本文選題：抗結(jié)核藥致肝損傷　切入點(diǎn)：發(fā)生率　出處：《南京醫(yī)科大學(xué)》2017年碩士論文　論文類(lèi)型：學(xué)位論文

【摘要】：結(jié)核病(Tuberculosis,TB)是由結(jié)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(wèn)題。隨著標(biāo)準(zhǔn)短期化療方案的全面覆蓋,我國(guó)結(jié)核病防治取得一定的成效。但由于長(zhǎng)時(shí)間、多種藥物的聯(lián)合使用,結(jié)核病人會(huì)出現(xiàn)各種不同程度的不良反應(yīng),其中以抗結(jié)核藥致肝損傷(anti-tuberculosis liver injury,ATLI)較為常見(jiàn)且最為嚴(yán)重。目前學(xué)者們對(duì)影響ATLI發(fā)生的因素進(jìn)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(yán)重程度、營(yíng)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(zhuǎn)移酶2、CYP450家族、GSTs轉(zhuǎn)移酶超家族等相關(guān)藥物代謝酶的基因突變,但是結(jié)果并不一致。除此之外,研究者們認(rèn)為結(jié)核藥在代謝過(guò)程中產(chǎn)生的過(guò)多毒性中間產(chǎn)物與肝細(xì)胞內(nèi)的脂類(lèi)、蛋白、核酸等大分子物質(zhì)共價(jià)結(jié)合,促進(jìn)活性氧(reactive oxygen,ROS)的產(chǎn)生,是ATLI發(fā)生的主要原因。機(jī)體在應(yīng)對(duì)ROS損傷時(shí),形成一整套復(fù)雜且有效的氧化應(yīng)激反饋系統(tǒng)。當(dāng)機(jī)體產(chǎn)生過(guò)高水平ROS時(shí),自身能誘導(dǎo)出一系列保護(hù)性蛋白,從而緩解細(xì)胞所受的損害。在此過(guò)程中,核因子E2相關(guān)因子2-抗氧化反應(yīng)元件(NRF2-ARE)信號(hào)通路誘導(dǎo)解毒酶和抗氧化物酶的表達(dá),是重要的抗氧化應(yīng)激信號(hào)通路。由此推測(cè)通路上相關(guān)蛋白(NRF2/KEAP1/MAFF/MAFK)的基因多態(tài)性會(huì)影響ROS的清除,進(jìn)而導(dǎo)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(diǎn),分別探討可能影響ATLI發(fā)生的有關(guān)因素。第一部分抗結(jié)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(gè)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(jié)核病人隨訪隊(duì)列,收集患者的流行病學(xué)資料及肝功能記錄;同時(shí),進(jìn)一步基于鎮(zhèn)江市第三人民醫(yī)院2006-2012年結(jié)核病人病案資料及出院后門(mén)診隨訪記錄,依據(jù)病案及肝功能檢測(cè)記錄,采用國(guó)際共識(shí)會(huì)議標(biāo)準(zhǔn)診斷抗結(jié)核藥致肝損傷(ATLI),對(duì)其相關(guān)因素進(jìn)行分析。主要結(jié)果如下:1.在2014-2016年隨訪隊(duì)列中,共納入2209名結(jié)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(shí)間為24天(四分位數(shù)間距為8.5～45天)。2006-2012年住院抗結(jié)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(shí)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(jìn)行多因素分析,結(jié)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(jié)核病人ATLI發(fā)生率高于非耐藥結(jié)核病人(HR=2.935,95%:1.121-7.681,P=0.028),其差異均有統(tǒng)計(jì)學(xué)意義。第二部分NRF2-ARE信號(hào)通路相關(guān)基因遺傳變異與抗結(jié)核藥致肝損傷易感性的關(guān)系利用江蘇地區(qū)四個(gè)醫(yī)院2014-2016年新登記報(bào)告的結(jié)核病人建成的隊(duì)列,采用1:2匹配的巢式病例對(duì)照研究設(shè)計(jì),以候選基因組策略選取NRF2-ARE信號(hào)通路上的NRF2、KEAP1、MAFF、MAFK四個(gè)基因的15個(gè)標(biāo)簽SNPs,應(yīng)用Sequenom Mass Array基因分型方法檢測(cè)全部研究對(duì)象(313例ATLI病例,626例無(wú)ATLI對(duì)照)各SNP位點(diǎn)的基因型,運(yùn)用條件Logistic回歸分析四個(gè)基因位點(diǎn)多態(tài)性與ATLI發(fā)生的關(guān)聯(lián)性。主要結(jié)果如下:條件Logistic回歸分析顯示,在調(diào)整保肝藥物和治療方案使用情況后,15個(gè)多態(tài)性位點(diǎn)基因型分布與ATLI的發(fā)生無(wú)統(tǒng)計(jì)學(xué)關(guān)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(xiǎn)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(gè)基因中的各個(gè)單倍型頻率分布在病例組與對(duì)照組間的差異均無(wú)統(tǒng)計(jì)學(xué)意義,未發(fā)現(xiàn)與ATLI有統(tǒng)計(jì)學(xué)關(guān)聯(lián)的單倍型(P0.05)。交互作用分析發(fā)現(xiàn),攜帶KEAP1-rs1048290位點(diǎn)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(fēng)險(xiǎn)(OR=2.410,95%CI:1.104-5.261,P=0.027),但經(jīng) Bonferroni 校正后P0.05。聯(lián)合作用分析發(fā)現(xiàn),隨著個(gè)體攜帶危險(xiǎn)等位基因數(shù)量的增加,ATLI的患病風(fēng)險(xiǎn)逐步增加(P趨勢(shì)=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(xué)位授予單位】：南京醫(yī)科大學(xué)
【學(xué)位級(jí)別】：碩士
【學(xué)位授予年份】：2017
【分類(lèi)號(hào)】：R52

【參考文獻(xiàn)】

相關(guān)期刊論文 前10條

1 吳玉華;武謙虎;;抗結(jié)核藥致肝損害1949例文獻(xiàn)分析[J];西北藥學(xué)雜志;2015年06期

2 史哲;賀蕾;高麗;鄭國(guó)穎;李世明;張朋;張中瑞;宋磊;馮福民;;UGT2B7基因多態(tài)性與抗結(jié)核藥物性肝損傷的相關(guān)性分析[J];中國(guó)抗生素雜志;2014年11期

3 董亮;何永志;王遠(yuǎn)亮;董志揚(yáng);;超氧化物歧化酶(SOD)的應(yīng)用研究進(jìn)展[J];中國(guó)農(nóng)業(yè)科技導(dǎo)報(bào);2013年05期

4 張金玲;朱學(xué)彬;李世明;張中瑞;宋磊;馮福民;;SLCO1B1/ABCB1基因多態(tài)性與抗結(jié)核藥物性肝損傷的相關(guān)性分析[J];中華疾病控制雜志;2013年06期

5 安慧茹;吳雪瓊;王仲元;;MnSOD的基因多態(tài)性與抗結(jié)核藥物性肝損害關(guān)系的研究[J];中國(guó)抗生素雜志;2012年11期

6 李冰;;Nrf2信號(hào)通路及其分子調(diào)控機(jī)制[J];國(guó)外醫(yī)學(xué)(醫(yī)學(xué)地理分冊(cè));2012年03期

7 吳雪瓊;朱冬林;張俊仙;鐘逾;席云;安慧茹;梁艷;陽(yáng)幼榮;;羧酸酯酶基因1多態(tài)性鑒定及其與抗結(jié)核藥物肝毒性相關(guān)性研究[J];中華內(nèi)科雜志;2012年07期

8 朱冬林;席云;吳雪瓊;;GSTM1和GSTT1基因多態(tài)性與抗結(jié)核藥物性肝損害的關(guān)系[J];中國(guó)抗生素雜志;2011年11期

9 郝金奇;陳怡;李世明;張朋;余艷琴;唐桂鈺;馮福民;;尿苷二磷酸葡萄糖醛酸轉(zhuǎn)移酶1A6基因多態(tài)性與抗結(jié)核藥致肝損害的相關(guān)性[J];中華肝臟病雜志;2011年03期

10 劉晨暉;樂(lè)江;;細(xì)胞色素P450 CYP2E1酶構(gòu)型特征及其表達(dá)調(diào)控機(jī)制的研究進(jìn)展[J];中國(guó)藥理學(xué)與毒理學(xué)雜志;2010年02期

，

本文編號(hào)：1568621