本文選題：慢加急性乙型肝炎肝衰竭　切入點(diǎn)：GSTM3　出處：《山東大學(xué)》2013年博士論文

【摘要】：第一部分慢加急性乙型肝炎肝衰竭患者GSTM3基因啟動(dòng)子甲基化狀態(tài)分析 慢加急性肝衰竭(acute-on-chronic liver failure, ACLF)是在慢性肝病基礎(chǔ)上出現(xiàn)急性肝功能失代償?shù)呐R床表現(xiàn),主要由感染、酒精、肝毒性藥物等因素誘發(fā),臨床表現(xiàn)為高膽紅素血癥、凝血功能障礙,并發(fā)腹水、肝性腦病和(或)肝腎綜合征以及多臟器功能衰竭等,全身血液動(dòng)力學(xué)改變伴隨ACLF的病情進(jìn)展,其病理生理過(guò)程包括全身炎癥反應(yīng)綜合征、炎癥及氧化應(yīng)激等,死亡率極高。在我國(guó),引起ACLF的首要病因是乙型肝炎病毒(hepatitis B virus, HBV)感染,由慢性乙型病毒性肝炎所致的ACLF稱為慢加急性乙型肝炎肝衰竭(acute-on-chronic hepatitis B liver failure, ACHBLF),是我國(guó)最常見(jiàn)的肝衰竭類型,占80%-90%。在臨床上ACHBLF缺乏特異、有效的治療手段,病情兇險(xiǎn),進(jìn)展迅速,絕大部分患者預(yù)后差。ACHBLF的發(fā)病機(jī)制尚不完全明確。 DNA甲基化是轉(zhuǎn)錄水平的DNA修飾方式之一,發(fā)生在CpG島上,它在調(diào)節(jié)基因表達(dá)及維持細(xì)胞正常分化中起著重要作用。目前認(rèn)為DNA甲基化可抑制基因表達(dá)。甲基化程度高,基因表達(dá)降低。谷胱甘肽-S-轉(zhuǎn)移酶M3(glutathione-S-transferase M3, GSTM3)是谷胱甘肽-S-轉(zhuǎn)移酶(glutathione-S-transferases, GSTs)超家族一種重要的同工酶,具有較強(qiáng)的抗氧化應(yīng)激功能,是機(jī)體內(nèi)抗氧化防御體系的重要成分之一,具備清除活性氧(或稱氧自由基)(reactive oxygen species, ROS)的能力。GSTM3基因啟動(dòng)子發(fā)生甲基化時(shí)可導(dǎo)致該基因表達(dá)下調(diào),造成其抗氧化功能下降,ROS在體內(nèi)或細(xì)胞內(nèi)蓄積,對(duì)肝臟的保護(hù)作用降低,可能會(huì)加重氧化損傷對(duì)肝功能的損害。 基因啟動(dòng)子甲基化是目前研究的熱點(diǎn),在惡性疾病的早期診斷、風(fēng)險(xiǎn)評(píng)估、早期復(fù)發(fā)預(yù)測(cè)、治療反應(yīng)監(jiān)測(cè)及預(yù)后判斷中,異常的DNA甲基化位點(diǎn)已經(jīng)成為最有前景的分子標(biāo)志物之一。目前有關(guān)GSTs超家族成員GSTM3基因啟動(dòng)子甲基化的研究多側(cè)重于與膀胱癌、肝癌、前列腺癌等腫瘤發(fā)生、發(fā)展的相關(guān)性。我國(guó)肝癌患者中約90%有HBV感染背景,但目前尚未見(jiàn)對(duì)慢性乙型肝炎(chronic hepatitis B, CHB),特別是重型肝炎患者進(jìn)行該基因啟動(dòng)子甲基化檢測(cè)的研究。 目的 本研究的目的是檢測(cè)IJACHBLF患者是否存在GSTM3基因啟動(dòng)子區(qū)的甲基化異常并通過(guò)比較臨床預(yù)后相關(guān)指標(biāo),評(píng)價(jià)其臨床意義從而指導(dǎo)臨床應(yīng)用。 方法 本研究采用病例對(duì)照研究設(shè)計(jì),病例選自2009年12月至2011年2月在山東大學(xué)齊魯醫(yī)院住院及門診就診患者,其中ACHBLF組30例,CHB組30例；10名健康志愿者作為正常對(duì)照組。記錄以上研究對(duì)象的年齡、性別等指標(biāo),收集肝功、腎功、凝血功能、HBV-DNA定量等臨床指標(biāo)并進(jìn)行比較。用試劑盒提取外周血DNA,并用重亞硫酸鹽法對(duì)其進(jìn)行甲基化修飾。應(yīng)用甲基化特異性聚合酶鏈反應(yīng)(methylation-specific polymerase chain reaction, MSP)方法檢測(cè)三組研究對(duì)象GSTM3基因的啟動(dòng)子甲基化狀態(tài)并進(jìn)行比較。根據(jù)檢測(cè)結(jié)果將ACHBLF組分為甲基化組和非甲基化組,計(jì)算各組的終末期肝病模型(model for end-stage liver disease, MELD)積分及死亡率,通過(guò)比較進(jìn)行臨床預(yù)后評(píng)價(jià)。 所有統(tǒng)計(jì)學(xué)處理采用統(tǒng)計(jì)軟件SPSS13.0for Windows分析。組間臨床資料比較、MELD積分比較應(yīng)用獨(dú)立樣本t檢驗(yàn),甲基化率的比較應(yīng)用卡方檢驗(yàn),死亡率比較應(yīng)用Fisher's確切概率法。P0.05定為差異有統(tǒng)計(jì)學(xué)意義。 結(jié)果 1、ACHBLF組的血清谷丙轉(zhuǎn)氨酶(alanine aminotransferase, ALT)水平(516.110±527.137IU/L)明顯高于CHB組(264.633±274.053IU/L,P=0.024),谷草轉(zhuǎn)氨酶(aspartate aminotransferase, AST)水平(396.283±337.062IU／L)明顯高于CHB組(212.153±222.816IU／L,P=0.016),總膽紅素(total bilirubin, TBIL)水平(383.483±137.034μmol/L)明顯高于CHB組(37.400±27.004μmol/L,P0.001),凝血酶原活動(dòng)度(prothrombin time activity, PTA)水平(31.187±8.013%)明顯低于CHB組(90.000±9.766%,P0.001)。 2、30例ACHBLF患者中9例檢測(cè)至GSTM3基因啟動(dòng)子甲基化,比率為30%,30例CHB患者中2例檢測(cè)至GSTM3基因啟動(dòng)子甲基化,比率為6.7%,兩組比較差異有統(tǒng)計(jì)學(xué)意義(X2=5.455,P=0.020)。 3、ACHBLF患者甲基化組的血清TBIL水平(527.922±113.564μmol/L)明顯高于非甲基化組(321.581±93.048μmol/L,P0.001),PTA水平(24.811±10.697%)明顯低于非甲基化組(33.919±4.604%,P=0.035)。 4、ACHBLF患者甲基化組的MELD積分(22.706±2.669)明顯高于非甲基化組(18.765±4.808,P=0.029)。ACHBLF患者有8人死亡,死亡率為26.7%,其中5人屬于甲基化組,死亡率為55.6%,3人屬于非甲基化組,死亡率為14.3%,甲基化組的死亡率明顯高于非甲基化組(P=0.032)。 結(jié)論 我們的研究結(jié)果首次表明ACHBLF患者存在GSTM3基因啟動(dòng)子甲基化的異常,啟動(dòng)子甲基化可能導(dǎo)致GSTM3基因表達(dá)下降,抑制其抗氧化功能,加重氧化損傷程度,在CHB進(jìn)展為ACHBLF的過(guò)程中可能具有重要作用,檢測(cè)該基因啟動(dòng)子甲基化狀態(tài)可作為判斷ACHBLF患者預(yù)后的重要指標(biāo)。 第二部分慢加急性乙型肝炎肝衰竭患者GSTM3基因啟動(dòng)子甲基化狀態(tài)與氧化應(yīng)激的相關(guān)性分析 氧化應(yīng)激是機(jī)體的氧化能力與抗氧化能力失衡,氧化程度超出氧化物質(zhì)的清除能力,導(dǎo)致活性氧(或稱氧自由基)(reactive oxygen species, ROS)在體內(nèi)或細(xì)胞內(nèi)蓄積而引起的細(xì)胞毒性,最終導(dǎo)致組織損傷的過(guò)程。氧化應(yīng)激可直接或間接引起脂質(zhì)、蛋白質(zhì)、酶和DNA的氧化或損傷,誘發(fā)基因突變、蛋白質(zhì)變性和脂質(zhì)過(guò)氧化,與腫瘤、心腦血管疾病、糖尿病、各種肝病(包括病毒性肝炎、肝纖維化、肝癌)等多種疾病密切相關(guān)。肝臟含有豐富的線粒體,是ROS攻擊的主要器官。線粒體呼吸鏈復(fù)合體利用電子傳遞生產(chǎn)三磷酸腺苷(adenosine triphosphate, ATP),是ROS的主要來(lái)源。氧化損傷可以加快肝臟病變的進(jìn)展。 慢加急性肝衰竭(acute-on-chronic liver failure, ACLF)是多種因素參與的復(fù)雜過(guò)程,炎癥和氧化應(yīng)激在其發(fā)生發(fā)展中起著重要作用。肝病時(shí)患者體內(nèi)免疫功能紊亂,炎癥反應(yīng)增強(qiáng),免疫復(fù)合物形成,補(bǔ)體活化及膠原纖維形成等均可刺激ROS生成增多,可引起肝細(xì)胞過(guò)氧化脂質(zhì)形成。機(jī)體內(nèi)ROS生成與清除處于失平衡狀態(tài)持續(xù)時(shí)間越久,組織細(xì)胞抗氧化防御保護(hù)功能越弱,肝損傷程度越重。 肝細(xì)胞氧化應(yīng)激可導(dǎo)致細(xì)胞膜脂質(zhì)過(guò)氧化,形成過(guò)氧化產(chǎn)物如丙二醛(malondialdehyde, MDA)、酮類、羥氫氧基等。MDA是脂質(zhì)過(guò)氧化的主要代謝產(chǎn)物,是研究脂質(zhì)過(guò)氧化并反映氧化損傷的重要生物標(biāo)志物,體內(nèi)MDA水平增高,提示存在氧化損傷；谷胱甘肽-S-轉(zhuǎn)移酶(glutathione-S-transferase, GST)是一種抗氧化酶,它可修復(fù)ROS損傷的膜磷脂、抑制微粒體過(guò)氧化反應(yīng)等,通過(guò)多種方式起到抗氧化作用。肝細(xì)胞受損時(shí)GST可以快速釋放入血,血清GST活性測(cè)定是一項(xiàng)理想的反映肝細(xì)胞損害程度的指標(biāo),具有良好的特異性和敏感性。二者的水平變化可反映體內(nèi)自由基產(chǎn)生和清除這一動(dòng)態(tài)平衡過(guò)程。 谷胱甘肽-S-轉(zhuǎn)移酶M3(glutathione-S-transferase M3, GSTM3)基因表達(dá)的改變會(huì)影響GST的抗氧化功能。我們第一部分的研究結(jié)果首次表明慢加急性乙型肝炎肝衰竭(acute-on-chronic hepatitis B liver failure, ACHBLF)患者存在GSTM3基因啟動(dòng)子甲基化的異常,啟動(dòng)子甲基化可能導(dǎo)致GSTM3基因表達(dá)下降,抑制其抗氧化功能,加重氧化損傷程度,在慢性乙型肝炎(chronic hepatitis B, CHB)進(jìn)展為ACHBLF的過(guò)程中可能具有重要作用,檢測(cè)該基因啟動(dòng)子甲基化可作為判斷ACHBLF患者預(yù)后的重要指標(biāo)。 目的 本研究的目的是通過(guò)檢測(cè)血清MDA和GST表達(dá)水平,并與終末期肝病模型(model for end-stage liver disease, MELD)積分進(jìn)行相關(guān)分析,探討ACHBLF患者GSTM3基因啟動(dòng)子甲基化狀態(tài)與氧化應(yīng)激的關(guān)系,從而對(duì)ACHBLF的病情發(fā)展、評(píng)估預(yù)后及臨床治療提供理論基礎(chǔ)。 方法 應(yīng)用甲基化特異性聚合酶鏈反應(yīng)(methylation-specific polymerase chain reaction, MSP)檢測(cè)GSTM3基因啟動(dòng)子甲基化狀態(tài),具體方法同實(shí)驗(yàn)第一部分,應(yīng)用酶聯(lián)免疫吸附測(cè)定(enzyme-linked immunosorbent assay, ELISA)技術(shù)檢測(cè)CHB患者、ACHBLF患者血清MDA及GST的表達(dá)水平,并對(duì)ACHBLF患者進(jìn)行MDA.GST水平與MELD積分的相關(guān)性分析。 所有統(tǒng)計(jì)學(xué)處理采用統(tǒng)計(jì)軟件SPSS13.0for Windows分析。組間MDA及GST水平的比較應(yīng)用獨(dú)立樣本t檢驗(yàn),應(yīng)用Spearman's檢驗(yàn)進(jìn)行MDA、GST水平與MELD積分的相關(guān)性分析。P0.05定為差異有統(tǒng)計(jì)學(xué)意義。 結(jié)果 1、ACHBLF組的血清MDA水平(13.045±5.416pmol/mg)明顯高于CHB組(9.387±5.332pmol/mg, P=0.011)。 2、ACHBLF甲基化組的血清MDA水平(16.956±.155pmol/mg)明顯高于非甲基化組(11.369±5.553pmol/mg, P0.001)。 3、ACHBLF組的血清GST水平(1318.081±273.887mIU/L)明顯高于CHB組(666.832±181.267mIU/L, P0.001)。 4、ACHBLF甲基化組的血清GST水平(1381.678±236.841mIU/L)與非甲基化組相比差異無(wú)統(tǒng)計(jì)學(xué)意義(1262.253±202.782mIU/L, P=0.170)。 5、ACHBLF組的血清MDA水平與MELD積分呈正相關(guān)(r=0.588,P=0.001),而血清GST水平與MELD積分無(wú)相關(guān)性(r=0.115,P=0.546)。 結(jié)論 ACHBLF患者GSTM3基因啟動(dòng)子甲基化狀態(tài)與氧化應(yīng)激存在相關(guān)性,該基因啟動(dòng)子甲基化異常參與氧化應(yīng)激對(duì)HBV感染患者的肝功能損害,并且氧化應(yīng)激損傷程度與患者的病情嚴(yán)重程度成正相關(guān),從而為抗氧化劑治療ACHBLF提供理論依據(jù)。
[Abstract]:Analysis of methylation status of GSTM3 gene promoter in patients with chronic hepatitis B liver failure in the first part

Acute - on - chronic liver failure ( ACLF ) is the main clinical manifestation of acute liver failure on the basis of chronic liver disease , mainly caused by infection , alcohol , hepatotoxic drugs , etc . The clinical manifestations include systemic inflammatory response syndrome , coagulation dysfunction , concurrent ascites , hepatic encephalopathy and / or hepatorenal syndrome as well as multiple organ failure .

DNA methylation is one of the DNA modification methods of transcription level . It plays an important role in regulating gene expression and maintaining normal differentiation of cells .

The methylation of GSTM3 gene promoter is one of the most promising molecular markers in the early diagnosis , risk assessment , early recurrence prediction , therapeutic response monitoring and prognosis of malignant disease .

Purpose

The purpose of this study was to evaluate the presence or absence of methylation abnormalities in the promoter region of the GSTM3 gene in IJACHBLF patients and to evaluate their clinical significance by comparing the clinical outcome - related indicators to guide the clinical application .

method

The case - control study was used in the study , and the cases were selected from December 2009 to February 2011 in the hospital in Qu Hospital of Shandong University and the outpatient visits . Among them , 30 cases were ACHBLF group and 30 patients in the group of the patients in the patients with the patients in the patients with the patients were treated with the treatment group ( 30 cases ) ;
Ten healthy volunteers were used as the normal control group . The age and sex indexes of these subjects were recorded and compared . DNA was extracted from peripheral blood by means of kit . The methylation state of the promoter of GSTM3 gene was detected by methylation - specific polymerase chain reaction ( MSP ) method and compared . The ACHBLF component was used as methylation group and non - methylation group to calculate the integral and mortality rate of the end - stage liver disease ( MELD ) of each group , and the clinical prognosis was evaluated by comparison .

All the statistical treatments were analyzed by SPSS 13.0 for Windows . The comparison of the clinical data between the groups , the comparison of the MELD integral with the independent sample t test , the comparison of methylation rate and the Fisher ' s exact probability method were compared with the Fisher ' s exact probability method ( P0.05 ) .

Results

1 . Serum alanine aminotransferase ( ALT ) level of ACHBLF group ( 516.110 鹵 527.137 IU / L ) was significantly higher than that in the control group ( 264.633 鹵 274.053 IU / L , P = 0 . 024 ) , and the level of total bilirubin ( TBIL ) ( 383.483 鹵 337.062IU / L ) was significantly higher than that in group B ( 37.400 鹵 27.004 渭mol / L , P0.001 ) , prothrombin activity ( PTA ) level ( 31.187 鹵 8.013 % ) was significantly lower than that in the group B ( 90.000 鹵 9.766 % , P0.001 ) .

2 . The methylation of GSTM3 gene was detected in 9 of 30 patients with ACHBLF , the ratio was 30 % , and the methylation of GSTM3 gene promoter was detected in 2 of 30 patients with hepatitis B . The ratio was 6.7 % . There was significant difference between the two groups ( X2 = 5.455 , P = 0.020 ) .

3 . The serum TBIL level of the methylated group of ACHBLF was significantly higher than that in the non - methylated group ( 321.581 鹵 93.48 渭mol / L , P0.001 ) , and the PTA level ( 24.811 鹵 10.697 % ) was significantly lower than that in the non - methylation group ( 33.919 鹵 4.604 % , P = 0.035 ) .

4 . The MELD integral ( 22.706 鹵 2.669 ) of the methylated group in ACHBLF was significantly higher than that in the non - methylation group ( 18.765 鹵 4.808 , P = 0.029 ) . Eight of ACHBLF patients died and the mortality rate was 26.7 % . Five of them belonged to methylated group , the mortality rate was 55.6 % , the mortality rate was 14.3 % , and the death rate of methylated group was significantly higher than that of non - methylation group ( P = 0.032 ) .

Conclusion

Our results show that the methylation of GSTM3 gene promoter is abnormal in ACHBLF patients . The methylation of promoter may decrease the expression of GSTM3 gene , inhibit its antioxidant function , increase the degree of oxidative damage , and may play an important role in the process of ACHBLF , and the methylation status of the promoter can be used as an important index to judge the prognosis of ACHBLF .

Correlation analysis of methylation status of GSTM3 gene promoter and oxidative stress in patients with chronic hepatitis B hepatic failure in the second part

Oxidative stress is the main organ of ROS attack . Oxidative stress can directly or indirectly cause oxidation or damage of lipid , protein , enzyme and DNA , induce gene mutation , protein denaturation and lipid peroxidation . It is the main organ of ROS attack . Mitochondrial respiratory chain complex uses electron transfer to produce adenosine triphosphate ( ATP ) , which is the main source of ROS . Oxidative stress can accelerate the progression of hepatic lesion .

Chronic liver failure ( ACLF ) plays an important role in the development of acute - on - chronic liver failure ( ACLF ) .

Oxidative stress in liver cells can lead to lipid peroxidation of cell membranes , and form peroxidic products such as malondialdehyde ( MDA ) , ketones , hydroxyhydrophones and the like . MDA is the main metabolite of lipid peroxidation , which is an important biomarker for lipid peroxidation and reflects oxidative damage , and the level of MDA in vivo is increased , suggesting oxidative damage ;
Glutathione - S - transferase ( GST ) is an anti - oxidant enzyme which can repair ROS - damaged membrane phospholipid , inhibit the peroxidation of microsomes and so on . GST can rapidly release blood into blood and serum GST activity is an ideal indicator reflecting the degree of damage of liver cells . The changes of GST activity can reflect the dynamic balance process of free radical generation and elimination in vivo .

The changes of glutathione - S - transferase M3 ( glutathione - S - transferase M3 , GSTM3 ) gene expression can affect the anti - oxidation function of GST . The results of the first part show that the methylation of GSTM3 gene promoter in patients with acute - on - chronic hepatitis B liver failure ( ACHBLF ) is abnormal . The methylation of the promoter may lead to a decrease in the expression of GSTM3 gene , inhibit its anti - oxidation function , increase the degree of oxidative damage , and detect the promoter methylation of the gene as an important index to judge the prognosis of ACHBLF .

Purpose

The aim of this study was to investigate the relationship between the methylation status of GSTM3 gene promoter and oxidative stress in patients with ACHBLF by detecting the level of serum MDA and GST expression , and to explore the relationship between methylation status and oxidative stress in patients with ACHBLF .

method

The methylation state of GSTM3 gene was detected by methylation - specific polymerase chain reaction ( MSP ) , and the methylation status of GSTM3 gene was determined by enzyme - linked immunosorbent assay ( ELISA ) . The level of serum MDA and GST were measured by enzyme - linked immunosorbent assay ( ELISA ) , and the correlation between the level of MDA and GST in patients with ACHBLF was analyzed .

All the statistical treatments were analyzed by SPSS 13.0 for Windows . The comparison of MDA and GST levels between the groups was independent of t - test , and the correlation between MDA and GST levels and the integration of MELD was analyzed by using the spearman ' s test ( P0.05 ) .

Results

1 . The level of serum MDA in ACHBLF group ( 13.45 鹵 5.41 pmol / mg ) was significantly higher than that in group B ( 9.387 鹵 5.332 pmol / mg , P = 0 . 011 ) .

2 . The serum MDA level ( 16.956 鹵 . 155pmol / mg ) in the ACHBLF methylated group was significantly higher than that in the non - methylation group ( 11.369 鹵 5.553pmol / mg , P0.001 ) .

3 . The serum GST level of ACHBLF group ( 1318 . 81 鹵 273 . 887mIU / L ) was significantly higher than that in group B ( 666.832 鹵 181.267mIU / L , P0.001 ) .

4 . The serum GST levels of ACHBLF methylation group ( 131.678 鹵 236.841mIU / L ) were not statistically significant ( 1262.253 鹵 202.782mIU / L , P = 0.170 ) .

5 . The level of serum MDA in ACHBLF group was positively correlated with the integration of MELD ( r = 0.588 , P = 0.001 ) , and serum GST level was not correlated with MELD integral ( r = 0.115 , P = 0.5546 ) .

Conclusion

The methylation status of the promoter of GSTM3 gene in ACHBLF was correlated with oxidative stress . The methylation of the promoter was involved in oxidative stress on the liver function of patients with HBV infection , and the degree of oxidative stress injury was positively correlated with the severity of the patient ' s disease , thus providing theoretical basis for the treatment of ACHBLF .

【學(xué)位授予單位】：山東大學(xué)
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2013
【分類號(hào)】：R575.3;R512.62

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