本文選題：抗結核藥致肝損傷　切入點：發(fā)生率　出處：《南京醫(yī)科大學》2017年碩士論文　論文類型：學位論文

【摘要】：結核病(Tuberculosis,TB)是由結核分支桿菌引起的慢性呼吸道傳染病,通常感染并破壞肺部及淋巴系統(tǒng),也可感染腦膜、腹膜、腸、皮膚、腎臟及骨骼等部位,為全球重大的公共衛(wèi)生問題。隨著標準短期化療方案的全面覆蓋,我國結核病防治取得一定的成效。但由于長時間、多種藥物的聯(lián)合使用,結核病人會出現(xiàn)各種不同程度的不良反應,其中以抗結核藥致肝損傷(anti-tuberculosis liver injury,ATLI)較為常見且最為嚴重。目前學者們對影響ATLI發(fā)生的因素進行廣泛探討,非遺傳因素涉及性別、年齡、疾病涉及的器官及其嚴重程度、營養(yǎng)狀況、飲酒情況、肝炎病毒攜帶情況、保肝藥使用情況等。遺傳因素研究主要集中在N-乙�；D移酶2、CYP450家族、GSTs轉移酶超家族等相關藥物代謝酶的基因突變,但是結果并不一致。除此之外,研究者們認為結核藥在代謝過程中產生的過多毒性中間產物與肝細胞內的脂類、蛋白、核酸等大分子物質共價結合,促進活性氧(reactive oxygen,ROS)的產生,是ATLI發(fā)生的主要原因。機體在應對ROS損傷時,形成一整套復雜且有效的氧化應激反饋系統(tǒng)。當機體產生過高水平ROS時,自身能誘導出一系列保護性蛋白,從而緩解細胞所受的損害。在此過程中,核因子E2相關因子2-抗氧化反應元件(NRF2-ARE)信號通路誘導解毒酶和抗氧化物酶的表達,是重要的抗氧化應激信號通路。由此推測通路上相關蛋白(NRF2/KEAP1/MAFF/MAFK)的基因多態(tài)性會影響ROS的清除,進而導致ATLI的發(fā)生。本研究從非遺傳因素和遺傳因素為出發(fā)點,分別探討可能影響ATLI發(fā)生的有關因素。第一部分抗結核藥致肝損傷的發(fā)生及影響因素分析基于2014-2016年江蘇地區(qū)4個醫(yī)院(鎮(zhèn)江市第三人民醫(yī)院、句容市人民醫(yī)院、泰興市人民醫(yī)院以及常熟市第二人民醫(yī)院傳染病分院)的結核病人隨訪隊列,收集患者的流行病學資料及肝功能記錄;同時,進一步基于鎮(zhèn)江市第三人民醫(yī)院2006-2012年結核病人病案資料及出院后門診隨訪記錄,依據(jù)病案及肝功能檢測記錄,采用國際共識會議標準診斷抗結核藥致肝損傷(ATLI),對其相關因素進行分析。主要結果如下:1.在2014-2016年隨訪隊列中,共納入2209名結核患者,其中313名患者發(fā)生ATLI,發(fā)生率為14.2%(95%CI:12.7%-15.7%),中位發(fā)生時間為24天(四分位數(shù)間距為8.5～45天)。2006-2012年住院抗結核治療病人共1967名,其中325名患者發(fā)生ATLI,發(fā)生率為16.5%(95%CI:14.9%-18.1%),中位發(fā)生時間為25天(四分位數(shù)間距為12-46.5天)。2.采用Cox回歸模型進行多因素分析,結果顯示男性ATLI發(fā)生率高于女性(HR=1.580,95%:1.076-2.315,P=0.019),使用包含 HRZ 治療方案組ATLI 發(fā)生率高于其他方案組(HR=1.654,95%:1.147-2.386,P=0.007),耐藥結核病人ATLI發(fā)生率高于非耐藥結核病人(HR=2.935,95%:1.121-7.681,P=0.028),其差異均有統(tǒng)計學意義。第二部分NRF2-ARE信號通路相關基因遺傳變異與抗結核藥致肝損傷易感性的關系利用江蘇地區(qū)四個醫(yī)院2014-2016年新登記報告的結核病人建成的隊列,采用1:2匹配的巢式病例對照研究設計,以候選基因組策略選取NRF2-ARE信號通路上的NRF2、KEAP1、MAFF、MAFK四個基因的15個標簽SNPs,應用Sequenom Mass Array基因分型方法檢測全部研究對象(313例ATLI病例,626例無ATLI對照)各SNP位點的基因型,運用條件Logistic回歸分析四個基因位點多態(tài)性與ATLI發(fā)生的關聯(lián)性。主要結果如下:條件Logistic回歸分析顯示,在調整保肝藥物和治療方案使用情況后,15個多態(tài)性位點基因型分布與ATLI的發(fā)生無統(tǒng)計學關聯(lián)(P0.05)。分層分析顯示,在女性患者中,KEAP1-rs11545829 TT基因突變型較CT+CC基因型發(fā)生ATLI 的危險性增加(隱性模型,OR=5.825,95%CI:1.800-18.850,P=0.003)。單倍型頻率分布比較顯示,四個基因中的各個單倍型頻率分布在病例組與對照組間的差異均無統(tǒng)計學意義,未發(fā)現(xiàn)與ATLI有統(tǒng)計學關聯(lián)的單倍型(P0.05)。交互作用分析發(fā)現(xiàn),攜帶KEAP1-rs1048290位點GC+CC基因型且使用保肝藥者較GG基因型而未使用保肝藥者增加ATLI發(fā)病風險(OR=2.410,95%CI:1.104-5.261,P=0.027),但經 Bonferroni 校正后P0.05。聯(lián)合作用分析發(fā)現(xiàn),隨著個體攜帶危險等位基因數(shù)量的增加,ATLI的患病風險逐步增加(P趨勢=0.023)。
[Abstract]:Tuberculosis (Tuberculosis, TB) is a chronic respiratory infectious disease caused by Mycobacterium tuberculosis, usually infection and damage to the lungs and lymph system, also can infect the meninges, peritoneum, intestinal, kidney and skin, bones and other parts, as the major public health problem in the world. With the comprehensive coverage of the standard short-term chemotherapy, tuberculosis prevention and control our country has made some achievements. But for a long time, the combined use of multiple drugs, TB patients will appear different degree of adverse reactions, including anti tuberculosis drug induced liver injury (anti-tuberculosis liver, injury, ATLI) is a common and most serious factors were widely discussed. At present scholars on the incidence of ATLI. Non genetic factors related to gender, age, disease severity and involved organs, nutritional status, alcohol consumption, carrying hepatitis B virus, drug use and so on. The study of genetic factors To concentrate on the N- acetyltransferase 2, CYP450 family, GSTs transferase superfamily and related drug metabolizing enzyme gene mutation, but the results are not consistent. In addition, the researchers think that the fat, tuberculosis drugs produced in the metabolic process of excessive toxicity of intermediate and liver cells protein covalent nucleic acid binding, promote ROS (reactive oxygen ROS) which is the main reason for the occurrence of ATLI. The body in response to ROS damage and oxidative stress in the formation of a set of complex and effective feedback system. When the body produces high levels of ROS, itself can induce a series of protective proteins, thereby relieve cell injury. In this process, the nuclear factor E2 related factor 2- antioxidant response element (NRF2-ARE) induced expression of detoxifying enzymes and antioxidant enzyme pathway, oxidative stress is an important signaling pathway inferred through. The road related protein (NRF2/KEAP1/MAFF/MAFK) gene polymorphism may affect the ROS removal, and then lead to the occurrence of ATLI. This study from non genetic factors and genetic factors as a starting point, respectively, to explore related factors may influence the occurrence of ATLI. The incidence and related factors of liver injury induced by antituberculosis drugs in the first part of 2014-2016 years in Jiangsu based on the 4 hospital (Zhenjiang Third People's Hospital, Jurong People's Hospital, Taixing City People's Hospital, Changshou City Second People's Hospital of Infectious Diseases Branch) the tuberculosis patient follow-up cohort, epidemiological data were collected and recorded the liver function; at the same time, based on further follow-up records of Zhenjiang Third People's Hospital medical records of tuberculosis patients and 2006-2012 years after discharge, according to medical records and liver function test record the international consensus criteria for the diagnosis of anti tuberculosis drug induced liver injury (ATLI), on the phase The relevant factors were analyzed. The main results are as follows: 1. in the 2014-2016 year follow-up cohort, 2209 tuberculosis patients were included, of which 313 patients had ATLI, the incidence rate was 14.2% (95%CI:12.7%-15.7%), the median time was 24 days (the four percentile interval is 8.5 ~ 45 days) of.2006-2012 hospital anti tuberculosis treatment patients a total of 1967, of which 325 patients had ATLI, the incidence rate was 16.5% (95%CI:14.9%-18.1%), the median time was 25 days (four percentile interval of 12-46.5 days).2. Cox regression model was used for multivariate analysis, results showed that the male incidence rate of ATLI is higher than that of the female (HR=1.580,95%: 1.076-2.315, P=0.019), including HRZ treatment group ATLI was higher than other groups (HR=1.654,95%: 1.147-2.386, P=0.007), drug-resistant TB incidence rate of ATLI was higher than that of non drug resistant tuberculosis (HR=2.935,95%: 1.121-7.681, P=0.028), the differences were statistically Meaning. Tuberculosis related to liver injury induced by susceptibility genes related to genetic variation in the second part of the NRF2-ARE signaling pathway and the use of anti tuberculosis drugs in four hospitals in Jiangsu 2014-2016 years of new registration report completion queue, a nested case control study, 1:2 design, the candidate genomic selection strategies in NRF2-ARE signal pathway of NRF2, KEAP1. MAFF, 15 tag SNPs MAFK four gene, using Sequenom Mass Array genotyping method for the detection of all subjects (313 ATLI cases, 626 cases of non ATLI control) genotypes of each locus SNP, using conditional Logistic regression analysis of four SNPs and ATLI. The main results are as follows conditional Logistic regression analysis showed that in the adjustment of hepatoprotective drugs and treatment programs use, 15 genotype distribution of polymorphic loci and ATLI no significant correlation (P0.05). Stratified analysis showed that in female patients, KEAP1-rs11545829 TT gene mutation risk type with CT+CC genotype of ATLI increased (recessive model, OR=5.825,95%CI:1.800-18.850, P=0.003). The comparison shows that the frequency distribution of haplotypes, four genes in each haplotype frequency distribution in the case group and the control group had no significant difference, there is no statistics associated with ATLI haplotypes was found (P0.05). The interaction analysis found that carrying the KEAP1-rs1048290 GC+CC genotype and liver protection drugs than GG genotype without the use of liver protection drugs increase the risk of ATLI (OR=2.410,95%CI:1.104-5.261, P=0.027), but the combined effect of P0.05. after Bonferroni correction analysis showed that with the increase of the individual carrying dangerous number of alleles, the risk of ATLI increased gradually (P =0.023).

【學位授予單位】：南京醫(yī)科大學
【學位級別】：碩士
【學位授予年份】：2017
【分類號】：R52

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