸敏感指标:T-lag(开始滴酸到最初出现症状的时间),I(症状强度评分,0-20cm的VAS评分),APSS(酸敏感积分,=症状持续时间×症状强度/100,单位cm·s),Td(症状消失时间,即滴酸后滴注NS的10min中,症状消失所需的时间)。同时进行自主神经(ANS)功能检查,分别记录四个时段的ANS功能:安静状态10min(Base stage);插入胃管后10min(Pre-stage);食管内滴酸时的10min(Acid stage);食管内滴NS的10min(NS stage)。结果1、HS、NERD和RE患者的人口学特征无差别,NERD和RE患者在反流症状和生活质量方面无显著差异(p＞0.05),NERD患者焦虑抑郁评分高于RE组患者(p＜0.05)。2、HS、NERD、RE三组的APT阳性率分别为5%、81.8%和61.3%;NERD与RE组患者APT阳性率、T-Lag、I和APSS比较均无显著差异(p＞0.05),滴酸后滴盐水时段中,RE患者症状均消失,但26%的NERD患者症状未消失,症状消失的NERD患者Td较RE患者明显延长(p＜0.05)。3、食管酸刺激不引起健康人ANS功能变化。但酸刺激使NERD和RE患者的交感迷走比值(P1/P2)明显升高;随后滴盐水时,RE患者P1/P2下降,而NERD患者无明显下降。RE患者主要表现食管酸刺激时迷走活性明显降低;而NERD患者静息时迷走活性低于健康人,酸刺激后表现为交感活性明显增加。4、pH监测阴性的24例NERD患者中,APT阳性者的焦虑抑郁评分明显高于APT阴性者,并且T-lag和APSS分别与抑郁评分呈显著性负相关和正相关。结论1.NERD和RE患者的食管酸高敏机制可能不同。2.NERD和RE患者均存在自主神经功能异常,但RE患者主要表现为迷走神经功能异常,可能与食管动力障碍有关;而NERD患者同时存在交感、迷走神经功能受损,可能参与食管内脏高敏感的产生。3.NERD患者精神心理异常与食管酸敏感显著相关。4.自主神经功能异常和精神心理因素可能参与NERD食管内脏高敏产生机制。摘要三非糜烂性反流病和功能性烧心患者食管内脏高敏及中枢机制探讨背景与目的非糜烂性反流病(NERD)和功能性烧心(FH)患者临床表现和病生机制有相同之处。目前关于NERD和FH患者食管高敏感机制,尤其在内脏高敏产生机制的中枢环节的研究尚少有报道。功能性磁共振成像(fMRI)技术可用于内脏高敏感的中枢机制研究,还可能发现精神心理因素通过中枢影响内脏高敏的机制。已有fMRI研究显示食管内脏高敏的NERD患者食管刺激时的中枢激活范围、强度与健康人明显不同。本研究目的:评价FH和NERD患者的食管内脏高敏和精神心理状态,并探讨FH和NERD患者内脏高敏中枢机制。对象和方法纳入8名HS(男4名,平均43.8岁)、5名NERD患者(男1名,年龄51.6岁)和6名FH患者(男2名,年龄42.8岁,符合罗马Ⅲ标准),并且HS者食管滴酸试验均阴性,NERD和FH患者食管滴酸试验均阳性后进入研究。三组受试者均排除精神疾病。首先,评价NERD和FH患者的临床症状、生活质量、焦虑抑郁评分、食管酸敏感指标和自主神经功能;然后,三组受试者均进行食管酸灌注的脑fMRI检查。脑fMRI试验包括两个时段:(1)真实酸刺激时段,采用“on—off”组块设计,食管内滴注盐水为静息状态,滴注酸为刺激,滴速1ml/min;(2)假刺激时段,受试者被告知滴酸而实际上仍滴注盐水。两个时段均进行fMRI功能像扫描。fMRI数据分析采用AFNI软件包:(1)真实酸刺激脑功能成像分析:组分析采用t检验,组间比较采用方差分析,获得脑区统计激活图。选取感兴趣区(ROI)后提取ROI激活的时间—信号强度曲线,比较各组的激活参数。(2)假刺激功能成像序列分析:采用相关分析,比较假刺激的脑区激活是否与真实酸刺激激活有可靠的相关性。结果1、FH患者比NERD患者病程长(p＜0.05)、生活质量更低(p＜0.05)。虽然均存在精神心理异常,但FH患者的焦虑抑郁评分比NERD患者更高(SAS 52.5±12.7 vs 46.4±7.6,SDS61.7±12.6 vs 55.8±5.8,p＜0.05)。2、食管酸高敏和ANS异常在FH患者和NERD患者间无差异(p＜0.05)。3、食管酸灌注时脑区激活情况:1)健康人食管酸刺激激活的脑区主要包括前扣带回、后扣带回、岛叶和岛盖、前额皮质、第一躯体感觉区等参与内脏感觉和情绪情感的相关脑区。2)两组患者脑区激活较健康人更广泛,尤其可见丘脑激活。3)两组患者与健康人的激活模式明显不同,两组患者的信号增加初始时间明显缩短、信号强度增加百分比更高。4)FH患者较NERD患者的脑区激活更广泛;FH和NERD患者的激活模式不同,前者信号达峰时间短于后者,而信号强度增加百分比低于后者。4、假刺激时段,HS(n=8)和NERD(n=5)患者在ACC激活与真实酸刺激的ACC激活相关性不显著,但FH(n=4)患者中有2例可见ACC的激活与真实酸刺激时的激活有可靠的相关性(R≥0.4,p＜0.001)。结论1.FH患者较NERD患者病程长、生活质量低,并且精神心理异常更突出。2.食管酸高敏和自主神经功能异常在FH与NERD患者间差别不大。3.食管酸高敏患者的脑区激活范围较健康人更广泛,并且脑区激活的时间更早、激活的强度更高。4.FH和NERD患者食管酸灌注的脑区激活模式存在不同,提示两者的内脏高敏中枢机制可能不同。5.精神心理因素可能参与FH患者内脏高敏中枢机制。摘要四西酞普兰治疗功能性烧心疗效评价及作用机制探讨背景与目的功能性烧心(FH)属于功能性胃肠病(FGIDs),对PPI治疗无效,并且患者常合并精神心理异常,生活质量显著下降。精神心理异常可能参与FH患者食管内脏高敏机制的中枢机制。抗抑郁药—5-羟色胺再摄取抑制剂(SSRIs)常能明显改善FGIDs患者症状和生活质量。最近国外有研究显示SSRIs中的西酞普兰(Citalopram)明显降低食管对机械和化学刺激的高敏感性,提示其对FH患者可能有治疗作用。本研究目的:观察西酞普兰对FH患者的疗效,并探讨西酞普兰治疗FH可能的中枢机制,旨在为FH患者寻找有效的治疗途径。对象和方法该研究纳入6名FH患者(男性2名,平均42.8岁,符合罗马Ⅲ标准),食管滴酸试验阳性,PPI治疗无效。给予患者西酞普兰治疗,10mg qn 9pm po(Day1-3),20 mg qn 9pmpo(Day4-42)。评价和比较治疗前后患者的烧心症状、睡眠质量、生活质量、精神心理状态、食管酸敏感性和食管酸灌注的脑fMRI检查,方法同第三部分研究。结果1、FH患者治疗后的烧心症状、睡眠质量、生活质量均较治疗前显著改善(p＜0.05)。2、治疗前FH患者均存在明显的焦虑抑郁状态,治疗后焦虑抑郁评分均明显下降至正常范围(p＜0.05)。3、食管滴酸试验的酸敏感性指标在治疗后显著改善:症状出现时间明显延长(262.5±148.9 vs 434.0±79.9sec,p＜0.05)、症状强度和酸敏感积分显著降低(10.8±3.8 vs 4.8±1.5,40.5±23.8 vs 8.4±4.4,p＜0.05)。4、食管酸灌注的脑区激活范围在治疗后与治疗前差别不显著,但前扣带回、丘脑、岛叶和岛盖的激活在治疗前后有显著差别(p＜0.05)。5、与治疗前相比,前扣带回激活在治疗后的信号达峰所需时间明显延长,峰信号强度增加百分比明显降低(p＜0.05)。6、分析4例患者假刺激的脑区激活:治疗前2例患者ACC假刺激激活与真实酸刺激激活相关性显著;治疗后其中1例患者的显著相关性消失,提示西酞普兰减轻食管假刺激引起的脑区激活。结论西酞普兰可改善FH患者临床症状、生活质量和精神心理异常;并可明显降低食管高敏感性,其作用途径可能是干预内脏感知的中枢机制和调整心理因素在中枢环节对内脏高敏的影响。脑fMRI可作为探讨SSRIs治疗FGIDs的中枢机制的有效手段。更多还原

【Abstract】 AbstractⅠInvestigation of Symptom Spectrum,Quality of Life and Psychological Status in Patients with RE and NERDBackgroundGastroesophageal reflux disease(GERD) is a common upper gastrointestinal disorder. Patients with GERD always have multiple symptoms and poor quality of life.It has been assumed that non-erosive reflux disease(NERD) and reflux esophagitis(RE) are two distinct entities of GERD instead of a continuous spectrum.However,until now,there hasn’t domestic data about the intimate clinical characteristics of NERD and RE.AimsThe aim of this study was to evaluate the demographics,symptom spectrum,quality of life,and psychological status in patients with NERD and RE.Subjects and MethodsWe prospectively recruited consecutive patients with acid reflux,regurgitation, heartburn or chest pain for at least 6 months.Exclusion criteria included those patients with peptic ulcer,systematic disease and second any esophagitis or history of gastrointestinal surgery.All patients were asked to complete symptom questionnaires,including reflux symptoms,extra-esophageal symptoms,overlapping symptoms,GERD-health related quality of life questionnaire(GERD-HRQL),SF-36 questionnaire,and questionnaires of psychological status(Zung depression and anxiety score).The patients divided into NERD and RE according to presenting of gastroendoscopy.Results1.278 patients(male 107,mean age 48.42,female 165,mean age 51.35) were investigated.The proportion of NERD and RE were 60.8%and 37.1%.2.Compared to patients with RE,patients with NERD were significantly younger(48.54±11.74 vs 52.39±14.28,p＜0.05),more likely to be female(68.4%vs 47.8%,p＜0.05),and higher H.pylori infection rate(50.9%vs 24.6%,p＜0.05).3.Reflux symptom score has no difference between NERD and RE,however,heartburn and retrosternal pain in NERD was more serious than RE(p＜0.05),and regurgitation in RE were more obvious than that in NERD(p＜0.05).4.The percentages of extra-esophageal symptoms and overlapping symptoms in patients with NERD and RE were not significantly different.5.Compared with RE patients,quality of life in patients with NERD were lower in several domains of SF-36(p＜0.05),although GERD-HRQL score has no difference between the two groups (p＞0.05).6.Prevalence of abnormal psychological status in patients with NERD was significantly higher than patients with RE(71.1%vs 58.0%,p＜0.05),especially prevalence of depression in NERD was predominant.7.There was significant correlation between impaired quality of life and abnormal psychological status in patients with NERD(R=0.36, p=0.001),but no correlation between severity of reflux symptoms and abnormal psychological status or impaired quality of life(p＞0.05).ConclusionsThe proportion of NERD in GERD was 60.8%in this investigation.There was no significant difference in reflux and related symptom spectrum between NERD and RE. Compared to patients with RE,patients with NERD were younger,more commonly in female,had a higher prevalence of abnormal psychological status and poorer quality of life, which suggested that NERD and RE may be exist different mechanisms.AbstractⅡInvestigation esophageal hypersensitivity,and related factors in patients with NERDBackgroudReflux symptoms in patients with NERD and RE are similarity.But compared to patients witht RE,patients with NERD tend to have normal esophageal acid exposure and abnormal psychological status.It is assumed that esophageal visceral hypersensitivity plays an important role in physiological mechanism of NERD.AimsTo evaluate the feature of visceral hypersensitivity and related factors including abnormal ANS function and psychological factors in patients with NERD.Subjects and Methods20 health subjects(HS)(male 11,average age 40.9),11 patients with RE(male 6, average age 49.3)and 31 patients with NERD(male 9,average age 45.3) were enrolled in this study.Evaluation of reflux symptom,depression and anxiety scores(SAS/SDS),and quality of life in patients with NERD and RE had been finished in StudyⅠ.24h esophageal pH monitoring were performed in patients with NERD.Then acid perfusion test(APT) was carried out in three groups,including three periods of esophageal perfusion,that was perfused saline(NS) for 3 min,0.1N HCl for 10 min and NS for 10 min in order.APT was considered positive while subject reported heartburn or chest pain.The Acid hypersensitivity parameters were T-lag(time to symptom perception after acid perfusion),Ⅰ(Sensory intensity rating,0-20cm),APSS(acid perfusion symptom score=duration of symptom perception×intensity rating/100,cm·s),Td(time of symptom disappearing during NS stage).Meanwhile,autonomic nerve symptom(ANS) function was assessed of four stages,including baseline stage,second stage which after inserting catheter and before perfusion,acid perfusion stage and NS perfusion stage.The parameters of ANS function included the power in the low-frequency(LF) band reflecting sympathetic tone,power in the high-frequency(HF) band reflecting vagal tone,and the LF/HF ratio(P1/P2) as an indicator of sympathovagal balance.Results1.There was no statistical difference in demographics between the three groups.2. Patients with NERD had similar reflux symptom and quality of life,but has higher abnormal psychological scores than patients with RE(p＜0.05).3.Positive rates of APT in groups of HS,NERD and RE were respectively 5%,81.8%and 61.3%.There were no differences in T-Lag,I and APSS(p＞0.05) between patients with NERD and RE,but Td was obviously prolonged in patients of NERD than that of RE(p＜0.05).4.Acid stimulation didn’t cause ANS function alteration in HS,but significantly increased the ratio of P1/P2 in the two patient groups(p＜0.05).The HF band power in patients of RE was significantly cut down to acid stimulation(p＜0.05).In patients of NERD,the LF band power was significantly step up to acid stimulation(p＜0.05),while the HF of baseline was lower than that of HS(p＜0.05).5.In patients with NERD who has normal acid exposure in pH monitoring,there existed positive correlation between the SDS and APSS(R=0.57,p＜0.05) and negative correlation between SDS and I in APT(R=-0.72,p=0.01).ConclusionsThere may be exist different mechanism of esophageal hypersensitivity between patients with NERD and RE.Patients with NERD and RE both existed abnormal ANS function.Abnormal vagal nerve function was presented in patients with RE,while both sympathetic and vagal function were impaired in patients with NERD.Psychosocial factors, esophageal hypersensitivity,and abnormal ANS function might play important roles in the pathophysiological mechanisms of NRED.AbstractⅢIdentification of Oesophageal hypersensitivity and central mechanisms between patients with NERD and FHBackgroudThere were similar symptoms and pathophysiological mechanisms between Non-erosive disease(NERD) and Functional heartburn(FH).But there were few studies investigating the mechanisms of oesophageal hypersensitivity,especially the potential central level mechanism.With the advance of functional magnetic resonance imaging (fMRI) of the brain,it is now possible to objectively investigate the central mechanism of visceral hypersensitivity.Studies using fMRI technique revealed the different patterns of cerebral activation in response to esophageal stimulus between the health and patients with NERD.AimsTo investigate oesophageal hypersensitivity in patients with NERD and FH,and elucidate the potential difference in central mechanisms of visceral hypersensitivity between patients with NERD and FH.Subjects and MethodsAfter acid perfusion test in which the healthy subjects presented negative and patients presented positive,there were 8 HS(4M/4F,mean age 43.8),5 patients with NERD(1M/4F, average age 51.6) and 6 patients with FH(2M/4F,average age 42.8)participated in the study. All subjects had no history of psychological disorders.The two patient groups were compared for symptom,depression and anxiety scores(SAS/SDS),quality of life, additionally,underwent APT and ANS function test.fMRI scan was performed in the three groups.There were two stages in a paradigm-driven fMRI experimental protocol.The first stage was actual acid perfusion,including two rounds,each round contained alternating 5-min intervals of 0.1 N HCl and saline perfusion following an initial 3-min interval of saline perfusion(both in rate of 1 ml/min).In the second stage(anticipated stage),the subjects were told being acid perfusion,but perfusion liquid is saline,fMRI scans were performed on a 3.0-T system(GE Signa VHi EXCITEⅡ) using quadrature head coil. Gradient-echo planar imaging sequences were used(TR=6000ms;TE=40ms;FOV=240×240 mm;flip angle=90°;matrix size=64×64).Data analysis was carried out using AFNI software package.Results1.There was no statistical difference in demographics between the three groups.2. Patients with FH had longer course of disease,poorer quality of life and higher SAS/SDS scores,when compared with patients with NERD(p＜0.05).3.There was no significantly difference between the two patient groups while all these patients had acid hypersensitivity and abnormal ANS function.4.Acid perfusion activated multiple cortical regions including the anterior and posterior cingulate cortices,the insula,operculum,prefrontal cortex and primary somatosensory cortices in all three groups,while thalamus only activated in the two patients group.5.Cerebral activity associated with acid exposure in the two patient groups occurred more rapidly and with greater intensity than the activity in HS.6.Patients with FH demonstrated a larger area of activation than NERD(p＜0.05).There existed different cortical activity between patients with FH and NERD:time from initial activation to the time of maximum signal change in FH was shorter than that of NERD(p＜0.05), while the average maximum percent signal increase in FH was significantly lower than in NERD(p＜0.05).7.During anticipated stage,2 patients with FH presented that activities within ACC were strongly correlated with the activity curve during the actual acid perfusion stage(R≥0.4,p＜0.001),while all of HS and patients with NERD didn’t demonstrate significant correlation.ConclusionsComparison with patients with NERD,patients with FH had longer course of disease, poorer quality of life and abnormal psychological status.In response to esophageal acid stimulus,patients with NERD and FH demonstrated extensive cortical regions activated, much more rapid activity and greater intensity in the activated cortex than HS.Compared to patients with NERD,activity in FH occurred more rapidly and lower intensity,which suggested patients with FH had different central mechanism of hypersensitivity with that of NERD. AbstractⅣClinical Efficacy of Citalopram in Patients with Functional Heartburn and Investigation Central MechanismBackgroudFunctional heartburn(FH),being one of functional gastrointestinal disorders(FGIDs), always failed to response to PPI therapy.The prevailing view is to consider visceral hypersensitivity and abnormal brain-gut axis as the major factors involved in pathogenesis. Clinically,antidepressants-selective serotonin reuptake inhibitors(SSRIs) appear to be useful for some patients with FGIDs for improving the symptom and quality of life.Recent study have shown that acute administration of SSRIs,citalopram,significantly decreased chemical and mechanical sensitivity in healthy volunteers with hypersensitivity to oesophageal stimulation,which suggests that citalopram may offer therapeutic potential in the treatment of patients with oesophageal hypersensitivity,such as patients with functional heartbum(FH).AimsTo evaluate the clinical efficacy of citalopram to patients with FH,and identify the therapeutic effect of citalopram through CNS mechanism,in order to search effective therapy to FH.Subjects and MethodsAccording with criteria of ROMEⅢ,6 FH patients(1M,5F,mean 42.8yrs),who failed to response to PPI therapy and presented positive in acid perfusion test(APT) participated in the study.The dose of citalopram treatment is 10mg qn 9pm po(1-3d),then 20mg qn 9pm po(4-42d).The efficacy of citalopram to symptom,quality of life,depression and anxiety score and esophageal acid sensitivity were evaluated.Additionally,cerebral activation during esophageal acid perfusion was assessed after treatment by fMRI(the protocol of fMRI is same as the studyⅢ).ResultsAfter six weeks of treatment,citalopram significantly improved heartburn symptom and quality of life(p＜0.05).After treatment,the depression and anxiety score was in normal range,comparing with that either score was abnormal before treatment.Citalopram significantly lowered esophageal acid hypersensitivity of patients with FH.After treatment, activated cortical regions during acid perfusion had no significantly different with before treatment,but activity in regions such as anterior cingulate cortices(ACC),thalamus,the insula and operculum after treatment were significantly different with pre-treatment(p＜0.05).After treatment,the average maximal percent of signal increase in fMRI was significantly lower than pre-treatment(0.64%vs 0.98%,p＜0.05),while the time from initial fMRI signal activation to the time of maximal signal change was longer than pre-treatment(3.58 min vs 3.08 min,p＜0.05).Before treatment,there were 2 patients presented that ACC activity during the anticipated stage was strongly correlated with that of actual acid stage.Citalopram diminished ACC activation during anticipation of acid perfusion in 1 patient.ConclusionsCitalopram,SSRIs,significantly improved FH symptoms,quality of life and also exerted beneficial effect on abnormal psychological status.Citalopram significantly lowered esophageal hypersensitivity in patients with FH and was likely to work through a central neuromodulation,fMRI may be a useful technique for future investigation of central level’s mechanism of SSRIs in FGIDs.更多还原