【作者】 丛衍群；

【导师】 戴宁；

【作者基本信息】 浙江大学 ， 内科学消化系病， 2009， 博士

【摘要】 肠易激综合征是一类严重影响罹患人群生活质量并耗费大量医疗资源的慢性疾病,其病因和发病机制至今未明。研究表明,饮食和心理因素与肠易激综合征关系密切,很可能是肠易激综合征发病的重要病因。由于乳糖酶缺乏导致的乳糖消化不良在我国人群中十分常见,饮食中的乳糖可能导致腹胀、腹痛和腹泻等症状,这些症状与肠易激综合征的症状难于区分,一个机理尚未阐明的现象是部分乳糖酶缺乏的个体仍然能够耐受中等量的乳糖,而其他却在少量摄入后即出现显著症状。近年来中国人群中饮食及工作、生活方式发生了巨大变化,越来越多的居民已开始将乳制品作为日常生活中一种重要的营养食品,因此乳糖对胃肠道症状的激发与影响不容忽视。而且随着生活节奏的加快,人群中应激性生活事件经历较前增多,乳糖不耐受与心理应激的相互作用可能是饮食与胃肠道病理生理、症状发生之间联系的主因。然而相关的系统性研究鲜见。本文通过大规模社区人群流行病学调查以及门诊肠易激综合征患者与健康志愿者的病例对照研究,探讨在原发性乳糖酶缺乏症高发的中国人群中饮食乳糖、应激性生活事件及心理应激与肠易激综合征发病的关联及相关机制。课题主体分为以下三个部分:第一部分:成人中饮食乳糖、应激性生活事件与肠易激综合征的关联研究目的:在原发性乳糖酶缺乏症高发的中国成人人群中探讨饮食乳糖、应激性生活事件及心理应激与肠易激综合征腹部症状的关联性。研究对象:采用分层随机整群抽样的方法于2008年1月至2008年12月间抽取杭州市区16-75岁常住居民进行研究。为消除随机误差,募集参与者将按照性别与年龄分层,每一层比例与一般人群年龄层分布相差不大于10%。研究方法:以面对面访谈形式问卷调查符合罗马Ⅲ标准的肠易激综合征患病率并评估调查人群的乳糖摄入水平、应激性生活事件经历、焦虑.抑郁状态、胃肠道症状相关的生活质量等。主要结果:①总计调查问卷1063份,剔除不合格问卷75份,实际分析资料988例（92.9%）。符合罗马Ⅲ分类诊断标准的肠易激综合征患病率为9.0%,以腹泻型最常见,男女患病率比例为1:1.27。肠易激综合征患病率在56-65岁间最高,其次为26-35岁组,16-25岁组患病率最低;②在近期经历较多应激性生活事件（12.3%vs.6.1%,p=0.025,OR=2.139,95%CI:1.086-4.214）以及存在心理焦虑（13.9%vs.8.1%,p=0.022,OR=1.827,95%CI:1.082-3.083）的人群中肠易激综合征发生率高,心理因素对肠易激综合征患病的影响在低乳糖摄入的人群中尤为显著（17.9%vs.6.4%,p=0.011,OR=3.212,95%CI:1.254-8.228）;③杭州市区一般人群中月人均乳糖摄入量约为285g,以奶类消费量折算的月人均乳糖摄入量为220g,其中多数人（54.5%）年奶类消费量超过2005年全国城镇居民年均消费量（24.8kg）;月平均乳糖摄入量高的人群中肠易激综合征患病率高于低乳糖摄入组,但差异未达统计学显著性意义（p=0.195）;④在肠易激综合征患者中主观乳糖不耐受的发生率高于一般人群（43.8%vs.27.1%,p<0.001）。主观乳糖不耐受合并较多应激性生活事件经历对肠易激综合征患病率的影响显著高于对照组（p<0.001,OR=3.184,95%CI:1.271-7.978）;⑤胃肠道症状相关的生活质量评分显示罹患肠易激综合征的患者生活质量较正常人群显著降低（p<0.001）。结论:①杭州市区常住居民中,符合罗马Ⅲ标准的肠易激综合征患病率高于以往研究得出的我国社区人群肠易激综合征患病率,该增长可能与人群平均乳糖摄入量增高有关;②近期应激性生活事件经历以及存在焦虑均与肠易激综合征患病相关,心理因素对肠易激综合征患病的影响在低乳糖摄入的人群中尤为显著;③在肠易激综合征患者中,主观乳糖不耐受的发生率高于一般人群,应激性生活事件经历及心理应激与乳糖摄入对胃肠道症状的激发存在叠加效应;④肠易激综合征患者与健康组相比生活质量降低,体现出躯体症状病人自身的感知度增加、对疾病的忧虑以及病人心理应激水平增加。第二部分:乳糖不耐受及应激性生活事件与门诊肠易激综合征腹泻型患者的临床关联研究目的:研究肠易激综合征腹泻型患者对不同负荷量乳糖的敏感性及其与应激性生活事件的临床关联,对乳糖消化不良高发地区肠易激综合征的诊疗方案做出补充。研究对象:应用功能性胃肠病罗马Ⅲ分类诊断标准选取2008年9月-2009年2月间邵逸夫医院消化科门诊就诊的连续的肠易激综合征腹泻型病人进行诊断和相关研究;另外社会招募无胃肠道症状的健康志愿者。向参加者详细解释研究计划并获取知情同意。研究方法:所有被试完成第一部分研究中所使用的调查问卷并随机双盲以10g,20g,40g三种乳糖剂量进行乳糖氢呼气试验检查,氢呼气试验记录时间为180分钟,症状随访24小时。结果:①参加研究的肠易激综合征腹泻型患者共计77例,健康志愿者39例中,三种不同乳糖剂量对胃肠道症状的激发效应在病例组与健康对照组之间均存在差异(P_10g=0.001;p_20g<0.001;p_40g=0.002),而三种乳糖剂量对乳糖消化不良的检出率,在两组间差异无统计学意义（p>0.05）;②健康组对10g乳糖的耐受率达97.4%,在该乳糖负荷量下,个体近期应激性生活事件经历对乳糖不耐受症状的发生存在影响（p=0.030）,但个体主观乳糖耐受与否对乳糖试餐是否能够激发症状并无预见价值（p=0.208）。结论:①肠易激综合征腹泻型患者对即使小剂量乳糖仍具有较高的敏感性而且这种高敏感与心理因素的影响关系密切;②在原发性乳糖酶缺乏症高发地区的拟诊肠易激综合征腹泻型病人中有必要依据病史进行乳糖不耐受筛检并给予饮食干预指导,以甄别哪些患者会从中受益而适合接受乳糖限制的饮食干预,这也将减少不必要的饮食干预对乳钙等营养成分的吸收带来的不利影响。第三部分:肠易激综合征腹泻型患者内脏敏感性评估及方法学研究研究目的:测定肠易激综合征腹泻型患者及健康对照的内脏敏感性,并对一种简易直肠感觉功能测定方法进行临床验证。研究对象:应用功能性胃肠病罗马Ⅲ分类诊断标准选取2008年12月至2009年2月间邵逸夫医院消化科门诊初诊为肠易激综合征腹泻型的病人,另外社会招募健康志愿者。向参加者详细解释研究计划并获取知情同意。研究方法:所有被试完成第一部分研究中的调查问卷并使用瑞典CTD-Synectics LTD生产的PC-Polygraf HR高分辨多道胃肠功能消化道检测仪以及一种新的简易恒压测压方法评估被试肛门直肠运动及感觉功能。结果:①共有肠易激综合征腹泻型患者30例、志愿者30例完成本部分直肠感觉功能评估分析。两组间性别、年龄差异均无统计学意义（p>0.05）;②以最大耐受容积作为参照,计算被试初始感觉容积、便意急迫感容积、疼痛/不适感容积相对最大耐受容积的百分比进行标化后,两组间标化疼痛/不适感阈值差异具统计学意义（p=0.017）,且被试内脏痛觉增敏与焦虑评分、抑郁评分及生活质量评分均有相关（p值分别为0.003,0.016,0.025）;③两组间肛门直肠动力学比较显示肠易激综合征腹泻型患者肛门括约肌静息压、最大缩榨压及引出直肠肛门抑制反射的最小松弛容积与健康志愿者相比差异均无统计学意义（p>0.05）。结论:①肠易激综合征腹泻型患者较健康对照内脏痛觉敏感性增高,心理应激如焦虑、抑郁状态以及症状相关的生活质量与被试直肠痛觉敏感性相关;②肠易激综合征腹泻型患者的症状出现与静息状态下的直肠肛管压力及其收缩功能无关;③本研究中应用的简易直肠感觉功能测定方法合理摒除了个体间直肠最大耐受容积变异带来的影响,使个体间测定结果更具可比性。总结论:研究的第一部分中,通过社区人群流行病学调查发现,人群中符合肠易激综合征罗马Ⅲ分类诊断标准的总体患病率较以往调查研究结果有所增高,该增高可能与人群乳糖摄入量增高有关;近期应激性生活事件经历以及焦虑性心理应激状态增加了肠易激综合征的患病风险,该效应在低乳糖摄入的人群中尤为显著。提示应激性生活事件经历与心理应激同乳糖摄入对胃肠道症状的激发存在叠加效应。随后在门诊肠易激综合征腹泻型患者与健康志愿者中的病例对照研究中证实,肠易激综合征腹泻型患者对即使小剂量乳糖仍具有较高的敏感性而且这种高敏感性受心理因素的影响;进一步在直肠感觉功能测定中发现肠易激综合征腹泻型患者内脏痛觉敏感性高于健康对照,心理应激如焦虑、抑郁状态均对直肠痛觉增敏有影响。以上研究结果揭示出乳糖不耐受与心理应激的相互作用在饮食与胃肠道病理生理、症状发生之间发挥重要作用,其主要机制在于增加了易感个体内脏敏感性。该结论验证了本文最初的假设。同时,根据本研究结果,我们认为在原发性乳糖酶缺乏症高发地区的拟诊肠易激综合征腹泻型病人中有必要依据病史进行乳糖不耐受筛检并给予饮食干预指导,以甄别哪些患者会从中受益而适合接受乳糖限制的饮食干预,这也将减少不必要的饮食干预对乳钙等营养成分的吸收带来的不利影响。此外,本研究中应用的简易直肠感觉功能测定方法合理摒除了个体间直肠最大耐受容积变异带来的影响,使个体间测定结果更具可比性,同时实用性强,值得推广应用。更多还原

【Abstract】 In modern China,with the development of economic,the people are more likely exposed to more stressful life events and the dietary lifestyle changes greatly simultaneously.Irritable bowel syndrome is one of the most common chronic disorders that impairing the sufferer’s quality of life and at the same time,IBS patients constitute a great deal of the load for the healthcare system.The pathogenesis and pathophysiology of irritable bowel syndrome is complex and still incompletely known. Rather than being a cause of irritable bowel syndrome or merely affecting fluctuations in the symptom pattern and determining the health care seeking behavior of the patients, psychosocial factors have been looked upon largely as being involved in the etiopathogenesis of irritable bowel syndrome.Dietary lifestyle is highly relevant to the health of the colon and rectum,especially to irritable bowel syndrome.Components of the diet influence function and biology of the bowel both directly and indirectly.Some patients find that certain foods can reproducibly trigger symptoms and almost half of patients suffering IBS can identify a food that triggers symptoms.A significant proportion of irritable bowel syndrome follows the Western type dietary lifestyle.More and more city dwellers take dairy products as one of the essential nutritional resources. However,a status that lactase deficiency is extremely prevalent in China which will cause uncomfortable symptoms when excess lactose intake occurs.Unfortunately,few investigations have been done focusing the relationship between lactose intake,stressful life events and the pathogenesis of irritable bowel syndrome in China.The present study aimed to focus on these two likely factors in the general population and the patients suffering irritable bowel syndrome as well.The main body of the present study consists of three parts detailed below: Part 1:The relationship between lactose,stressful life events and irritable bowel syndrome in general population.Aims:To assess the clinical relevance of dietary lactose,stressful life events and stress as a cause of abdominal symptoms in patients suffering irritable bowel syndrome in an adult Chinese population with a high prevalence of lactase deficiency.Subjects:Individual adults will be invited to participate in this study by health visitors based in their community.Addresses will be selected at random from general population listing of urban Hangzhou.To counteract recruitment bias,subjects will be recruited in strata by gender and age group with margins on the number in each stratum set as 10 percent of the estimate the general population age distribution.Methods:A stratified randomized study by cluster sampling performed via face-to-face interview,the participants fill in the questionnaires with the help of investigators.Main results:Of all the original dwellers enrolled,1063 fully completed the questionnaire.All analyses were limited to the final sample size of 988(92.9%) when subjects who had a history of peptic ulcers or inflammatory bowel disease or major abdominal surgery,which might cause gastrointestinal symptoms,were excluded.The overall prevalence of irritable bowel syndrome in this population is 9.0%,and irritable bowel syndrome with diarrhea is the most prevalent.We found that the prevalence of IBS was higher in women than in men(the ratio of female to male with irritable bowel syndrome was 1.27:1) by the Rome III criteria although the difference not reach the statistical significant level.Irritable bowel syndrome patients have a higher score of stressful life events than the controls(12.3%vs.6.1%,p=0.025,OR=2.139,95%CI: 1.086-4.214) and the score for anxiety is also higher(13.9%vs.8.1%,p=0.022, OR=1.827,95%CI:1.082-3.083).The effect of psychological factors is much more significant in the group with a low dose of lactose intake(17.9%vs.6.4%,p=0.011, OR=3.212,95%CI:1.254～8.228).The average dose of lactose intake is 285g in this population with a large proportion(65.9%) took more lactose than the average level of the Chinese city dwellers.The prevalence of subjective lactose intolerance is 27.1% while the value is 43.8%in irritable bowel syndrome(p<0.001).subjects with subjective lactose intolerance and with more stressful life events are more likely to suffer in irritable bowel syndrome(p<0.001,OR=3.184,95%CI:1.271-7.978).Score from the "B.E.S.T" questionnaire which represents the quality of life correlates with the abdominal symptoms is much higher in irritable bowel syndrome than in controls (37.1±14.3vs.21.8±14.2,p<0.001).Conclusions:Irritable bowel syndrome,especially the subtype of irritable bowel syndrome with diarrhea,is more prevalent in Hangzhou area.The average dose of lactose intake is 285g and is more than the average level of the Chinese city dwellers. Compared with the healthy controls,the quality of life impairment is more significant in irritable bowel syndrome patients.There is a strong correlation between dietary lactose, stressful life events and stress and irritable bowel syndrome.Part 2:The clinical relationship between lactose intolerance,stressful life events and irritable bowel syndrome in patients attending a gastroenterology clinic.Aims:To assess the impact of dietary lactose,stressful life events and stress in patients attending a gastroenterology clinic with irritable bowel syndrome with diarrhea symptoms compared to age and sex matched controls.Also in this population ’enriched’ with patients complaining of functional gastrointestinal symptoms,we predict that those individuals that report symptoms even to low amounts of lactose in the diet are those with risk factors for irritable bowel syndrome.In addition to the questionnaire based assessment performed in study 1,this proposition will be tested directly by assessing the response to 10,20 and 40g lactose in terms of H2 breath test(mal-digestion) and symptoms(intolerance).In addition,a dietary intervention will be recommended in IBS patients in the population with high prevalence of lactase deficiency.Subjects:77 new patients of irritable bowel syndrome with diarrhea to the gastroenterology clinic at Sir Run Run Shaw Hospital and 50 healthy volunteers were recruited.The study protocol explained and written consent obtained.Methods:All of the participants involved were asked to fill in the questionnaire used in study 1 and 10,20 and 40g lactose H2 breath test performed in a double-blind way.The test time frame is 180 min and symptoms recorded in 24h after lactose intake. Main results:The patients of irritable bowel syndrome with diarrhea group are much more sensitive to all these three doses of lactose(p10g =0.001;p20g<0.001; p40g=0.002),however,the prevalence of lactose maldigestion is similar in both groups. Most of the healthy volunteers can tolerant 10g lactose(97.4%),while the percentage from patients group is only 71.7%.We also found that the quality of life impaired more in patients’ group than in healthy volunteers.What’s more,the patients experienced much more stressful life events show a significant sensitivity to even low dose lactose challenge.Conclusions:The patients of irritable bowel syndrome with diarrhea are much more sensitive to lactose challenge than healthy controls,even in the low dose.Recent stressful life events and stress is correlated with the sensitivity as well.In the area where there is a high prevalence of lactase deficiency,we strongly recommend that a lactose tolerate test with the challenge dose based on the average intake level in the daily life preferred before the diagnosis of irritable bowel syndrome with diarrhea be made. Thereafter,a suitable dietary intervention may be recommended and a follow-up be expected.Part 3:Role of visceral sensitivity in patients of irritable bowel syndrome with diarrhea and the study on methodology.Aims:This study will investigate the effects of visceral sensitivity in a Chinese hospital attendee population with irritable bowel syndrome with diarrhea and appropriate controls.In addition,a simple,short-protocol barostat study will be applied in this study to assess if patients with D-IBS have visceral hypersensitivity and whether this is related to their response to diet(as assessed by food diaries or the lactose tolerance test) and reports of life events and psychosocial stress.Subjects:30 patients with irritable bowel syndrome with diarrhea and 50 healthy controls were recruited.The study protocol explained and written consent obtained.Methods:All of the participants complete the foresaid questionnaire,and finish the anorectal manometry via a simple,short-protocol barostat investigation and the traditional manometry as well.Main results:Totally there are 30 patients and 30 healthy controls completed this study.No differences on anorectal motility function found between these two groups (p>0.05).The standardized sensory threshold shows that the discomfort/pain threshold is lower in irritable bowel syndrome patients than in controls(p=0.017).Conclusions:Rectal hypersensitivity has been found in the irritable bowel syndrome with diarrhea patients.Stressful life events,stress and psychological factors affect the sensitivity.The new,simple short-protocol barostat is proved useful in the clinical practice.In conclusion,we found a higher prevalence of irritable bowel syndrome in the general population in Hangzhou area,and a more lactose intake in this population. Compared with the healthy controls,the quality of life impairment is more significant in irritable bowel syndrome patients.There is a strong correlation between dietary lactose, stressful life events and stress and irritable bowel syndrome.The patients of irritable bowel syndrome with diarrhea are much more sensitive to lactose challenge than healthy controls,even in the low dose.Recent stressful life events and stress is correlated with the sensitivity as well.Rectal hypersensitivity has been found in the irritable bowel syndrome with diarrhea patients.Stressful life events,stress and psychological factors affect the sensitivity.These results indicate that lactose intolerance, stressful life events and psychosocial factors may play a important role in the correlation between diet and irritable bowel syndrome.In the area where there is a high prevalence of lactase deficiency,we strongly recommend that a lactose tolerate test with the challenge dose based on the average intake level in the daily life preferred before the diagnosis of irritable bowel syndrome with diarrhea be made.Thereafter,a suitable dietary intervention may be recommended and a follow-up be expected.The new, simple short-protocol barostat applied in this study has been proved useful and effective in clinical practices.更多还原