【作者】 乔蓉；

【导师】 黄承钰；

【作者基本信息】 四川大学 ， 营养与食品卫生学， 2007， 博士

【摘要】 乳糖不耐受(lactose intolerance，LI)是因肠道乳糖酶减少或活性低下(乳糖酶缺乏，lactose deficiency，LD)，使奶及奶制品中的乳糖不能在小肠内分解而直接进入结肠产生腹胀、腹鸣、排气增多、腹痛、腹泻、等一系列不耐受症状。因此，一些乳糖不耐受者自动避免饮用奶及奶制品，即使继续饮用者也不能充分吸收和利用奶中的营养成分。乳糖不耐受最突出的影响是钙摄取量降低，最终引起一系列与缺钙相关的亚临床症状和疾病，如婴幼儿佝偻病、中老年骨质疏松、骨质软化症等，还可能与心血管疾病、癌症的发生有关。我国人群乳糖不耐受高发，健康成人乳糖不耐受发生率为65．5-67％。儿童的乳糖不耐受也在28．2-32％，中国人低奶消费量很大程度与乳糖不耐受有关。因此解决我国人群乳糖不耐受问题，提高中国人奶及奶制品的摄入量，改善人群钙营养状况是我国营养学界面临的一项重要任务。尽管不少流行病学调查提示长期不饮奶与乳糖不耐受可能有关，但中国人长期以来没有饮奶习惯或饮奶很少是否是乳糖酶活性下降的原因?仍没有定论。本课题组研究表明乳糖不耐受者尽管肠道乳糖酶活性降低，但仍然存在一定活性可以消化一定量的乳糖。乳糖不耐受者可以喝奶吗?可以喝多少奶?迄今为止，缺乏研究。本课题组研究还表明乳糖不耐受症状的发生除了与小肠乳糖酶活性下降有关，还受胃排空、肠转运时间和结肠菌群的构成等胃肠因素的影响。探讨与牛奶同食时能延缓胃排空的食物种类和饮奶的方式，也是提高乳糖不耐受者饮奶量的有效途径之一。本研究以国内外学者对乳糖不耐受的研究为基础，在我课题组前期研究的基础上调查分析祖孙三代饮奶、饮奶相关因素对乳糖不耐受发生率的影响，结合我国居民用膳方式在人体实验和人群调查的基础上提出我国健康人成人可接受牛奶摄入量、改善乳糖不耐受症状切实可行的膳食措施。对指导中国人正确饮奶，增加奶及奶制品的消费量，推进全民饮奶，改善人群钙营养状况有重要的实用价值。全文从以下三个部分进行研究：一．祖孙三代乳糖不耐受发生率及其影响因素分析目的：了解祖孙三代饮奶现况及相关因素对健康的影响，分析祖孙三代乳糖不耐受发生情况及其饮奶相关因素，探讨长期、多代饮奶行为对乳糖酶活性的影响。方法：在成都市区及其郊县某城镇共3个幼儿园中采用随机整群抽样的方法选取55名3-6岁儿童及其父母、祖父母303名总共358人用儿童问卷、成人问卷进行调查，对获取的资料根据饮奶频率、一次饮奶量等计算出每份问卷的年平均累计饮奶量(AMIy)。243人进行了氢呼气试验(HBT)并结合粪便乳糖(醋酸铅法)诊断出乳糖不耐受的患者。用SPSS11．0作χ~2检验、相关、等级相关、Binary Logistic回归等统计分析。结果：1．儿童饮奶率为74．6％，最主要的原因是家长让喝(56．1％)、喜欢喝(41．5％)；父母代饮奶率为48．1％，祖父母代的饮奶率为32．0％。成人喝奶的原因以有营养为主(97．36％)，不喝牛奶的原因以不习惯和不喜欢为主(66．14％)；儿童和成人饮奶种类以鲜牛奶为主(70．7％、74．6％)，饮酸奶的人数分别为2．4％、7．9％；饮奶儿童身高、体重高于不饮奶儿童，差异有统计学意义(P＜0．05)，儿童AMIy与儿童的身高、体重呈正相关，r分别为0．353、0．380(P＜0．05)。成人饮奶者中，经常腿抽筋、腰酸背痛的发生率为14．2％、19．9％，明显低于不饮奶者(85．8％、80．2％)，差异有统计学意义(P均＜0．005)：经常腿抽筋、腰酸背痛的成人AMIy均明显低于腿不抽筋、不腰酸背痛的人(P=0．000)；儿童AMIy与其母亲、祖代AMIy呈正相关(r分别为0．614、0．447，P＜0．05)；成人AMIy与其文化程度有一定关系，高中、大学学历的人AMIy明显高于初中及以下文化程度的人，差异有统计学意义(P＜0．05)。2．醋酸铅法与氢呼气试验判定乳糖酶缺乏(LD)的一致性：Kappa值为0．421(P＜0．01)，灵敏度为83．3％，特异度60．7％。3．用醋酸铅法与氢呼气试验结合诊断幼儿、父母、祖父母的乳糖不耐受发生率分别为51．0％、68．8％、67．6％；成人不饮奶者乳糖不耐受发生率(74．54％)高于每天饮奶者(26．67％)，差异有统计学意义(χ~2=21．452，P＜0．05)；祖父母、父母两代均不饮奶的家庭中儿童乳糖不耐受发生率(88．3％)高于两代均饮奶(45．5％，P＜0．05)和两代部分饮奶家庭中儿童乳糖不耐受发生率(32．1％，P＜0．01)，差异有统计学意义。4．年平均累计饮奶量(AMIy)与乳糖不耐受严重程度呈负相关(r=-0．353，P＜0．05)，差异有统计学意义。用Binary Logistic回归模型分析结果为：饮奶年限、饮奶频率、一次饮奶量对乳糖不耐受发生的危险性有影响，差异有统计学意义(p＜0．05)，饮奶年限和饮奶频率与乳糖不耐受发生的危险性呈负相关，OR分别为0．317、0．465；一次饮奶量与乳糖乳糖不耐受发的危险性呈正相关，OR为6．337。结论：1．儿童饮奶率为74．6％，父母代为48．1％，祖父母代为32．0％；饮奶能促进儿童生长发育；成人腿抽筋、腰酸背痛等症状与年平均累计饮奶量有关；儿童饮奶受母亲影响较大；成人的文化程度对自身饮牛奶的行为有影响。2．饮奶与乳糖乳糖不耐受有关：饮奶频率、饮奶年数与乳糖乳糖不耐受症状发生的危险性呈负相关，一次饮奶量与乳糖乳糖不耐受症状发生的危险性呈正相关。长期低剂量饮奶，可改善乳糖乳糖不耐受症状。3．祖代、父母代不饮牛奶与儿童乳糖不耐受有关。4．平均年累计饮奶量(AMIy)是一个估算长期饮奶量的较好指标。5．醋酸铅法(半定量检测粪便乳糖的方法)，简便、安全、经济，适宜于规模大的现场调查。二．严重乳糖乳糖不耐受者可接受牛奶摄入量的实验研究目的：找出严重乳糖不耐受者可接受牛奶摄入量，观察此量后在健康成人的耐受情况。方法：采用氢呼气试验从38名受试者中筛选出8名有水样状腹泻的乳糖不耐受者，分成低、高剂量组(分别为A、B组)参加饮奶试验。两组的症状评分之和大致相等，据文献报道及单因素优选法(黄金分割法)确定两组对象分别饮用25g和38．2g奶粉(分别含6．25g和9．55g乳糖)和水冲调成的200ml牛奶，分析受试者△HBT值、症状评分、粪便乳糖含量(醋酸铅法)。采用随机整群抽样方法选取健康的100名青年、80名中年、100名老年人，观察摄入25g奶粉(含乳糖6．25g)后出现的乳糖不耐受症状。结果：两组受试者在饮奶试验中无一例腹泻发生，仅有不同程度的轻微症状(打嗝、胀气)；高剂量组(B组)对象饮奶后，其△HBT值、症状评分、粪便乳糖均高于低剂量组(A组)。健康成人饮用25g奶粉(含乳糖6．25g)冲调的牛奶后，80．3％的对象未产生任何乳糖不耐受症状。结论：曾有严重腹泻的乳糖不耐受者在食用25g奶粉后，仅表现轻微乳糖不耐受症状，无腹痛、稀便和水样腹泻；健康成人即使为乳糖不耐受者也能饮用适量牛奶，大多数健康成人摄入25g奶粉(含乳糖6．25g)后不会出现任何乳糖不耐受症状，结合我国的实际情况建议20g奶粉(含乳糖5g，配成160ml牛奶)作为我国健康成年人可接受牛奶摄入量。三．改善乳糖不耐受症状的膳食措施研究目的：结合我国居民用膳方式，寻找饮牛奶时改善乳糖不耐受症状的膳食措施。方法：采用氢呼气试验从38名受试者中筛选出8名有水样状腹泻的乳糖不耐受者，参加用正交实验设计的不同食物与25g奶粉(含乳糖6．25g)搭配的饮奶试验；采用随机整群抽样方法选取100名健康大学生参加以不同方式摄入25g奶粉(含乳糖6．25g)的饮奶试验，观察饮奶试验后出现的乳糖不耐受症状。结果：受试者饮牛奶，同时摄入鸡蛋、馒头、锅魁、面包后△HBT值比单独饮用牛奶均有降低(均小于1．786 mg╱m~3)；正交直观分析、方差分析均表明：鸡蛋与牛奶混食者粪便乳糖和症状评分比馒头与牛奶混食者低，差异有统计学意义(P＜0．05)，全麦面包与牛奶混食者症状评分最高；不同饮奶方式引起乳糖不耐受症状的发生率不同，早餐空腹饮牛奶者乳糖不耐受发生率27．6％(27／98)高于午餐或晚餐饮牛奶者13．7％(13／98)，χ~2=6．16，P＜0．05，差异有统计学意义。结论：食物种类和不同饮奶方式对乳糖不耐受症状有明显影响，建议不要空腹饮奶，而在正餐饮牛奶，并注意与高蛋白膳食、固体(干)的食物搭配，避免与含膳食纤维高的食品(如全麦面包)一起食用。总之，乳糖不耐受者也能饮用适量牛奶，乳糖不耐受者应当解除不能饮奶的“枷锁”，只要坚持长期一次饮或食用含乳糖不超过5g的奶及奶制品，不要空腹饮奶，而在正餐饮牛奶，并注意与高蛋白膳食、固体(干)的食物搭配，避免与含膳食纤维高的食品(如全麦面包)一起食用，可以改善乳糖不耐受症状，还能增加饮奶量，维护乳糖不耐受人群健康。祖父母代、父母代不饮牛奶与儿童乳糖不耐受有关，此结论为明确长期是否饮奶的膳食模式与乳糖酶持续活性与无持续活性的基因多态性差异的关系提供了有力证据。但要阐明长期不饮奶与乳糖不耐受发生的关系，还需要类似的扩大样本量和不同种族人群的研究证据。更多还原

【Abstract】 Lactose intolerance (LI)exists in the subjects with lactase deficiency(LD),which have gastrointestinal symptoms including abdominal distension,cramps,flatulence,and watery stools after consuming lactose and its foods. For this reason, milk and dairy products are eliminated from the diet of many LI subjects, which could lead to the nutrition-related diseases, especially disease related to calcium-deficiency,such as rickets, osteoporosis and asteomalacia etc. In China, the prevalence of LI is 65.5-67% in adults and 28.2-32% in children. Therefore, increasing calcium intake via ameliorating LI symptoms is one of important issue in nutrition.Despite the results from a lot of epidemiological studies indicate LI maybe relate with long-term non-milk drinking, but whether is the decline of lactase activity in adult of Chinese caused by less milk drinking or non-milk drinking habit is not clear yet. Results from our research group suggested that subjects with LI had low lactase activity but still had residual lactase activity that can absorb some amount of lactose. Can LI subjects drink milk? How much milk could they accept? These questions should be answered. Studies by our research group also demonstrations that the serious symptoms after milk ingestion in LI subjects may vary widely, depending upon not only the degree of intestinal lactase deficit but also gastric emptying time ,orocecal transit time and colonic micro flora in subjects. It is a good way to increasing intake of cow’s milk in LI subjects by exploring various foods and milk drinking manner to delaying gastric emptying.The aim in present study is to investigate milk consumption in three generations, including children, their parents and grandparents, and to analyze the effects of drinking cow’s milk on prevalence of LI based on many studies including our program. The acceptable intake of cow’s milk for healthy adults and measures of alleviating symptoms of LI were put forward in the present study. When people drank the milk, combining eating habits of our residents by epidemiology survey and human trail. Therefore the results of the present study will play an important role in the practice in pushing civil milk drinking program, improving calcium level of Chinese people.The present study includes three parts as follows:1. Study on prevalence and influencing factors of lactose intolerance in three generations include children, parents and grandparentsObjective: To investigate milk consumption and effect on health of three generations include children, parents and grandparents, and to analyze the prevalence and influencing factors of LI among them, and to explore the effect of long-term and generations’s milk drinking behavior to lactase. Methods: 55 children aged 3-6 include their parents and grandparents 358, which selected from 3 three kindergartens in Chengdu and its suburb by clustered random sampling, were investigated by questionnaire, accumulative Cow’s Milk Intake per year(AMIy) by frequencies,years,amounts of milk that they drank in their lifetime..LI were diagnosed by Hydrogen Breath Test (HBT) and stool lactose (by the way of lead acetate with aqueous ammonia) in 243 persons among those three generations. Statistical analysis is carried out by SPSS11.0.Results 1.The rate of milk drinking in children, parents and grandparents was 74.6%,48.1% and 32.0% respectively; 66.1% of parents and grandparents take a dislike to milk and are unaccustomed to it .The height and weight of children with milk drinking habit were more higher and heavier than those with non-milk drinking habit(P＜0.05, respectively) .There were positive correlations between AMIy of children and their height、weight (r is 0.353、0.380 ,P=0.000 ,respectively) .The rate of milk drinking and AMIy in adults with leg cramp and waist ache were significant in comparing with that of those with non-symptoms (P＜0.005、P=0.000,respectively) .There were positive correlations between AMIy of children and that of mother, grandparents (r is 0.614、0.447, P＜0.01 respectively) .There were correlation between AMIy of adults and their cultural standard. AMIy of person graduated from senior high school and college is significant in comparing with that of which graduated from junior high school or below (P＜0.05) .2. Concordance of diagnose LD by HBT and the way of lead acetate with aqueous ammonia: Kappa value was 0.421 (P＜0.01) ,sensitivity was 83.3%, specificity was 60.7%.3. The prevalence of LI in children ,parents and grandparents was 50.9%、68.8%、67.6% respectively. The prevalence of LI in adults those with un-milk drinking habit was significant in comparing with those with milk drinking per day (x~2=21.452 P＜0.05). The prevalence of LI in child whose parents and grandparents with un-milk drinking habit was significant in comparing with those milk drinking habit (x~2=4.57 P＜0.01) .4.There were negative correlations between AMIy and severity degree of LI symptom (r=-0.353, P＜0.05)。Binary Logistic regression showed that: years, frequency, and amount of milk per time that they drank in their lifetime were with statistical significance (P＜0.05) There were negative correlations between years , frequency of milk drinking and LI ,OR were 0.317、0.465, respectively. There were positive correlations between amount milk of per time and LI, OR was 6.337Conclusion: 1.The rate of milk drinking in children, parents and grandparents was 74.6%,48.1% and 32.0% respectively. Drinking milk can improve children’s growth and development. Leg cramp and waist ache of adults are related with accumulative Cow’s Milk Intake per year (AMIy).Children’s milk drinking habits were significantly influenced by mother. Cultural standard of adults can affect their milk drinking habits2. LI is related to milk drinking. There were negative correlations between years , frequency of milk drinking and LI symptoms. There were positive correlations between amount of milk per time and LI symptoms.Drinking moderate amount milk for years per day might alleviate the symptoms of intolerance3. LI of the child is related to un-milk drinking of his parents and grandparents.4. A MIy is preferable index to rough estimate milk intake.5. stool lactose eaxamined by the way of lead acetate with aqueous can be used for screening LD.2. Study on the acceptable intake of cow’s milk for severe LI Objective: To find out the acceptable intake of cow’s milk in subjects with severe LI and then observe intolerance symptoms in healthy adults after they drank thus allowance.Methods: Eight LI subjects with watery diarrhea who were selected from 38 subjects by HBT were divided into group A, group B to go on drinking cow’s milk test. The subjects in group A ingested 25g milk powder, the subjects in group B ingested 38.2g milk powder(contain 6.25g,9.55g lactose and make 200 ml of milk solution respectively) according to literature and single factor optimization method(0.618 golden mean) to analyze their△hydrogen excretion(mg/m~3) ,symptom score and stool lactose. The 100 younger, the 80 middle-age and the 100 elder subjects were selected by clustered random sampling to observe symptoms after they ingested 25g milk powder.Results: No case with diarrhea occurred in these two group but mild symptoms (burp, break wind). hydrogen excretion(mg/m~3) and symptom score in the high dose group (group B)are a little higher than those in low dose group (group A) . Most of healthy adults (80.3%) have no intolerance symptoms after they ingested 25g milk powder (make 200 ml of milk solution).Conclusion: There was only mild symptoms after LI with diarrhea ingested 25g cow’s milk powder ,no bellyache ,loose and water stool occurre.The study demonstrates that most of adults, even with LI, can tolerance 25g cow’s milk powder(6.25g lactose). According to the condition of our country. It is suggested 20g cow’s milk powder(5g lactose, make 160 ml of milk solution) is the acceptable intake of healthy adults in China.3. Study on measures of ameliorating symptoms of LI during drinking milkObjective: To find out measurements of alleviating symptoms of LI when people drank the milk, combining diet habits of our residents.Methods: Eight LI subjects with watery diarrhea who were selected from 38 subjects by HBT were divided into 4 groups to go on drinking cow’s milk test with various foods by orthogonal trail. The 100 healthy college students were selected by clustered random sampling to observe symptoms after they ingested 25g milk powder by different manners.Results:△hydrogen excretion of groups which ingested milk with various food is lower than those ingested milk only(all less than 1.786 mg/m~3). Egg is better than Manitou in alleviating symptoms. (F value of stool lactose and symptom score are 7.5、9.0 ,respectively＜0.05) .Whole wheat bread can aggravate flatus. The prevalence of the symptom in 100 college students by drinking milk in fast state (27/98) was significantly comparing with that by drinking milk with regular meal (13/98), (x~2=6.16, P＜0.05) .Conclusion: The study demonstrates that various foods, various milk drinking manner can affect the intolerance symptom .We suggested:Don’t drink milk in fast state, milk with egg and staple food such as steamed bread, bread or gomuti is best selection for breakfast. Drinking milk with regular manner can alleviate symptom of intolerance. For lactose intolerance, don’t take whole wheat bread. In general, LI of the child is related to un-milk drinking of his parents and grandparents .It is provided powerful evidence to demonstrate that lactase gene polymorphism (lactase persistence and nonpersistence)is related with long-term drinking and non drinking milk.LI subject should release from incapable of drinking milk .It is not only alleviating symptoms of LI but also improving intake of cow’s milk when LI subjects keep on drinking milk or eat other dairy products which contain less 5g lactose per time for long term.更多还原