根除幽门螺杆菌及药物治疗对功能性消化不良影响的研究
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摘要
背景和目的：功能性消化不良(functional dyspepsia,FD)是指存在一种或多种源于胃十二指肠区域的消化不良症状,并且缺乏能解释这些症状的任何系统性、器质性或代谢性疾病,这些症状包括上腹痛、上腹烧灼感、餐后饱胀和早饱。根据其主要症状,功能性消化不良分为两个亚组：餐后不适综合征(PDS)和上腹痛综合征(EPS)。文献报道,FD作为最常见的功能性胃肠病之一,其在世界范围内的发病率约为11.0%-29.2%,严重影响患者健康相关的生活质量,并且给患者和社会带来巨大的经济负担。值得注意的是,尽管FD被建议按症状标准进行分类,但其仍是一排他性诊断,缺乏病理学诊断依据。FD的病因目前仍然不甚明了,在一些研究中其发病机制被认为与胃排空延迟、近端胃对食物的容受性下降、胃对扩张的高敏感性、十二指肠-空肠运动异常、精神心理因素及幽门螺杆菌感染等因素有关。从病理生理机制角度上来讲FD很可能是一种异质性疾病。
有研究发现FD病人较对照组的十二指肠粘膜内嗜酸性粒细胞明显增高,并且嗜酸性粒细胞浸润程度与早饱症状相关。这些有关FD病人嗜酸性粒细胞增高现象的研究为FD的发病机制提出了一个嗜酸性粒细胞假说：十二指肠嗜酸性粒细胞的变化可能是FD的基本病理特征(并且可能是主要致病过程)。Gargala, Talley和Walker研究发现十二指肠嗜酸性粒细胞的免疫激活与FD密切相关,而胃粘膜的嗜酸性粒细胞增高与FD无关。就上述现象有假说推测：某些原因促使嗜酸性粒细胞激活后脱颗粒并释放多种活性物质,这些活性物质又辅助肥大细胞释放一系列化学物质,后者诱发平滑肌收缩以致出现腹痛或进食相关的临床症状。如此看来,胃肠道嗜酸性粒细胞增多这一表现至少可作为FD有用的生物标记,并且这些强力的效应细胞可能会成为这些相关疾病有价值的治疗靶点。
有关H.pylori在FD发病机制中所扮演的角色一直以来颇有争议,近期部分研究资料显示根除H.pylori在治疗FD时有少许但确切的益处。然而,另外一些荟萃分析研究结果表明在治疗非溃疡性消化不良时根除H.pylori并无多大价值。事实上,有关H.pylori在FD发病机制中的作用及FD治疗时是否需根除H.pylori一直尚无定论。
对于FD的治疗一直以来都颇具挑战性。FD经药物治疗后相关症状的改善常常是不完全的,其好转率经常不到60%。治疗效果差很可能是因为FD为一异质性疾病。一般来说,对FD病人的治疗方法常常基于其主要症状。事实证明这种做法是实用的、有效的。质子泵抑制剂、促动力药、根除H.pylori及抗抑郁药是治疗FD的常用选择。
先前发表的文献资料缺乏H.pylori清除或药物治疗与FD患者胃肠道嗜酸性粒细胞相关性的临床前瞻对照研究。我们的研究目的有二：一方面,评价FD病人H.pylori根除前后及根除与否对症状的影响；另一方面,观察H.pylori根除和药物治疗是否影响胃肠道嗜酸性粒细胞。我们尤为关注的是在治疗前后FD症状变化是否与胃肠道嗜酸性粒细胞水平存在某种联系。
方法：18-70岁符合Rome III标准的FD成年病人纳入本研究。对过去3个月来腹部主要症状用腹部症状自评量表进行问卷调查,并在三个时间点分别进行评估。问卷内容包括如下腹部症状：上腹痛、嗳气、早饱、餐后饱胀、恶心、呕吐、干呕、厌食、腹胀、上腹不适、咽下困难和胸骨后痛。
在不同时间点(第0周：基线,初始诊断和胃镜检查；第2周：药物治疗结束时；第6周：基线后6周)分别联系病人询问临床症状,并记录临床症状。用5-point Likert量表评估症状分值,无症状、轻微、中等、严重、非常严重分别赋分0、1、2、3、4分,并计算总分。
在基线时间点病人分别进行胃镜、活检病理及14C呼气试验。所有病人的胃镜检查由2位内镜医师在检查前和检查时不了解病人症状的情况下进行。胃镜检查时活检标本分别取材于胃体(小弯侧和大弯中部)、胃窦(小弯和大弯侧)、十二指肠球部、十二指肠降部,每一部位取标本2块。第6周末部分病人复查胃镜和活检病理,H.pylori阳性病人复查14C呼气试验。活检标本福尔马林固定、常规制成3／μm层厚石蜡切片,进行H&E和Warthin-Starry染色备用。H.pylori病理检查阳性定义为Warthin-Starry染色病理切片上可见细菌,否则为阴性。
入组病人根据14C尿素呼气试验和Warthin-Starry染色结果分为H.pylori阳性组和H.pylori阴性组。H.pylori阳性组病人接受四联抗幽门螺杆菌治疗,依据根除结果,阳性组病人分为H.pylori根除组(A组)和H.pylori未根除组(B组)2个亚组。H.pylori阴性组病人随机分成2个亚组,分别给予埃索美拉唑镁(C组)和替普瑞酮(D组)治疗。在3个时间点(基线时、第2周和第6周)分别行腹部症状自评量表问卷调查,并用上腹痛、烧心、餐后饱胀和早饱的总评分作症状评估。胃十二指肠嗜酸性粒细胞通过计数活检部位(胃体、胃窦、十二指肠球部和降部)每5个高倍视野的嗜酸性粒细胞数之和进行统计学分析。两位病理科医师在不明病例分组情况下分别对病理切片进行阅片并进行嗜酸性粒细胞计数。每一切片随机选取5个高倍视野(放大倍数×40),计数每一高倍视野的嗜酸性粒细胞数,计算5个高倍视野的嗜酸性粒细胞数之和。任一高倍视野的嗜酸性粒细胞计数大于等于10个定义为嗜酸性粒细胞集簇现象阳性。
病人分组及治疗情况如下：1.H.pylori阳性组(1组)：四联抗幽门螺杆菌治疗(埃索美拉唑镁20mg,每日两次；克拉霉素分散片0.5g,每日两次；阿莫西林1g,每日两次；枸橼酸铋钾0.6g,每日两次)。2. H.pylori阴性组(2组)：埃索美拉唑镁20mg,每日两次或替普瑞酮50mg,每日三次,入组时病人依随机数字表随机用上述二者之一。3.H.pylori根除组(A组)：1组中成功根除H.pylori者。4. H.pylori未根除组(B组)：1组中根除H.pylori失败者。5.埃索美拉唑组：2组中接受埃索美拉唑镁治疗者。6.替普瑞酮组：2组中接受替普瑞酮治疗者。每组病人治疗疗程均为2周。
结果：
1.本研究共纳入病人215人,其中Warthin-Starry染色和14C呼气试验双阳性者97例,双阴性82例,Warthin-Starry染色阳性14C呼气试验阴性19例,Warthin-Starry染色阴性14C呼气试验阳性17例。研究过程中失访12例(其中H.pylori阳性组7例,替普瑞酮组2例,埃索美拉唑组3例),由于难以忍受的腹泻或胃部不适而中途退出者11例(其中H.pylori阳性组6例,替普瑞酮组3例,埃索美拉唑组2例)。最后完成试验者人数分别为：H.pylori阳性组84例,H.pylori阴性组72例,其中,纳入A组58人,B组26人,C组36人,D组36人,第6周末复查胃镜及病理活检者在四组中分别为36、19、18和16人。H.pylori阳性组病人在6周末经14C呼气试验证实幽门螺杆菌根除率为69.0%(58/84)。
2. H.pylori阳性组与H.pylori阴性组在基线时的症状评分无显著差异。H.pylori根除组与H.pylori未根除组在3个时间点的症状评分均无显著差异。
3.在基线时H.pylori阳性组病人胃体和胃窦的嗜酸性粒细胞计数均较H.pylori阴性组明显升高,而在十二指肠球部和十二指肠降部两组间的嗜酸性粒细胞水平无显著差异。
4.基线时H.pylori根除组与H.pylori未根除组在胃十二指肠4个活检部位的嗜酸性粒细胞计数均无差异。在6周时H.pylori根除组在胃体和胃窦的嗜酸性粒细胞计数均较H.pylori未根除组明显下降,而在十二指肠球部和降部两组间的嗜酸性粒细胞计数均无显著差异。
5.第2周末时埃索美拉唑组和替普瑞酮组的症状评分均较基线时明显改善。埃索美拉唑组在第6周末时症状评分较基线时也明显改善,但替普瑞酮组未见显著改变。基线时埃索美拉唑组和替普瑞酮组的症状评分无差异,但第6周末时前者较后者症状显著减轻。
6.在基线或第6周末,埃索美拉唑组和替普瑞酮组两组间在胃十二指肠4个活检部位的嗜酸性粒细胞计数均无显著差别。在第6周末埃索美拉唑组或替普瑞酮组的胃肠道嗜酸性粒细胞计数与基线时相比也均无显著差异。
7.基线时H.pylori阳性组胃体、胃窦粘膜嗜酸性粒细胞集簇现象出现率较H.pylori阴性组显著增高,而两组间十二指肠球部或降部嗜酸性粒细胞集簇现象发生率均无显著差异。在6周末,H.pylori根除组与H.pylori未根除组相比及埃索美拉唑组与替普瑞酮组相比,胃十二指肠嗜酸性粒细胞集簇现象出现率均无显著差异。H,pylori根除组、H.pylori未根除组、埃索美拉唑组或替普瑞酮组其嗜酸性粒细胞集簇现象在治疗前后均无差异。
结论：
1.H.pylori感染与FD病人胃粘膜嗜酸性粒细胞增多相关,但不影响十二指肠嗜酸性粒细胞水平。
2.根除H.pylori能降低FD病人胃嗜酸性粒细胞,但不影响十二指肠嗜酸性粒细胞水平。
3. H.pylori感染与FD患者的消化不良症状评分无关,并且H.pylori成功根除与否与病人症状改善无关。
4.埃索美拉唑和替普瑞酮均不影响H.pylori阴性FD患者的胃十二指肠嗜酸性粒细胞水平。
5.埃索美拉唑和替普瑞酮治疗后的短期随访中,埃索美拉唑对H.pylori阴性FD病人的治疗效果优于替普瑞酮。
6.FD病人经H.pylori根除治疗、埃索美拉唑或替普瑞酮治疗后,其消化不良症状改善与十二指肠嗜酸性粒细胞数量无关。
研究意义：
本研究通过观察FD病人治疗前后胃十二指肠嗜酸性粒细胞水平的变化,发现H.pylori上调胃粘膜的嗜酸性粒细胞但不影响十二指肠嗜酸性粒细胞水平,埃索美拉唑和替普瑞酮均不影响FD病人胃十二指肠嗜酸性粒细胞水平。
本研究结果阐明了H.pylori根除、埃索美拉唑和替普瑞酮对FD的治疗作用与十二指肠嗜酸性粒细胞无关。
本研究结果为埃索美拉唑和替普瑞酮对FD的治疗作用提供了证据,对H.pylori阴性FD病人的治疗具有重要的指导价值,并且结果表明H.pylori阳性FD病人可能根本不需根除H.pylori治疗,从而减轻病人的经济负担并减少抗生素应用的不良反应。
Background and Objectives
Functional dyspepsia (FD) is a syndrome which is described as epigastric burning,epigastric pain, postprandial fullness and early satiation, in the absence of any systemic, organic, or metabolic disease that is likely to explain the symptoms. According to the main symptoms, FD was divided into two subgroups, which were postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). FD is thought to originate in the gastroduodenal region. As one of the most prevalent functional gastrointestinal disorders (FGIDs), the prevalence rate of FD has been noted to vary between11.0%-29.2%globally, and it induced a major impaired health-related quality of life and economic burden. Notably,although symptom criteria have been proposed for FD, it remains a diagnosis of exclusion owing to lack of diagnostic pathology. The pathogenesis of FD remains obscure although delayed gastric emptying,impaired proximal gastric accommodation to a meal, abnormal duodenojejunal motility, gastric hypersensitivity to distension, psychological disturbance, Helicobactor pylori (H.pylori) infection have been proposed in several investigations,and the pathophysiological mechanism of functional dyspepsia most likely is a heterogeneous disorder.
A study reported that markedly increased numbers of duodenal mucosal eosinophils in individuals with functional dyspepsia compared with controls,and the degree of eosinophilic infiltration was correlated with early satiety. The studies of duodenal eosinophils in FD provided an eosinophil hypothesis for functional dyspepsia, proposing that changes in duodenal eosinophils perhaps are an underlying feature (and primary pathogenic process) of FD. Gargala, Talley and Walker found that immune activation of the duodenal eosinophilia were closely related to functional dyspepsia, while the increase of gastric eosinophilic granulocyte were not related to functional dyspepsia. It was hypothesized that the eosinophils degranulate and release of various of substances after activation, and help mast cell release substances to stimulate the neurons,leading to contraction of smooth muscle, resulting in symptoms such as meal-related symptoms or abdominal pain.In the very least it seems that the presence of increased numbers of gastrointestinal eosinophils might act as a useful biomarker in FD,and these potent effector cells will yet prove to be worthy therapeutic targets in the quest to combat these disorders.
The role of H.pylori in functional dyspepsia continues to be a matter of debate, part of recent data indicate that there is some modest but clear benefit of eradication of H.pylori in patients with functional dyspepsia. However,another meta-analysis provides little support for the use of H. pylori eradication therapy in patients with nonulcer dyspepsia. In fact,the role of H.pylori in FD is controversial and whether H.pylori eradication is necessary for FD remains unclear.
To date, the treatment for FD remains challenging.Symptomatic improvement of patients with FD after therapy is often incomplete and obtained in no more than60%of patients. Perhaps this is because functional dyspepsia is a heterogeneous disease. In general, the approach to treat patients with FD based on the main symptoms is practical and effective. Proton-pump inhibitors,prokinetics,Helicobacter pylori eradication and antidepressant drug are the usual choice for the treatment of FD.
Previously published data was lack of prospective clinical controlled study which focused on the relationship between gastrointestinal eosinophil levels and H.pylori clearance or drugs therapy for FD.This study had two objective:on the one hand,we wanted to appreciate eradication treatment for H.pylori in the symptomatic response of patients with FD;on the other hand,we wanted to evaluate whether H.pylori eradication and drugs therapy would affect gastroduodenal eosinophils.In particular,we wanted to discover whether there was certain relationship between symptom improvement and changes of gastroduodenal eosinophil counts before and after treatment.
Methods
Adult FD patients (18-70years) fulfilling Rome III criteria were recruited in the study. The self-administered abdominal symptom questionnaire assessed symptoms from the lower and upper part of the abdomen over the preceding three months has been used in the study. A standardized procedure for the administration of the questionnaire at3time points was conducted. The questionnaire includes abdominal symptom as follows, such as epigastric pain, belching, early satiety, or an uncomfortable feeling of fullness after a meal, vomiting,nausea, retching, the eructation, anorexia, abdominal distension,epigastric discomfort,retrosternal pain and dysphagia.
Patients were connected to ask clinical symptoms at different time points(week0:baseline, initial diagnosis and gastroscopy; week2:end of drug therapy; week6:6weeks later after baseline), and the clinical symptoms were marked. In the5-point Likert table, the degrees of the abdominal symptom (asymptomatic, mild,moderate,severe, very severe) were recorded as0,1,2,3,4points,and the scores were accumulated.
Patients underwent gastroscopy, pathology and14C-urea breath test respectively at week0. Gastroscopy of all patients was performed by2physicians who were unaware of the symptoms of the subjects before and during endoscopy.At endoscopy, biopsy specimens were taken from body (lesser curvature and middle of greater curvature), antrum (lesser curvature and greater curvature), duodenal bulb (D1), and descending part of duodenum (D2),and2blocks were taken from each site. At week6, part of the patients were reexamined,including gastroscopy,biopsy and pathology, and H.pylori-positive patients received14C-urea breath test again. Biopsy specimens were fixed in formalin and routinely processed to paraffin wax. Sections were cut at3 ,um,with levels and stained with H&E and Warthin-Starry stain for further study. The H.pylori status was defined as either positive or negative according to whether the bacteria was visible on the Warthin-Starry stain.
According to the results of14C urea breath test and Warthin-Starry stain, the patients were divided into H.pylori-positive group and H.pylori-negative group In H.pylori-positive group, a quadruple therapy was performed to eradicate Helicobacter pylori,and then H.pylori-positive group was divided into two subgroups: H.pylori-eradicated group and H.pylori-uneradicated group. H.pylori-negative group was randomly divided into two subgroups, patients of these two subgroups were treated with esomeprazole or teprenone seperately. The self-administered abdominal symptom questionnaire assessed symptoms has been completed at different time points(baseline,week2, and week6),and then assessed the symptom scores (for a total of upper abdominal pain, heartburn, postprandial fullness, and early satiety). The gastroduodenal eosinophils were quantified by counting the number per5high-power fields at each of4sites (body, antrum, duodenal bulb, and second portion of duodenum), and total counts were summed over the5fields at each site.
Two pathologists who were blinded to the case-control status assessed the biopsy specimens independently. For each subject, eosinophil counts were obtained from body, antrum, D1, and D2.Eosinophils were quantified by counting the number per high-power field (magnification×40);5high-power fields were selected randomly in each section.The sum over the5-fields counts then were calculateded in every subject. The non-overlapping HPF eosinophil count greater than or equal to10was set for eosinophil cluster positive.
Definitions of Symptom Groups were as follows:First,the patients were divided into group1(H.pylori positive group) and group2(H.pylori negative group) according to the results of Warthin-Starry stain and14C urea breath test.Second, patients of group1received H.pylori eradication treatment,and were divided into groupA(H.pylori-eradicated group)and groupB(H.pylori-uneradicated group) according to the H.pylori status confirmed through14C urea breath test at week6.Third,subjects of group2(H.pylori negative group) were randomly assigned into groupC(esomeprazole group) and groupD(teprenone group) by the random number table.
Subjects were classified and treated through the following methods:(1) group1(H.pylori positive group):both Warthin-Starry stain and14C urea breath test were positive, the quadruple therapy (esomeprazole magnesium tablets20mg twice a day; amoxicillin tablets1g twice a day; clarithromycin dispersible tablets0.5g twice a day; citron acid bismuth potassium0.6g twice a day; the course of treatment was2weeks)was used to eradicate H.pylori.(2) group2(H.pylori negative group):both Warthin-Starry stain and14C urea breath test were negative, esomeprazole magnesium (20mg twice a day) or teprenone (50mg three times a day) was used according to the random number table.(3) group A (H.pylori-eradicated group):patients of groupl who obtained successful H.pylori eradication confirmed through14C urea breath test at week6.(4) group B (H.pylori-uneradicated group):patients of groupl who failed to eradicate H.pylori confirmed through14C urea breath test at week6.(5) group C (esomeprazole group):patients of group2who were treated with esomeprazole magnesium for2weeks.(6) group D(teprenone group):patients of group2who were treated with teprenone for2weeks.
Results
1. a total of215patients were involved in the test, in which,the number of people that both Warthin-Starry stain and14C urea breath test positive was97; the number that both Warthin-Starry stain and14C urea breath test negative was82; the number that Warthin-Starry stain positive but14C-urea breath test negative was19, the number that Warthin-Starry stain negative but14C-urea breath test positive was17, lost was12(7in the H.pylori positive group,2in the teprenone group and3in the esomeprazole group), out of the test was11owing to adverse reactions such as unbearable diarrhea and stomach discomfort(6in the H.pylori positive group,3in the teprenone group and2in the esomeprazole group). Then,the number of patients in group1,group2,groupA,groupB,groupC and groupD was84,72,58,26,36and36respectively,and the number of the subjects who reviewed gastroscopy at week6was36,19,18and16respectively in the4subgroups.In the H.pylori positive group, the successful H.pylori eradication rate was69.0%(58/84).
2. Symptom scores were overall not significantly different between the H.pylori-positive group and the H.pylori-negative group at baseline.At baseline, week2and week6,symptom scores of the H.pylori-eradicated group were overall not significantly different from that of the H.pylori-uneradicated group.
3. In the baseline level, the eosinophil counts of body and antrum were significantly increased in the H.pylori-positive group vs the H.pylori-negative group. In duodenum area, compared to the H.pylori-negative group, the H.pylori-positive group did not show marked increase in eosinophil counts.
4.At baseline, gastroduodenal eosinophil counts of H.pylori-eradicated groups were overall not significantly different from that of H.pylori-uneradicated groups. While at week6,compared with the H.pylori-uneradicated groups, eosinophil counts of antrum and body were all significantly decreased in the H.pylori-eradicated groups. In the duodenal bulb and the descending duodenum, eosinophil counts of the H.pylori-eradicated groups were not significantly different from that of the H.pylori-uneradicated groups at week6.
5. The symptoms of esomeprazole group and teprenone group were all improved respectively at week2compared with that at baseline.The similar phenomenon can be observed between baseline and week6in groupC,but there was not significantly different in groupD between baseline and week6. At baseline, symptom scores of the esomeprazole group were not different from that of the teprenone group,but the symptom scores of the esomeprazole group were improved significantly than that of teprenone group at week6.
6. The eosinophil counts of the4sites in the esomeprazole group were all not statistically different from that of the teprenone group at baseline and week6.The gastric and duodenal eosinophil counts of groupC and groupD were all not significantly different respectively between baseline and week6.
7. At baseline, compared with H.pylori-negative groups,gastric eosinophil clusters were significantly increased in H.pylori-positive groups, whereas the duodenal eosinophil clusters of the H.pylori-positive groups were not different from that of the H.pylori-negative groups. At week6,the gastroduodenal eosinophil clusters were not significantly different between H.pylori-eradicated group and H.pylori-uneradicated group,between esomeprazole group and teprenone group. The gastroduodenal eosinophil clusters showed no significant difference before and after treatment in4subgroups.
Conclusions
1.H.pylori infection was associated with the increased eosinophil counts of stomach but did not affect the eosinophil amount of duodenum in patients with FD.
2.H.pylori eradication can reduce the gastric eosinophil counts but not affect the duodenal eosinophils level in patients with FD.
3.H.pylori infection was not associated with the symptoms of FD and H.pylori eradication or not showed no difference on symptomatic improvement of patients with functional dyspepsia
4.Neither esomeprazole nor teprenone showed effect on the eosinophils level of stomach and duodenum in H.pylori-negative patients with FD.
5.The effect of esomeprazole was better than that of teprenone on improving symptoms of H.pylori-negative patients with FD during a short follow-up period of6weeks.
6. The duodenal eosinophils were not involved in the symptoms improvement obtained after treatment of H.pylori eradication, esomeprazole or teprenone.
The significance of study
This study explored the change of eosinophils level of stomach and duodenum before and after treatment,found out H.pylori up-regulate gastric eosinophils but did not affect duodenal eosinophils level, neither esomeprazole or teprenone was related to gastroduodenal eosinophils in FD patients.
It theoretically revealed that the benefits of H.pylori eradication,esomeprazole or teprenone on FD was not involved in duodenal eosinophils.
The results provide evidence for the effect of esomeprazole or teprenone, it has important practical value on H.pylori-negative FD patients,and the study revealed that H.pylori eradication probablly is not necessary when treating H.pylori-positive FD,thus reduce the economic burden and avoid the adverse reactions of antibiotics.
有研究发现FD病人较对照组的十二指肠粘膜内嗜酸性粒细胞明显增高,并且嗜酸性粒细胞浸润程度与早饱症状相关。这些有关FD病人嗜酸性粒细胞增高现象的研究为FD的发病机制提出了一个嗜酸性粒细胞假说：十二指肠嗜酸性粒细胞的变化可能是FD的基本病理特征(并且可能是主要致病过程)。Gargala, Talley和Walker研究发现十二指肠嗜酸性粒细胞的免疫激活与FD密切相关,而胃粘膜的嗜酸性粒细胞增高与FD无关。就上述现象有假说推测：某些原因促使嗜酸性粒细胞激活后脱颗粒并释放多种活性物质,这些活性物质又辅助肥大细胞释放一系列化学物质,后者诱发平滑肌收缩以致出现腹痛或进食相关的临床症状。如此看来,胃肠道嗜酸性粒细胞增多这一表现至少可作为FD有用的生物标记,并且这些强力的效应细胞可能会成为这些相关疾病有价值的治疗靶点。
有关H.pylori在FD发病机制中所扮演的角色一直以来颇有争议,近期部分研究资料显示根除H.pylori在治疗FD时有少许但确切的益处。然而,另外一些荟萃分析研究结果表明在治疗非溃疡性消化不良时根除H.pylori并无多大价值。事实上,有关H.pylori在FD发病机制中的作用及FD治疗时是否需根除H.pylori一直尚无定论。
对于FD的治疗一直以来都颇具挑战性。FD经药物治疗后相关症状的改善常常是不完全的,其好转率经常不到60%。治疗效果差很可能是因为FD为一异质性疾病。一般来说,对FD病人的治疗方法常常基于其主要症状。事实证明这种做法是实用的、有效的。质子泵抑制剂、促动力药、根除H.pylori及抗抑郁药是治疗FD的常用选择。
先前发表的文献资料缺乏H.pylori清除或药物治疗与FD患者胃肠道嗜酸性粒细胞相关性的临床前瞻对照研究。我们的研究目的有二：一方面,评价FD病人H.pylori根除前后及根除与否对症状的影响；另一方面,观察H.pylori根除和药物治疗是否影响胃肠道嗜酸性粒细胞。我们尤为关注的是在治疗前后FD症状变化是否与胃肠道嗜酸性粒细胞水平存在某种联系。
方法：18-70岁符合Rome III标准的FD成年病人纳入本研究。对过去3个月来腹部主要症状用腹部症状自评量表进行问卷调查,并在三个时间点分别进行评估。问卷内容包括如下腹部症状：上腹痛、嗳气、早饱、餐后饱胀、恶心、呕吐、干呕、厌食、腹胀、上腹不适、咽下困难和胸骨后痛。
在不同时间点(第0周：基线,初始诊断和胃镜检查；第2周：药物治疗结束时；第6周：基线后6周)分别联系病人询问临床症状,并记录临床症状。用5-point Likert量表评估症状分值,无症状、轻微、中等、严重、非常严重分别赋分0、1、2、3、4分,并计算总分。
在基线时间点病人分别进行胃镜、活检病理及14C呼气试验。所有病人的胃镜检查由2位内镜医师在检查前和检查时不了解病人症状的情况下进行。胃镜检查时活检标本分别取材于胃体(小弯侧和大弯中部)、胃窦(小弯和大弯侧)、十二指肠球部、十二指肠降部,每一部位取标本2块。第6周末部分病人复查胃镜和活检病理,H.pylori阳性病人复查14C呼气试验。活检标本福尔马林固定、常规制成3／μm层厚石蜡切片,进行H&E和Warthin-Starry染色备用。H.pylori病理检查阳性定义为Warthin-Starry染色病理切片上可见细菌,否则为阴性。
入组病人根据14C尿素呼气试验和Warthin-Starry染色结果分为H.pylori阳性组和H.pylori阴性组。H.pylori阳性组病人接受四联抗幽门螺杆菌治疗,依据根除结果,阳性组病人分为H.pylori根除组(A组)和H.pylori未根除组(B组)2个亚组。H.pylori阴性组病人随机分成2个亚组,分别给予埃索美拉唑镁(C组)和替普瑞酮(D组)治疗。在3个时间点(基线时、第2周和第6周)分别行腹部症状自评量表问卷调查,并用上腹痛、烧心、餐后饱胀和早饱的总评分作症状评估。胃十二指肠嗜酸性粒细胞通过计数活检部位(胃体、胃窦、十二指肠球部和降部)每5个高倍视野的嗜酸性粒细胞数之和进行统计学分析。两位病理科医师在不明病例分组情况下分别对病理切片进行阅片并进行嗜酸性粒细胞计数。每一切片随机选取5个高倍视野(放大倍数×40),计数每一高倍视野的嗜酸性粒细胞数,计算5个高倍视野的嗜酸性粒细胞数之和。任一高倍视野的嗜酸性粒细胞计数大于等于10个定义为嗜酸性粒细胞集簇现象阳性。
病人分组及治疗情况如下：1.H.pylori阳性组(1组)：四联抗幽门螺杆菌治疗(埃索美拉唑镁20mg,每日两次；克拉霉素分散片0.5g,每日两次；阿莫西林1g,每日两次；枸橼酸铋钾0.6g,每日两次)。2. H.pylori阴性组(2组)：埃索美拉唑镁20mg,每日两次或替普瑞酮50mg,每日三次,入组时病人依随机数字表随机用上述二者之一。3.H.pylori根除组(A组)：1组中成功根除H.pylori者。4. H.pylori未根除组(B组)：1组中根除H.pylori失败者。5.埃索美拉唑组：2组中接受埃索美拉唑镁治疗者。6.替普瑞酮组：2组中接受替普瑞酮治疗者。每组病人治疗疗程均为2周。
结果：
1.本研究共纳入病人215人,其中Warthin-Starry染色和14C呼气试验双阳性者97例,双阴性82例,Warthin-Starry染色阳性14C呼气试验阴性19例,Warthin-Starry染色阴性14C呼气试验阳性17例。研究过程中失访12例(其中H.pylori阳性组7例,替普瑞酮组2例,埃索美拉唑组3例),由于难以忍受的腹泻或胃部不适而中途退出者11例(其中H.pylori阳性组6例,替普瑞酮组3例,埃索美拉唑组2例)。最后完成试验者人数分别为：H.pylori阳性组84例,H.pylori阴性组72例,其中,纳入A组58人,B组26人,C组36人,D组36人,第6周末复查胃镜及病理活检者在四组中分别为36、19、18和16人。H.pylori阳性组病人在6周末经14C呼气试验证实幽门螺杆菌根除率为69.0%(58/84)。
2. H.pylori阳性组与H.pylori阴性组在基线时的症状评分无显著差异。H.pylori根除组与H.pylori未根除组在3个时间点的症状评分均无显著差异。
3.在基线时H.pylori阳性组病人胃体和胃窦的嗜酸性粒细胞计数均较H.pylori阴性组明显升高,而在十二指肠球部和十二指肠降部两组间的嗜酸性粒细胞水平无显著差异。
4.基线时H.pylori根除组与H.pylori未根除组在胃十二指肠4个活检部位的嗜酸性粒细胞计数均无差异。在6周时H.pylori根除组在胃体和胃窦的嗜酸性粒细胞计数均较H.pylori未根除组明显下降,而在十二指肠球部和降部两组间的嗜酸性粒细胞计数均无显著差异。
5.第2周末时埃索美拉唑组和替普瑞酮组的症状评分均较基线时明显改善。埃索美拉唑组在第6周末时症状评分较基线时也明显改善,但替普瑞酮组未见显著改变。基线时埃索美拉唑组和替普瑞酮组的症状评分无差异,但第6周末时前者较后者症状显著减轻。
6.在基线或第6周末,埃索美拉唑组和替普瑞酮组两组间在胃十二指肠4个活检部位的嗜酸性粒细胞计数均无显著差别。在第6周末埃索美拉唑组或替普瑞酮组的胃肠道嗜酸性粒细胞计数与基线时相比也均无显著差异。
7.基线时H.pylori阳性组胃体、胃窦粘膜嗜酸性粒细胞集簇现象出现率较H.pylori阴性组显著增高,而两组间十二指肠球部或降部嗜酸性粒细胞集簇现象发生率均无显著差异。在6周末,H.pylori根除组与H.pylori未根除组相比及埃索美拉唑组与替普瑞酮组相比,胃十二指肠嗜酸性粒细胞集簇现象出现率均无显著差异。H,pylori根除组、H.pylori未根除组、埃索美拉唑组或替普瑞酮组其嗜酸性粒细胞集簇现象在治疗前后均无差异。
结论：
1.H.pylori感染与FD病人胃粘膜嗜酸性粒细胞增多相关,但不影响十二指肠嗜酸性粒细胞水平。
2.根除H.pylori能降低FD病人胃嗜酸性粒细胞,但不影响十二指肠嗜酸性粒细胞水平。
3. H.pylori感染与FD患者的消化不良症状评分无关,并且H.pylori成功根除与否与病人症状改善无关。
4.埃索美拉唑和替普瑞酮均不影响H.pylori阴性FD患者的胃十二指肠嗜酸性粒细胞水平。
5.埃索美拉唑和替普瑞酮治疗后的短期随访中,埃索美拉唑对H.pylori阴性FD病人的治疗效果优于替普瑞酮。
6.FD病人经H.pylori根除治疗、埃索美拉唑或替普瑞酮治疗后,其消化不良症状改善与十二指肠嗜酸性粒细胞数量无关。
研究意义：
本研究通过观察FD病人治疗前后胃十二指肠嗜酸性粒细胞水平的变化,发现H.pylori上调胃粘膜的嗜酸性粒细胞但不影响十二指肠嗜酸性粒细胞水平,埃索美拉唑和替普瑞酮均不影响FD病人胃十二指肠嗜酸性粒细胞水平。
本研究结果阐明了H.pylori根除、埃索美拉唑和替普瑞酮对FD的治疗作用与十二指肠嗜酸性粒细胞无关。
本研究结果为埃索美拉唑和替普瑞酮对FD的治疗作用提供了证据,对H.pylori阴性FD病人的治疗具有重要的指导价值,并且结果表明H.pylori阳性FD病人可能根本不需根除H.pylori治疗,从而减轻病人的经济负担并减少抗生素应用的不良反应。
Background and Objectives
Functional dyspepsia (FD) is a syndrome which is described as epigastric burning,epigastric pain, postprandial fullness and early satiation, in the absence of any systemic, organic, or metabolic disease that is likely to explain the symptoms. According to the main symptoms, FD was divided into two subgroups, which were postprandial distress syndrome (PDS) and epigastric pain syndrome (EPS). FD is thought to originate in the gastroduodenal region. As one of the most prevalent functional gastrointestinal disorders (FGIDs), the prevalence rate of FD has been noted to vary between11.0%-29.2%globally, and it induced a major impaired health-related quality of life and economic burden. Notably,although symptom criteria have been proposed for FD, it remains a diagnosis of exclusion owing to lack of diagnostic pathology. The pathogenesis of FD remains obscure although delayed gastric emptying,impaired proximal gastric accommodation to a meal, abnormal duodenojejunal motility, gastric hypersensitivity to distension, psychological disturbance, Helicobactor pylori (H.pylori) infection have been proposed in several investigations,and the pathophysiological mechanism of functional dyspepsia most likely is a heterogeneous disorder.
A study reported that markedly increased numbers of duodenal mucosal eosinophils in individuals with functional dyspepsia compared with controls,and the degree of eosinophilic infiltration was correlated with early satiety. The studies of duodenal eosinophils in FD provided an eosinophil hypothesis for functional dyspepsia, proposing that changes in duodenal eosinophils perhaps are an underlying feature (and primary pathogenic process) of FD. Gargala, Talley and Walker found that immune activation of the duodenal eosinophilia were closely related to functional dyspepsia, while the increase of gastric eosinophilic granulocyte were not related to functional dyspepsia. It was hypothesized that the eosinophils degranulate and release of various of substances after activation, and help mast cell release substances to stimulate the neurons,leading to contraction of smooth muscle, resulting in symptoms such as meal-related symptoms or abdominal pain.In the very least it seems that the presence of increased numbers of gastrointestinal eosinophils might act as a useful biomarker in FD,and these potent effector cells will yet prove to be worthy therapeutic targets in the quest to combat these disorders.
The role of H.pylori in functional dyspepsia continues to be a matter of debate, part of recent data indicate that there is some modest but clear benefit of eradication of H.pylori in patients with functional dyspepsia. However,another meta-analysis provides little support for the use of H. pylori eradication therapy in patients with nonulcer dyspepsia. In fact,the role of H.pylori in FD is controversial and whether H.pylori eradication is necessary for FD remains unclear.
To date, the treatment for FD remains challenging.Symptomatic improvement of patients with FD after therapy is often incomplete and obtained in no more than60%of patients. Perhaps this is because functional dyspepsia is a heterogeneous disease. In general, the approach to treat patients with FD based on the main symptoms is practical and effective. Proton-pump inhibitors,prokinetics,Helicobacter pylori eradication and antidepressant drug are the usual choice for the treatment of FD.
Previously published data was lack of prospective clinical controlled study which focused on the relationship between gastrointestinal eosinophil levels and H.pylori clearance or drugs therapy for FD.This study had two objective:on the one hand,we wanted to appreciate eradication treatment for H.pylori in the symptomatic response of patients with FD;on the other hand,we wanted to evaluate whether H.pylori eradication and drugs therapy would affect gastroduodenal eosinophils.In particular,we wanted to discover whether there was certain relationship between symptom improvement and changes of gastroduodenal eosinophil counts before and after treatment.
Methods
Adult FD patients (18-70years) fulfilling Rome III criteria were recruited in the study. The self-administered abdominal symptom questionnaire assessed symptoms from the lower and upper part of the abdomen over the preceding three months has been used in the study. A standardized procedure for the administration of the questionnaire at3time points was conducted. The questionnaire includes abdominal symptom as follows, such as epigastric pain, belching, early satiety, or an uncomfortable feeling of fullness after a meal, vomiting,nausea, retching, the eructation, anorexia, abdominal distension,epigastric discomfort,retrosternal pain and dysphagia.
Patients were connected to ask clinical symptoms at different time points(week0:baseline, initial diagnosis and gastroscopy; week2:end of drug therapy; week6:6weeks later after baseline), and the clinical symptoms were marked. In the5-point Likert table, the degrees of the abdominal symptom (asymptomatic, mild,moderate,severe, very severe) were recorded as0,1,2,3,4points,and the scores were accumulated.
Patients underwent gastroscopy, pathology and14C-urea breath test respectively at week0. Gastroscopy of all patients was performed by2physicians who were unaware of the symptoms of the subjects before and during endoscopy.At endoscopy, biopsy specimens were taken from body (lesser curvature and middle of greater curvature), antrum (lesser curvature and greater curvature), duodenal bulb (D1), and descending part of duodenum (D2),and2blocks were taken from each site. At week6, part of the patients were reexamined,including gastroscopy,biopsy and pathology, and H.pylori-positive patients received14C-urea breath test again. Biopsy specimens were fixed in formalin and routinely processed to paraffin wax. Sections were cut at3 ,um,with levels and stained with H&E and Warthin-Starry stain for further study. The H.pylori status was defined as either positive or negative according to whether the bacteria was visible on the Warthin-Starry stain.
According to the results of14C urea breath test and Warthin-Starry stain, the patients were divided into H.pylori-positive group and H.pylori-negative group In H.pylori-positive group, a quadruple therapy was performed to eradicate Helicobacter pylori,and then H.pylori-positive group was divided into two subgroups: H.pylori-eradicated group and H.pylori-uneradicated group. H.pylori-negative group was randomly divided into two subgroups, patients of these two subgroups were treated with esomeprazole or teprenone seperately. The self-administered abdominal symptom questionnaire assessed symptoms has been completed at different time points(baseline,week2, and week6),and then assessed the symptom scores (for a total of upper abdominal pain, heartburn, postprandial fullness, and early satiety). The gastroduodenal eosinophils were quantified by counting the number per5high-power fields at each of4sites (body, antrum, duodenal bulb, and second portion of duodenum), and total counts were summed over the5fields at each site.
Two pathologists who were blinded to the case-control status assessed the biopsy specimens independently. For each subject, eosinophil counts were obtained from body, antrum, D1, and D2.Eosinophils were quantified by counting the number per high-power field (magnification×40);5high-power fields were selected randomly in each section.The sum over the5-fields counts then were calculateded in every subject. The non-overlapping HPF eosinophil count greater than or equal to10was set for eosinophil cluster positive.
Definitions of Symptom Groups were as follows:First,the patients were divided into group1(H.pylori positive group) and group2(H.pylori negative group) according to the results of Warthin-Starry stain and14C urea breath test.Second, patients of group1received H.pylori eradication treatment,and were divided into groupA(H.pylori-eradicated group)and groupB(H.pylori-uneradicated group) according to the H.pylori status confirmed through14C urea breath test at week6.Third,subjects of group2(H.pylori negative group) were randomly assigned into groupC(esomeprazole group) and groupD(teprenone group) by the random number table.
Subjects were classified and treated through the following methods:(1) group1(H.pylori positive group):both Warthin-Starry stain and14C urea breath test were positive, the quadruple therapy (esomeprazole magnesium tablets20mg twice a day; amoxicillin tablets1g twice a day; clarithromycin dispersible tablets0.5g twice a day; citron acid bismuth potassium0.6g twice a day; the course of treatment was2weeks)was used to eradicate H.pylori.(2) group2(H.pylori negative group):both Warthin-Starry stain and14C urea breath test were negative, esomeprazole magnesium (20mg twice a day) or teprenone (50mg three times a day) was used according to the random number table.(3) group A (H.pylori-eradicated group):patients of groupl who obtained successful H.pylori eradication confirmed through14C urea breath test at week6.(4) group B (H.pylori-uneradicated group):patients of groupl who failed to eradicate H.pylori confirmed through14C urea breath test at week6.(5) group C (esomeprazole group):patients of group2who were treated with esomeprazole magnesium for2weeks.(6) group D(teprenone group):patients of group2who were treated with teprenone for2weeks.
Results
1. a total of215patients were involved in the test, in which,the number of people that both Warthin-Starry stain and14C urea breath test positive was97; the number that both Warthin-Starry stain and14C urea breath test negative was82; the number that Warthin-Starry stain positive but14C-urea breath test negative was19, the number that Warthin-Starry stain negative but14C-urea breath test positive was17, lost was12(7in the H.pylori positive group,2in the teprenone group and3in the esomeprazole group), out of the test was11owing to adverse reactions such as unbearable diarrhea and stomach discomfort(6in the H.pylori positive group,3in the teprenone group and2in the esomeprazole group). Then,the number of patients in group1,group2,groupA,groupB,groupC and groupD was84,72,58,26,36and36respectively,and the number of the subjects who reviewed gastroscopy at week6was36,19,18and16respectively in the4subgroups.In the H.pylori positive group, the successful H.pylori eradication rate was69.0%(58/84).
2. Symptom scores were overall not significantly different between the H.pylori-positive group and the H.pylori-negative group at baseline.At baseline, week2and week6,symptom scores of the H.pylori-eradicated group were overall not significantly different from that of the H.pylori-uneradicated group.
3. In the baseline level, the eosinophil counts of body and antrum were significantly increased in the H.pylori-positive group vs the H.pylori-negative group. In duodenum area, compared to the H.pylori-negative group, the H.pylori-positive group did not show marked increase in eosinophil counts.
4.At baseline, gastroduodenal eosinophil counts of H.pylori-eradicated groups were overall not significantly different from that of H.pylori-uneradicated groups. While at week6,compared with the H.pylori-uneradicated groups, eosinophil counts of antrum and body were all significantly decreased in the H.pylori-eradicated groups. In the duodenal bulb and the descending duodenum, eosinophil counts of the H.pylori-eradicated groups were not significantly different from that of the H.pylori-uneradicated groups at week6.
5. The symptoms of esomeprazole group and teprenone group were all improved respectively at week2compared with that at baseline.The similar phenomenon can be observed between baseline and week6in groupC,but there was not significantly different in groupD between baseline and week6. At baseline, symptom scores of the esomeprazole group were not different from that of the teprenone group,but the symptom scores of the esomeprazole group were improved significantly than that of teprenone group at week6.
6. The eosinophil counts of the4sites in the esomeprazole group were all not statistically different from that of the teprenone group at baseline and week6.The gastric and duodenal eosinophil counts of groupC and groupD were all not significantly different respectively between baseline and week6.
7. At baseline, compared with H.pylori-negative groups,gastric eosinophil clusters were significantly increased in H.pylori-positive groups, whereas the duodenal eosinophil clusters of the H.pylori-positive groups were not different from that of the H.pylori-negative groups. At week6,the gastroduodenal eosinophil clusters were not significantly different between H.pylori-eradicated group and H.pylori-uneradicated group,between esomeprazole group and teprenone group. The gastroduodenal eosinophil clusters showed no significant difference before and after treatment in4subgroups.
Conclusions
1.H.pylori infection was associated with the increased eosinophil counts of stomach but did not affect the eosinophil amount of duodenum in patients with FD.
2.H.pylori eradication can reduce the gastric eosinophil counts but not affect the duodenal eosinophils level in patients with FD.
3.H.pylori infection was not associated with the symptoms of FD and H.pylori eradication or not showed no difference on symptomatic improvement of patients with functional dyspepsia
4.Neither esomeprazole nor teprenone showed effect on the eosinophils level of stomach and duodenum in H.pylori-negative patients with FD.
5.The effect of esomeprazole was better than that of teprenone on improving symptoms of H.pylori-negative patients with FD during a short follow-up period of6weeks.
6. The duodenal eosinophils were not involved in the symptoms improvement obtained after treatment of H.pylori eradication, esomeprazole or teprenone.
The significance of study
This study explored the change of eosinophils level of stomach and duodenum before and after treatment,found out H.pylori up-regulate gastric eosinophils but did not affect duodenal eosinophils level, neither esomeprazole or teprenone was related to gastroduodenal eosinophils in FD patients.
It theoretically revealed that the benefits of H.pylori eradication,esomeprazole or teprenone on FD was not involved in duodenal eosinophils.
The results provide evidence for the effect of esomeprazole or teprenone, it has important practical value on H.pylori-negative FD patients,and the study revealed that H.pylori eradication probablly is not necessary when treating H.pylori-positive FD,thus reduce the economic burden and avoid the adverse reactions of antibiotics.
引文
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2. Mahadeva S, Goh KL:Epidemiology of functional dyspepsia:A global perspective. World J Gastroenterol 2006; 12:2661-2666.
3. Talley NJ, Weaver AL, Zinsmeister AR:Impact of functional dyspepsia on quality of life. Dig Dis Sci 1995; 40:584-589.
4. Chang L:Review article:epidemiology and quality of life in functional gastrointestinal disorders. Aliment Pharmacol Ther 2004; 7:31-39.
5. Talley NJ:Functional gastrointestinal disorders as a public health problem. Neurogastroenterol Motil 2008; 1:121-129.
6. Powell N, Walker MM, Talley NJ:Gastrointestinal eosinophils in health, disease and functional disorders. Nat Rev Gastroenterol Hepatol 2010; 7:146-156.
7. Robert S, Elizabeth E, Nicholas M:A Role for Eosinophils in Adaptive Humoral Immunity. The Open Immunology Journal 2009; 2:168-186.
8. Stanghellini V, Tosetti C, Paternico A, Barbara G, Morselli-Labate AM, Monetti N, Marengo M, Corinaldesi R:Risk indicators of delayed gastric emptying of solids in
patients with functional dyspepsia. Gastroenterology 1996; 110:1036-1042.
9. Sarnelli G, Caenepeel P, Geypens B, Janssens J, Tack J:Symptoms associated with impaired gastric emptying of solids and liquids in functional dyspepsia. Am J Gastroenterol 2003; 98:783-788.
10. Tack J, Piessevaux H, Coulie B, Caenepeel P, Janssens J:Role of impaired gastric accommodation to a meal in functional dyspepsia. Gastroenterology 1998; 115:1346-1352.
11. Tack J, Caenepeel P, Fischler B, Piessevaux H, Janssens J:Symptoms associated with hypersensitivity to gastric distention in functional dyspepsia. Gastroenterology 2001; 121:526-535.
12. Haug TT, Svebak S, Wilhelmsen I, Berstad A, Ursin H:Psychological factors and somatic symptoms in functional dyspepsia. A comparison with duodenal ulcer and healthy controls. J Psychosom Res 1994; 38:281-291.
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