尿酸与血管内皮损伤的基础与临床研究

发布时间：2018-02-14 20:53

本文关键词： 高尿酸血症痛风内皮功能炎症因子肾素-血管紧张素系统　出处：《北京协和医学院》2012年硕士论文　论文类型：学位论文

【摘要】：背景尿酸是嘌呤代谢产物,人类进化过程中尿酸酶基因突变,使人的血尿酸水平较其它哺乳动物高。高尿酸血症和痛风的患病率呈逐年上升趋势,临床观察到高尿酸血症与心血管疾病有密切联系,除此之外在慢性肾脏疾病患者中高尿酸血症也不少见。尽管很早人们就发现血清高浓度尿酸可作为心血管疾病危险性的标志,但两者之间的没有得出确切的因果关联。高尿酸血症和此类疾病之间的病理生理基础或许是内皮功能和炎症水平的变化。但是尿酸在这其中发挥的作用却存在一定分歧。目的 1)通过建立痛风门诊数据库分析本院痛风患者的临床特点；2)分析痛风患者内皮功能水平和降尿酸治疗后痛风患者的内皮功能变化；3)观察高尿酸血症大鼠和痛风患者血管内皮功能和内皮肾素-血管紧张素系统(renin-angiotensin system,RAS)的变化。方法 1.1)2008年1月到2012年2月间就诊于北京协和医院普通内科痛风门诊的358例痛风患者,填写调查问卷,收集人口学、病史、痛风石、既往生活方式、发作诱因、肾结石和合并疾病等资料；并进行体格检查和实验室检查,将以上资料录入痛风门诊数据库系统并进行数据导出和分析。2)对就诊于北京协和医院普通内科痛风门诊的33例痛风患者和在我院进行健康查体的31例高尿酸血症患者进行人口学资料、病史、合并疾病、合并用药询问,进行体格检查和实验室检查,E1ISA法测试血清TNF-α、sICAM-1。对痛风患者进行28周降尿酸治疗,评价TNF-α、sICAM-1水平变化。3)使用2%的氧嗪酸饲料和100umol/L的尿酸水,后增加氧嗪酸灌胃的方法建立长期高尿酸血症动物模型,对高尿酸大鼠和痛风患者血管内皮eNOS、ICAM、ACE和Ang-Ⅱ进行免疫组化染色寻找血管损伤和RAS激活的证据。结果 1)男性350例(97.8%),女性8例(2.2%),年龄46±13岁,平均病程99月,多关节受累多见,占78.4%,血清尿酸586±123μmol/L.77例患者(21.5%)发现痛风石,logistic回归显示尿酸水平和病程与痛风石的发生相关(P0.001),256例(71.5%)合并基础疾病,基础疾病的合并存在与高龄相关(P0.001)。青年组病程较中老年组短(P0.01),尿酸水平高于中老年组(P0.05),秩和检验结果显示累计关节数方面两组无统计学差异(P0.05)；中老年基础疾病合并率较青年组高(P0.01)。2)痛风患者组舒张压高于高尿酸血症组；痛风患者组血尿酸水平、TNF-α和sICAM水平高于高尿酸血症组,差异有统计学意义。年龄、BMI、收缩压、HDL-C、LDL-C、TC、TG、GFR、Cr和Glu差异无统计学意义。Logistic回归结果显示痛风和sICAM显著相关。别嘌醇、非布司他40mg和80mg能显著降低痛风患者的尿酸水平,其中80mg疗效次于前两者,可能与患者的病程和尿酸水平相关。中国人非布司他应尽量从小剂量用起。剔除两次随访期间有发作的患者后,降尿酸治疗后TNF-α和s-ICAM水平下降。3)高尿酸血症模型大鼠肾内局部ICAM表达增强,经别嘌醇处理后尽管ICAM水平有所降低,但无统计学意义。Ang-Ⅱ在高尿酸血症大鼠模型中和痛风组患者中有表达增强。结论 1)痛风患者的临床特征更具多样化、复杂化,表现为病程较长,痛风石受累多见,多关节受累多见,非典型关节受累并不罕见,基础疾病合并率高,肾损伤多见。痛风在发病率普遍提高的同时,临床特点也发生着变化。积极早期控制痛风的可逆性危险因素如肥胖、饮酒、高嘌呤饮食、药物可使更多的患者从中获益,减少重症难治性痛风,关节致残,痛风肾病的发生,改善患者的生活质量和预后。近年来,青年痛风患者发病也呈上升趋势,需特别关注这一人群的关节和合并的临床问题,积极寻找可控制的因素并针对以上因素加以管理。2)痛风患者相对于无症状高尿酸血症TNF-α水平s-ICAM水平有所增高,但仅血尿酸和sICAM独立相关。降尿酸治疗可有效改善内皮功能和炎症状态。3)提示尿酸存在对大鼠肾脏内皮功能损伤作用和局部RAS激活作用；尿酸可明显激活痛风患者血管内皮RAS,可能机制包括为非ACE途径。
[Abstract]:background
Uric acid is a product of purine metabolism, uricase gene mutation in human evolution, so that the blood uric acid level of people than other mammals. The prevalence of gout and hyperuricemia increased year by year, the clinical observation of hyperuricemia is closely related to cardiovascular disease, besides hyperuricemia in patients with chronic kidney disease is not uncommon. Although it is as early as it was found that high serum uric acid as a marker for cardiovascular disease risk, but they did not draw the exact causal association between hyperuricemia and disease. This disease may be the physiological basis of physical changes of endothelial function and inflammation levels. But uric acid play role in this but there are some differences.
objective
1) by analyzing the clinical characteristics of gout patients in our hospital to establish gout out-patient database; 2) analysis of the level of endothelial function in patients with gout and uric acid after treatment of endothelial function in patients with gout change; 3) were observed in rats with hyperuricemia and gout in patients with vascular endothelial function and endothelial renin-angiotensin system (renin-angiotensin, system, RAS) changes.
Method
1.1) 358 cases of gout patients from January 2008 to February 2012 in Peking Union Medical College Hospital from general medical outpatient gout, fill in the questionnaire to collect demographic, medical history, history of tophi, lifestyle, inducement, data of kidney stones and complications; and physical examination and laboratory examination, the data of database system and gout clinic export data and analysis.2) 33 cases of gout patients admitted to Peking Union Medical College Hospital outpatient and general medical gout in our hospital 31 cases of patients with hyperuricemia health examination of demographic data, medical history, concomitant diseases, medication enquiry, physical examination and laboratory test, serum TNF- E1ISA alpha, sICAM-1. gout patients 28 weeks of urate lowering therapy, evaluation of TNF- alpha,.3 changes in sICAM-1 levels) using 2% oxonate feed and 100umol /L acid water, then increased A long-term hyperuricemia animal model was established by intragastric administration of oxazine. Immunohistochemical staining of eNOS, ICAM, ACE and Ang- II in vascular endothelial cells of hyperuricemia rats and gout patients was performed to detect the evidence of vascular injury and RAS activation.
Result
1) male 350 cases (97.8%), 8 cases of female (2.2%), age 46 + 13 years old, the average duration of 99 months, multiple joint involvement was more common, accounting for 78.4%, 586 + 123 mol/L.77 of serum uric acid in patients (21.5%) found tophi, logistic regression analysis showed that uric acid level and the course of disease and gout. Students (P0.001), 256 cases (71.5%) with basic diseases, and age related with basic diseases (P0.001). The youth group course is in the elderly group (P0.01), short of uric acid is higher than that of the elderly group (P0.05), rank sum test results show that the total number of joint (no significant difference between two groups P0.05); in the elderly compared with young group based disease with high rate of (P0.01).2) in patients with gout group diastolic pressure was higher in hyperuricemia group; group of blood uric acid in patients with gout, TNF- and sICAM levels were higher than that in hyperuricemia group, the difference was statistically significant. The age, systolic blood pressure, BMI, HDL-C, LDL-C, TC, TG, GFR Cr, and the difference of Glu No statistical significance of.Logistic regression showed significant correlation of gout and sICAM. Allopurinol, febuxostat 40mg and 80mg can significantly reduce the level of uric acid in patients with gout, including the effect of 80mg to the first two, may be associated with disease related and uric acid levels. Chinese febuxostat should be small dose used. The onset of patients during follow-up after excluding two, down.3 TNF- alpha and s-ICAM levels of uric acid after treatment) enhanced the expression of hyperuricemia rat model of kidney in the local ICAM, by allopurinol treatment while the ICAM level decreased, but there was no statistical significance of.Ang- II expression in hyperuricemia rat model and gout patients.
conclusion
1) the clinical features of patients with gout are more diverse, complex, showed a longer course of disease, gout involvement was more common, multiple joint involvement, atypical joint involvement is not uncommon, basic disease with high rate of kidney injury. A general increase in the incidence of gout and clinical features are also changing. The reversible risk factors of early active control gout such as obesity, alcohol consumption, high purine diet, drugs can make more patients benefit from less severe refractory gout, joint disability, gout nephropathy, improve life quality and prognosis of the patients. In recent years, the incidence of young patients with gout is also on the rise. Clinical problems need special attention of this group of joint and combined, actively looking for the control factors and management of.2 in view of the above factors) asymptomatic hyperuricemia TNF- alpha level of s-ICAM levels increased compared to patients with gout , but only the blood uric acid and sICAM independently. Urate lowering therapy can effectively improve endothelial function and inflammation.3) suggest that uric acid activation on renal endothelial function injury in rats and the local RAS; uric acid can obviously activate vascular endothelial RAS in patients with gout, including possible mechanism for non ACE way.

【学位授予单位】：北京协和医学院
【学位级别】：硕士
【学位授予年份】：2012
【分类号】：R363

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