【作者】 马玲；

【导师】 姚华；

【作者基本信息】 新疆医科大学 ， 劳动卫生与环境卫生学， 2013， 博士

【摘要】 目的：以新疆维、汉族无症状高尿酸血症患者为研究对象，调查膳食质量，分析膳食模式，找出膳食危险因素，并检测其血清维生素水平，比较维、汉族无症状高尿酸血症患者膳食营养与血清维生素水平差异。同时采用复合维生素干预实验，观察膳食补充维生素对高尿酸血症患者血清尿酸水平的影响，并从氧化应激、胰岛素抵抗、炎症因子和脂肪因子等层面对相应指标进行分析，初探维生素干预对血清尿酸水平影响的机制，进一步阐明高尿酸血症的发病机理，、为防治本病从营养学角度提供一种更为经济、有效、更少毒副作用的新思路和新策略。方法：采用病例-对照研究，选择维吾尔族、汉族无症状高尿酸血症患者204例作为病例组，并选择健康体检者204人为正常对照组，利用问卷调查研究对象的生活饮食行为，采用24小时回顾法和食物频率表了解研膳食摄入情况，在传统的膳食营养素分析方法的基础上，结合DBI指数和因子分析法对高尿酸血症患者的膳食质量、膳食模式及膳食危险因素进行分析，并对其体格指标及生化指标进行检测，采用高效液相色谱法和酶联免疫吸附法检测其血清维生素A、D、E、B1、B2和C水平，比较病例组与对照组的差异，将民族分层后，进一步比较维、汉民族差异，进行相关分析和Logistic回归分析，评估体格指标、生化指标、膳食营养素和血清维生素水平等自变量对高尿酸血症的影响。在此基础上，将无症状高尿酸血症患者随机分为干预组和对照组，复合维生素干预4周后，采用试剂盒和酶联免疫法检测干预前后抗氧化酶活力、脂质过氧化、空腹胰岛素、空腹血糖、胰岛素抵抗指数、炎症因子（TNF–α、IL-6和CRP）和脂肪因子（Leptin，APN和Resistin）的变化，采用自身配对前后t检验评价复合维生素干预对高尿酸血症尿酸、血脂、氧化应激、胰岛素抵抗、炎症因子和脂肪因子水平的影响。结果：（1）维、汉民族无症状高尿酸血症患者生活饮食行为、膳食营养素、膳食质量及膳食模式研究：1）饮食行为：高尿酸血症患者中有吸烟行为者占31.9%，饮酒为45.6%，饮茶为41.1%，体育锻炼为23.2%。病例组中吸烟和饮酒的人群构成比高于正常对照组，汉族吸烟人群构成比高于维吾尔族，差异均有统计学意义（P＜0.05）。2）每日膳食营养素摄入水平：病例组每日膳食能量、蛋白质、脂肪、碳水化合物、胆固醇、钠、视黄醇当量、维生素E、硫胺素摄入均高于对照组膳食纤维、维生素C低于对照组，差异有统计学意义（P＜0.05）。病例组与DRIs比较，每日膳食中蛋白质、铁、钠、烟酸摄入过量，热量与维生素E摄入正常、视黄醇当量、硫胺素摄入不足，钙、锌、硒、核黄素和维生素C摄入缺乏。维吾尔族病例组每日膳食中热量、脂肪、碳水化合物、钠、维生素E、核黄素的摄入水平高于汉族，膳食纤维、铁、硒、视黄醇当量、维生素C摄入低于汉族，差异有统计学意义（P＜0.05）。3）膳食能量营养素构成及来源：高尿酸血症患者蛋白质、脂肪供能比例分别为15%和32%，高于DRIs的12%和25%。食物蛋白质来源中动物蛋白比例偏高，豆类蛋白偏低。食物脂肪来源中动物脂肪偏高，植物脂肪偏低。维吾尔族的脂肪供能比高于汉族。4）每日各类食物摄入量：病例组每日谷类、奶类、豆类、畜禽肉类、盐类、油类和酒精类摄入高于对照组，蔬菜和水果摄入低于对照组。汉族的蔬菜、豆类、水产类和蛋类每日摄入高于维吾尔族，奶类、畜禽肉类、盐类和油类摄入低于维吾尔族，差异有统计学意义（P＜0.05）。5）DBI评价膳食质量：病例组DBI得分为-6.59，对照组为-8.19，其中食物多样性不足、每日奶类和豆类摄入不足，谷类、畜禽肉类、油类和酒精的摄入过量。病例组的DBI-LBS、DBI-HBS、DBI-DQD均高于对照组，差异有统计学意义（P＜0.05）。尿酸水平越高，DBI-LBS、DBI-HBS、DBI-DQD值越大。病例组与对照组的膳食模式均以模式B和模式E为主。维吾尔族DBI-TS，DBI-LBS、DBI-HBS、DBI-DQD均高于汉族。汉族人群中符合模式A、B、C、E的比例高于维吾尔族，维吾尔族人群中符合膳食模式D、F、G的比例高于汉族。6）因子分析法评价膳食模式：特征根大于1.5的因子共有3个，即3种膳食模式，按因子贡献率的大小分别为因子1（18.40%），因子2（10.87%）和因子3（8.8%）。第一因子（模式1）主要体现在小麦面粉和肉类为主的膳食。第二因子（模式2）主要体现在以肉类和酒精为主的膳食。第三因子（模式3）是以白肉、蛋类、蔬菜和水果为主的膳食。单因素Logistic回归分析3种膳食模式的OR值依次为2.23、1.40和0.52。多因素调整民族、性别、年龄、BMI、能量摄入等变量后，结果不变。7）膳食营养危险因素分析：多因素Logistic回归分析结果显示脂肪、维生素C、TG、WC和FINs与高尿酸血症相关，其中维生素C是保护因素，OR值为0.989，,脂肪、TG、WC和FINs是危险因素，分别为1.871、1.423、1.040、1.017。（2）维、汉民族无症状高尿酸血症血清维生素水平研究：1）病例组血清视黄醇、维生素B1水平升高，维生素C和25（OH）D水平下降，差异有统计学意义（P＜0.05）。将尿酸进一步分级后发现，随着尿酸水平增高，血清视黄醇、维生素B1、B2随之升高，血清25（OH）D先升高，到达SUA-4后，血清25（OH）D开始下降。2）民族比较：维吾尔族血清视黄醇和维生素B1高于汉族，维生素E低于汉族，差异有统计学意义（P＜0.05）。民族间异质性在对照组中更为明显，在病例组仅有血清视黄醇表现出民族差异。3）性别比较：男性血清视黄醇、25（OH）D、维生素E、B1、B2、C高于女性，差异有统计学意义（P＜0.05）。两性差异在对照组更为明显，在病例组仅有维生素B1表现出性别差异。4）不同年龄段比较：高尿酸血症各年龄段的维生素B1的差异有统计学意义（P＜0.05），从30岁到70岁，随年龄的增加，血清维生素B1的水平逐渐下降。血清视黄醇、25（OH）D、E、C、B2在各年龄段的差异无统计学意义（P＞0.05）。5）人体维生素营养状况评价：病例组血清视黄醇过量，25（OH）D缺乏、维生素C缺乏比例高于对照组，差异有统计学意义（P＜0.05）。女性血清视黄醇、25（OH）D和维生素C的缺乏比例均高于男性。6）血清维生素与尿酸水平的相关分析：汉族血清尿酸与血清视黄醇、维生素B1、B2呈正相关，相关系数分别是0.405，0.341和0.370；维吾尔族血清尿酸与视黄醇、维生素B1呈正相关，相关系数分别是0.217和0.185，与维生素C呈负相关，相关系数为0.188；男性血清尿酸水平与视黄醇、维生素B1呈正相关，相关系数分别为0.176和0.179，与25（OH）D、维生素C呈负相关，相关系数分别为0.148和0.175；女性血清尿酸与视黄醇、25（OH）D、维生素E、B1呈正相关，相关系数分别为0.350，0.186，0.175和0.313；固定民族与性别后，偏相关分析显示血清尿酸水平与血清视黄醇、维生素B1、B2呈正相关，相关系数分别为0.277，0.244和0.151。血清维生素之间也存在相关性。7）危险因素分析：回归分析显示血清视黄醇和维生素B1是高尿酸血症的危险因素，OR值分别为1.013和1.015，维生素E和维生素C是保护因素，OR分别是0.718和0.664。（3）维、汉民族无症状高尿酸血症患者复合维生素干预效果：1）尿酸水平：高尿酸血症患者尿酸水平下降2.27μmol/L，差异有统计学意义（P＜0.05）。将患者按民族分层后，两民族的尿酸水平均下降，差异有统计学意义（P＜0.05）。2）血脂水平：高尿酸血症患者TC和LDL-C浓度下降，差异有统计学意义（P＜0.05），TG和HDL-C的变化无统计学意义（P＞0.05）。3）糖代谢：高尿酸血症患者的FINs、HOMA-IR较干预前降低，差异有统计学意义（P＜0.05）。将患者按民族分层后，两民族的FINs、HOMA-IR均下降，差异仍有统计学意义（P＜0.05）。4）氧化应激：高尿酸血症患者血清SOD和GSH-Px酶活力增加，MDA含量下降，差异有统计学意义（P＜0.05）。将患者按民族分层后，汉族和维吾尔族干预后的抗氧化酶和过氧化脂质变化趋势一致。5）炎症因子：高尿酸血症患者的TNF–α和IL-6降低，差异有统计学意义（P＜0.05），CRP的差异无统计学意义。民族分层后，维吾尔族和汉族高尿酸血症患者炎症因子干预后的变化趋势相同。6）脂肪因子：高尿酸血症患者的APN和Leptin水平上升（P＜0.05），但Resistin变化无统计学意义（P＞0.05）。民族分层后，仅有维吾尔族患者干预后的APN发生变化。结论：（1）高尿酸血症患者膳食营养素摄入不均衡，蛋白质、胆固醇、铁、钠摄入过量，能量与维生素E摄入正常，摄入硫胺素摄入不足，核黄素、维生素C、钙、锌、与硒缺乏。供热比失衡，蛋白质和脂肪供热较高，为高蛋白和高脂膳食。DBI评价高尿酸血症患者膳食结构不均衡，质量较低，食物多样性不足，以蔬菜、水果、水产类、奶类和豆类食物摄入不足为主，伴有畜肉、禽肉、动物内脏、盐类和酒精摄入过量，膳食失衡较正常组程度更严重。主因子分析显示研究人群膳食模式分为小麦面粉、动物性食物模式（小麦面粉、畜肉、内脏类）和动物性食物与酒精模式（牛羊肉、禽肉、内脏类、蛋类、酒精）为高尿酸血症的危险因素，而蔬菜、水果和白肉模式（禽肉、蛋类、奶类、豆制品、蔬菜和水果）为高尿酸血症的保护因素。（2）维吾尔族与汉族每日膳食营养素摄入水平、膳食结构及膳食模式均存在差异。维吾尔族的热量、脂肪、碳水化合物、钠、核黄素及维生素E摄入高于汉族，但膳食纤维、维生素A、维生素C摄入低于汉族。脂肪供能比高于汉族。DBI膳食质量评价显示维吾尔族高尿酸血症患者摄入不足和摄入过量的程度均高于汉族，膳食总体失衡更为严重。因子分析中显示汉族病例组倾向于高小麦面粉和肉类型膳食。维吾尔病例组倾向于高肉类和酒精膳食。（3）膳食脂肪、维生素C、畜肉、动物内脏、酒类、蔬菜、TG、WC和FINs与高尿酸血症相关，其中维生素C、蔬菜是保护因素，膳食脂肪、畜肉、动物内脏、酒类、TG、WC和FINs是危险因素。（4）高尿酸血症患者的血清视黄醇和维生素B1升高，25（OH）D和维生素C下降，将尿酸水平分级后，视黄醇、维生素B1、B2随之升高。视黄醇、维生素B1为高尿酸血症的危险因素，维生素E和维生素C是保护因素。维吾尔族的血清视黄醇、维生素B1高于汉族，维生素E低于汉族。男性的血清维生素水平均高于女性。血清维生素C随年龄增加而变化。进入病例组，血清维生素的民族和性别差异减弱，发病特征趋向一致。（5）复合维生素干预4周后尿酸水平下降可能与改善机体胰岛素抵抗，增强抗氧化酶活力，降低脂质过氧化物含量，以及降低炎症因子TNF-α、IL-6表达和升高APN、Leptin水平有关。维吾尔族和汉族高尿酸血症患者干预效果趋于一致。干预后尿酸水平下降的幅度有限，可能与干预的实验周期较短有关。更多还原

【Abstract】 Objectives:This project conducted asymptomatic hyperuricemia in Xinjiang Uyghur and Hansubjects to investigate dietary quality, analyze dietary pattern, deduce the dietary riskfactors and check the metabolic level of vitamins. Moreover, double blindnessintervention of multiple vitamins was conducted to observe the SUA level effect ofdietary vitamin supplementation in hyperuricemia and analyze the index of oxidativestress, insulin resistance, inflammatory factors and adipocyte factors. This work willpreliminary study the effect mechanism of SUA level after vitamins intervention andelucidate further the pathogenesis of hyperuricemia and provide a more economic,effectively and less side effect approaches to control hyperuricemia from the nutritionalview.Methods:Based on hyperuricemia diagnosis criteria confirmed by China Doctors Association,204Uyghur and Han cases with confirmed asymptomatic hyperuricemia from the FirstAffiliated Hospital and Affiliated TCM Hospital of Xinjiang Medical University and204controls were frequency matched on age, gender and area of residence. Factor analysiswas conducted by using dietary information from a validated food frequencyquestionnaire to derive dietary behavior and nutritional status. DBI index and factorsanalysis were combined with traditional dietary nutrients analysis approach to analyzethe dietary quality, pattern and risk factors. General health index and biochemical indexwere checked. HPLC and ELISA were performed to check the serum level of vitamin A、 D、E、B1、B2and C. The difference of dietary and serum vitamins level were comparedin patients and controls groups and in Uyghur and Han populations. Association analysisand non-conditional multiple factors Logistic regression was performed to evaluate theeffect of general index, biochemical index, diet habits, nutrients and serum vitamins levelto asymptomatic hyperuricemia. Cases with confirmed asymptomatic hyperuricemia wereseparated randomly into intervention and control groups.4weeks of multiple vitaminsintervention later, the change of antioxidase, lipid peroxidation, fasting insulin, fastingblood glucose, insulin resistance index, inflammatory factors (TNF–α、IL-6and CRP)and adipocyte factors (Leptin，APN and Resistin) were checked. T test was performed toevaluate the effect of multiple vitamins intervention to the levels of UA, blood lipid,oxidative stress, insulin resistance, inflammatory factors and adipocyte factors inasymptomatic hyperuricemia.Results:(1) Diet habits, dietary nutrients, quality and patterns of hyperuricemia in Uyghurand Han populations:1) Diet behavior: the proportion of smokers, alcohol drinker, tea drinker andphysical trainer were31.9%,45.6%,41.1%and23.2%respectively in hyperuricemiapatients group. The constituent ratio of smokers and alcohol drinker in patients groupwere significantly higher than those of control group. Smoker in Han population wassignificantly higher than that in Uyghur.2) Daily dietary nutrients intake level: intake of daily dietary energy, protein, lipid,carbohydrate, cholesterol, Na, retinol equivalent, vitamin E and thiamin weresignificantly higher in patients group than those in control group. But intake of dietaryfiber and vitamin C were significantly lower in patients group than those in control group.Compare with DRIS, intake of daily protein, Fe, Na and nicotinic acid were excessivewhile heat, vitamin C intake level normal. In addition, intake of retinol equivalent andthiamin were insufficient and Ca, Zn, Se, lactoflavin and vitamin C were lack. Intakelevel of daily dietary heat, lipid, carbohydrate, Na, vitamin E and lactoflavin were highersignificantly while the intake of dietary fiber, Fe, Se, retinol equivalent and vitamin Cwere significantly lower in Uyghur patients group than those in Han ethnic.3) Constitution and resource of dietary energy nutrients: from the view of energyconstituent ratio in hyperuricemia, the energy providing percentage of protein and lipidwere15%and32%respectively. It was higher than12%and28.4%of national average level and12%and25%from DRIs. From the view of food protein resource, proportionof animal protein was much higher than bean protein. From the view of food lipidresource, proportion of animal lipid was higher than plant lipid. Energy provided fromlipid and animal lipid resource were higher while lower of bean protein in Uyghur thanthose in Han population.4) Daily food intake: intake amount of cereal, milk, beans, livestock and poultrymeat, salt, oil and alcohol were significantly higher while lower of vegetables and fruitsin patients group than those in control group. Intake amount of vegetables, beans,fisheries and eggs were significantly higher while lower of milk, livestock and poultrymeat, salt and oil in Han than those in Uyghur population.5) Dietary quality assessment from DBI: DBI score in hyperuricemia and controlgroup were-6.59and-8.19respectively. It demonstrated the insufficient of food diversity,daily milk and beans intake and excess of cereal, livestock and poultry meat, oil andalcohol intake. DBI-LBS、DBI-HBS、DBI-DQB were higher significantly in patientsgroup than those in control group. The higher UA level was, the score of DBI-LBS、DBI-HBS、DBI-DQB were higher. The most common dietary pattern in patients andcontrol groups were pattern B and E. DBI total score, DBI-LBS、DBI-HBS andDBI-DQB were higher in Uyghur than Han population. Constituent ratio with pattern A,B, C and E in Han population were higher than that in Uyghur while pattern D, F and Gwere higher in Uyghur population.6) Dietary quality assessment from factors analysis: there were three factors ordietary pattern whose characteristic root was more than1.5. According to their denotation,three dietary pattern were classified into factor1(18.40%), factor2(10.87%) and factor3(8.8%). Wheat flour and meat, meat and alcohol as well as white meat, eggs, vegetableand fruit were main of dietary pattern in factor1(pattern1),2(pattern2) and3(pattern3)respectively. Single factor logistic regression analysis showed that the OR value of threedietary pattern were2.23,1.40and0.52. Unchangeable result showed after adjusting thevariable of ethnic, age, gender, BMI and energy in multiple factors logistic regressionanalysis.7) Dietary nutrients risk factor analysis: multiple factors logistic regression analysisresult demonstrated that lipid, vitamin C, TG, WC and FINS were related withhyperuricemia. Vitamin C was protective factor, lipid, TG, WC and FINS were riskfactors. Their OR value were0.989,1.871,1.423,1.040and1.017respectively.(2) Relationship between serum vitamin level and UA of hyperuricemia in Uyghur and Han populations and national heterogeneity:1) Comparison between patients group and control group: serum level of retinol andB1were significantly increased while vitamin C and25(OH)D were significantlydecreased. Serum retinol and vitamins level of B1and B2increased following the increaseof UA level. Serum level of25(OH)D increased firstly while decreased after it reached toSUA-4level.2) Comparison between Uyghur and Han populations: serum retinol and vitamin B1level were significantly higher while vitamin E was lower significantly in Uyghur thanthose in Han population. Serum retinol level in patient group showed the ethnicheterogeneity obviously.3) Comparison between men and women: serum retinol and vitamins level of D, E,B1, B2and C were significantly higher in men than those in women. Serum vitamin B1level in patient group showed the ethnic heterogeneity obviously.4) Comparison among different ages: there were significantly different of serumvitamin B1level among different age control groups. Serum vitamin B1level decreasedgradually with growth from30to70.5) Assessment of vitamin status: the proportion difference of retinol excess and25(OH)D, C lack were significant in patient and control groups. Patients group washigher than control group. In control group, the proportion of retinol lack was lower inUyghur than that in Han population. In patients group, the proportion difference ofvitamin lack disappeared. Proportion of retinol, D and C lack was higher in women thanthose in men.6) Correlation analysis between serum vitamins level and UA level: in Hanpopulation, there was a positive correlation between UA level and serum retinol, B1andB2, the correlation coefficient were0.405,0.341and0.370. In Uyghur population, therewas a positive correlation between UA level and serum retinol and vitamin B1, thecorrelation coefficient were0.217and0.185. Moreover, there was a negative correlationbetween UA level and serum vitamin C, the correlation coefficient was0.188. There wasa positive correlation in men between UA level and serum retinol and vitamin B1, thecorrelation coefficient were0.176and0.179. Moreover, there was a negative correlationbetween UA level and serum25(OH)D and C, the correlation coefficient was0.148and0.175. There was a positive correlation in women between UA level and serum retinol,vitamin D, E and B1, the correlation coefficient were0.350,0.186,0.175and0.313. Afterfixing the ethnic and gender, the result of partial correlation analysis demonstrated positive correlation between UA level and retinol, vitamin B1and B2, the correlationcoefficient were0.277,0.244and0.151.7) Risk factors analysis: regression analysis result indicated that retinol and vitaminB1were risk factors of hyperuricemia, OR values were1.013and1.015. Vitamin C and Ewere protective factors, OR values were0.718and0.664respective.(3) Multiple vitamins intervention effect in hyperuricemia of Uyghur and Hanpopulations: relationship between serum vitamin level and UA and national heterogeneity:4weeks of multiple vitamins intervention later.1) UA level: UA level reduced2.27μmol/L in intervention group and there weresignificant difference in Uyghur and Han ethnics.2) Blood lipid level: the concentration of TC and LDL decreased significantly inintervention group than those in control group.3) Carbohydrate metabolism: FINS and HOMA-IR level reduced significantly inintervention group than those in control group and they reduced significantly in Uyghurand Han ethnics.4) Oxidative stress: activity of enzymes SOD and GSH-PX increased significantlyin intervention group than those in control group. The trend of antioxidase and lipidperoxidation in Uyghur and Han intervention group were uniform.5) Inflammatory factors: TNF–α and IL-6reduced significantly in interventiongroup than those in control group. The trend of inflammatory factors in Uyghur and Hanintervention group were uniform.6) Adipocyte factors: Leptin and APN level increased significantly in interventiongroup than those in control group. Only APN level increased significantly in Uyghurintervention group after ethnic stratified.Conclusions:(1) Daily dietary nutrients intake is unbalance. Intake of protein, cholesterol, Fe andNa are excess, insufficient intake of thiamine and lack of lactoflavin, vitamin C, Ca, Zn,Se intake in hyperuricemia. High proportion of animal protein and lipid and lowproportion of bean protein and plant lipid in food resource as well as the intakeinsufficiencies of vegetables, fruits, fisheries, milk and beans and intake excess oflivestock meat, poultry meat, animal viscera, salt and alcohol in dietary structure allindicate severe unbalance of dietary in hyperuricemia. Main factors analysisdemonstrates that wheat flour with animal food pattern (wheat flour, livestock meat, viscera) and animal food with alcohol food pattern (beef and mutton, poultry meat,viscera, eggs and alcohol) are risk factors of hyperuricemia while vegetable, fruit withwhite meat food pattern (poultry meat, eggs, milk, beans products, fruit and vegetable)are protective factors.(2) Daily dietary nutrients intake level, dietary structure and dietary pattern aredifferent in Uyghur and Han ethnics. In Uyghur, intake amount of heat, lipid,carbohydrate, Na, lactoflavin, vitamin and energy provided by lipid are higher whileintake of dietary fiber, vitamin A and C are lower than Han ethnic. The result of DBIdietary quality analysis indicates that the degree of intake insufficiency and lack is higherin Uyghur than those in Han ethnic. Food pattern in patients group of Han and Uyghurethnics tends to high wheat flour with meat and high meat with alcohol respectively.(3) Daily intake of lipid and vitamin C, livestock meat, animal viscera, vegetable,alcohol, TG, WC and FINS are related with hyperuricemia. Among them, vitamin C andvegetable are protective factors while lipid intake, livestock meat, animal viscera, alcohol,TG, WC and FINS are risk factors.(4) Serum vitamin level alters in hyperuricemia. Retinol and B1increase while25(OH)D and vitamin C decrease. Serum retinol and vitamins level of B1and B2increased following the increase of UA level. Retinol, vitamin B1and B2are protectivefactors while vitamin C and E are risk factors. In Uyghur, level of retinol and vitamin B1are higher while level of vitamin E is lower than Han ethnic. Serum vitamins level inmen is higher than that in women. In patient group, the difference of serum vitamins levelin different ethnics and gender are small.(5) UA level reduction after4weeks multiple vitamins intervention relates probablywith improvement of insulin resistance, promotion of antioxidase activity, reduction oflipid peroxidation, regulation of inflammatory factors (TNF-α、IL-6) expression andincrease of APN and Leptin level. Reduction degree of UA level maybe due to shortperiod of intervention.更多还原