本文關(guān)鍵詞： 慢加急性乙型肝炎 肝衰竭 SOCS1 甲基化 免疫損傷 糖皮質(zhì)激素　出處：《山東大學(xué)》2014年博士論文　論文類(lèi)型：學(xué)位論文

【摘要】：中文摘要第一部分SOCSl基因在慢加急性乙型肝炎肝衰竭中的表達(dá)及其甲基化狀態(tài)的檢測(cè) 研究背景 慢加急性乙型肝炎肝衰竭(Acute-on-chronic hepatitis B liver failure, ACHBLF)是指由乙型肝炎病毒(Hepatitis B virus, HBV)慢性感染的基礎(chǔ)上,出現(xiàn)急性肝功能失代償,繼發(fā)嚴(yán)重的肝臟損害的嚴(yán)重癥候群。ACHBLF在我國(guó)慢性乙型肝炎患者中發(fā)病率較高,以凝血功能障礙,黃疸,肝性腦病,腹水為主要表現(xiàn),最終導(dǎo)致多器官功能障礙綜合征,病程兇險(xiǎn)死亡率極高。目前,細(xì)胞因子在肝衰竭的發(fā)病機(jī)制中的作用日益受到人們的重視,一方面細(xì)胞因子可使淋巴細(xì)胞活化,參與免疫反應(yīng)清除病毒；另一方面細(xì)胞因子直接參與和加重肝衰竭的演變過(guò)程,引起免疫病理反應(yīng)導(dǎo)致肝細(xì)胞的壞死。 細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)抑制因子(Suppressor of cytokine signaling, SOCS)1屬于SOCS蛋白家族,是一類(lèi)由細(xì)胞產(chǎn)生并反饋性阻斷細(xì)胞因子信號(hào)轉(zhuǎn)導(dǎo)過(guò)程的負(fù)性調(diào)節(jié)因子之一。研究發(fā)現(xiàn)SOCS1可通過(guò)負(fù)反饋環(huán)抑制炎癥細(xì)胞因子信號(hào)的傳導(dǎo),在多種免疫反應(yīng)中發(fā)揮重要作用。而HBV可能導(dǎo)致宿主基因甲基化,使SOCS1表達(dá)降低,對(duì)炎癥因子的抑制作用減弱,可能會(huì)加重肝臟的炎癥損害。 研究表明,SOCS1基因的甲基化與慢性病毒性肝炎的炎癥、纖維化及抗病毒治療存在著一定的相關(guān)性。但是在慢加急性乙型肝炎肝衰竭中SOCS1基因表達(dá)及啟動(dòng)子的甲基化的情況與炎癥因子的關(guān)系還未有研究。 研究目的 通過(guò)檢測(cè)ACHBLF患者外周血單個(gè)核細(xì)胞內(nèi)SOCS1的mRNA表達(dá)情況、啟動(dòng)子區(qū)甲基化狀態(tài)及血漿中相關(guān)炎癥因子白介素-6(interleukin-6,IL-6)、干擾素-γ(interferon-γ, IFN-γ)和腫瘤壞死因子-α (tumor necrosis factor-α, TNF-α)水平。并與慢性乙型病毒性肝炎(CHB)患者及正常人進(jìn)行比較,分析SOCS1的甲基化與肝臟免疫損傷的關(guān)系,并初步探討其在慢加急性乙型肝炎肝衰竭患者發(fā)病機(jī)制中的作用及臨床相關(guān)性。 研究方法 研究對(duì)象為2009年6月到2013年3月問(wèn)在山東大學(xué)齊魯醫(yī)院和煙臺(tái)傳染病醫(yī)院就診和治療的60例ACHBLF患者,60例CHB患者,以及30例門(mén)診健康體檢者作為對(duì)照。ACHBLF患者診斷符合亞太肝臟研究協(xié)會(huì)年會(huì)(APASL)標(biāo)準(zhǔn)。采用實(shí)時(shí)熒光定量PCR(real-time quantitative PCR, RT-PCR)方法檢狽ACHBLF、CHB患者及健康對(duì)照外周血單個(gè)核細(xì)胞中SOCSl的表達(dá)情況,并通過(guò)甲基化特異性PCR(Methylation-specific PCR, MSP)檢測(cè)SOCSl啟動(dòng)子區(qū)的甲基化狀態(tài)。應(yīng)用酶聯(lián)免疫吸附劑測(cè)定(Enzyme linked immunosorbent assay, ELISA)方法檢測(cè)ACHBLF、CHB患者及健康對(duì)照血漿中IL-6,IFN-γ和TNF-α的水平。并將SOCS1表達(dá)量IL-6,IFN-γ和TNF-α的水平與病情嚴(yán)重指標(biāo)總膽紅素(Total bilirubin, TBIL)、凝血酶原活動(dòng)度(Prothrombin activity, PTA)、血清丙氨酸轉(zhuǎn)氨酶(Alanine aminotransferase, ALT)、HBV-DNA及MELD評(píng)分進(jìn)行相關(guān)分析。比較不同SOCS1基因啟動(dòng)子去甲基化狀態(tài)患者臨床指標(biāo)及預(yù)后。統(tǒng)計(jì)學(xué)分析采用SPSS13.0軟件包進(jìn)行,結(jié)果用均數(shù)±標(biāo)準(zhǔn)差(x±s)表示,組間差異采用兩組獨(dú)立樣本資料的t檢驗(yàn)或卡方檢驗(yàn),相關(guān)分析采用Pearson線性相關(guān)分析。P0.05為差異具有統(tǒng)計(jì)學(xué)意義。 研究結(jié)果 1.ACHBLF患者組和CHB患者組血漿IL-6及TNF-α水平明顯高于健康對(duì)照組(P0.05)；ACHBLF患者組的IL-6及TNF-α水平在三組中最高,明顯高于CHB患者組(P0.05)。ACHBLF患者組血漿IFN-γ水平明顯高于CHB患者組,但與健康對(duì)照組相比無(wú)明顯統(tǒng)計(jì)學(xué)差異。 2.ACHBLF及CHB患者的SOCS1mRNA表達(dá)量明顯高于健康對(duì)照組(P0.01)；ACHBLF患者組的SOCS1表達(dá)量明顯高于CHB患者組(P0.05)。 3.ACHBLF患者細(xì)胞因子IL-6/IFN-γ/TNF-α水平與TBIL、ALT及MELD評(píng)分呈正相關(guān),與PTA呈負(fù)相關(guān),與HBV-DNA載量無(wú)明顯相關(guān)性。 4ACHBLF患者的SOCS1基因mRNA水平與TBIL、ALT成負(fù)相關(guān),與PTA成正相關(guān)。另夕SOCS1表達(dá)量與ACHBLF患者IL-6/IFN-γ/TNF-α水平分別成負(fù)相關(guān)。與HBV DNA載量及MELD評(píng)分無(wú)明顯相關(guān)性。 5ACHBLF患者組的SOCS1基因啟動(dòng)子的甲基化率(35.0%)明顯高于CHB患者組(16.7%,χ2=3.52,P=0.003),在30例健康對(duì)照中均未發(fā)現(xiàn)SOCS1啟動(dòng)子區(qū)的甲基化。 6.在ACHBLF及CHB患者患者中,甲基化組的SOCS1基因表達(dá)量明顯低于非甲基化組。ACHBLF患者SOCS1啟動(dòng)子區(qū)甲基化組的IL-6/IFN-γ/TNF-α水平、TBIL和ALT水平明顯高于非甲基化組,而PTA水平則明顯低于非甲基化組。另外,ACHBLF患者甲基化組的MELD積分及死亡率高于非甲基化組。 結(jié)論 SOCS1的表達(dá)量與患者的病情嚴(yán)重程度成負(fù)相關(guān),SOCS1基因啟動(dòng)子區(qū)的甲基化可能參與了相關(guān)炎癥因子對(duì)慢加急性乙型肝炎肝衰竭患者肝功能的免疫損害。 中文摘要第二部分SOCS1基因甲基化及表達(dá)與糖皮質(zhì)激素治療慢加急性乙型肝炎肝衰竭的研究 研究背景 慢加急性肝衰竭的發(fā)生不同時(shí)相依次經(jīng)受了免疫損傷、缺血缺氧性損傷和內(nèi)毒素血癥的三重打擊,其中炎癥因子參與的免疫損傷在肝衰竭發(fā)生中起著至關(guān)重要的作用。肝病尤其是肝衰竭患者普遍存在著腎上腺功能不全的情況,因此早期使用糖皮質(zhì)激素是治療慢加急性肝衰竭的方法之一,近年來(lái)隨著對(duì)糖皮質(zhì)激素不良反應(yīng)及并發(fā)癥防治手段的增強(qiáng),使用糖皮質(zhì)激素調(diào)節(jié)患者機(jī)體免疫功能、抑制炎性反應(yīng)已經(jīng)成為治療慢加急性肝衰竭的一種選擇。 第一部分的研究已經(jīng)證實(shí)了SOCS1基因啟動(dòng)子區(qū)的甲基化參與了相關(guān)炎癥因子對(duì)ACHBLF患者的肝功能損害。但ACHBLF患者中糖皮質(zhì)激素對(duì)SOCS1的影響及對(duì)患者預(yù)后是否有提示作用尚未有研究。既往研究資料證實(shí)糖皮質(zhì)激素在體內(nèi)、體外環(huán)境均能夠促進(jìn)SOCS1基因表達(dá)并引起甲基化狀態(tài)改變。據(jù)此我們推測(cè)對(duì)ACHBLF患者采用糖皮質(zhì)激素治療可能影響SOCS1對(duì)相關(guān)的炎癥反應(yīng)的調(diào)控。本研究有助于我們認(rèn)識(shí)糖皮質(zhì)激素治療對(duì)ACHBLF患者SOCS1的表達(dá)及甲基化狀態(tài)的影響,揭示SOCS1對(duì)糖皮質(zhì)激素治療ACHBLF的提示作用,為提供臨床治療理論依據(jù)和新的途徑。 研究目的 通過(guò)研究糖皮質(zhì)激素治療對(duì)ACHBLF患者SOCS1表達(dá),甲基化狀態(tài)及相關(guān)基因、細(xì)胞因子的影響,進(jìn)一步探討分析SOCS1表達(dá)與糖皮質(zhì)激素激素治療預(yù)后的相關(guān)性。 研究方法 研究對(duì)象為2007年12月到2013年5月間在山東大學(xué)齊魯醫(yī)院就診和治療的ACHBLF患者47例,以及30例門(mén)診健康體檢者作為對(duì)照。ACHBLF患者診斷符合亞太肝臟研究協(xié)會(huì)年會(huì)(APASL)標(biāo)準(zhǔn)。所有ACHBLF患者確診后均給予糖皮質(zhì)激素治療4周。應(yīng)用RT-PCR法檢鋇ACHBLF患者治療前,治療第3天及治療28天后SOCSl及干擾素調(diào)節(jié)受體(interferon regulatory factors, IRF)-1,趨化因子配體(C-X-C motif ligand, CXCL)9, CXCL10, CXCL11的表達(dá)情況,應(yīng)用ELISA技術(shù)檢測(cè)ACHBLF患者和健康對(duì)照血漿中IL-6及TNF-α水平,結(jié)合患者臨床指標(biāo),與MELD評(píng)分進(jìn)行相關(guān)分析,用甲基化特異性PCR法(Methylation Specific PCR,MSP)測(cè)定SOCSl基因啟動(dòng)子的甲基化狀態(tài),分析糖皮質(zhì)激素對(duì)SOCSl基因啟動(dòng)子區(qū)甲基化狀態(tài)的影響,探討SOCSl表達(dá)與糖皮質(zhì)激素治療的相關(guān)性。統(tǒng)計(jì)學(xué)分析采用SPSSl3.0軟件包進(jìn)行,結(jié)果用均數(shù)±標(biāo)準(zhǔn)差(x±s)表示,組間差異采用兩組獨(dú)立樣本資料的t檢驗(yàn),相關(guān)分析采用Pearson線性相關(guān)分析。P0.05為差異具有統(tǒng)計(jì)學(xué)意義。 研究結(jié)果 1.激素治療后ACHBLF患者肝性腦病和腹水癥狀均有明顯改善。MELD積分明顯下降。 2.激素治療前,ACHBLF患者SOCS1基因mRNA基因表達(dá)水平明顯高于健康對(duì)照(P0.05)；ACHBLF生存組的SOCS1mRNA表達(dá)量明顯高于死亡組(P=0.007)。激素治療第三天,生存組SOCS1表達(dá)量上升；治療第28天,生存組SOCSl基因(?)mRNA表達(dá)量明顯下降,而死亡組在治療中及治療后SOCS1基因mRNA表達(dá)量無(wú)明顯變化。 3.激素治療前,ACHBLF患者血漿IL-6及TNF-α水平明顯高于健康對(duì)照(P0.05)；激素治療后第三天,ACHBLF患者IL-6及TNF-α水平出現(xiàn)明顯下降,其中死亡組TNF-α水平明顯高于生存組,而兩組IL-6水平在治療第3天無(wú)明顯差異。激素治療第28天,生存組IL-6及TNF-α水平均明顯低于死亡組(P0.05)。ACHBLF患者中IFN-γ及STATl相關(guān)基因表達(dá)量與健康對(duì)照相比均有不同程度上升,并在激素治療3天出現(xiàn)明顯下降,在第28天下降均超過(guò)30%。 4.SOCS1表達(dá)水平與MELD積分在激素治療前、后均存在明顯的負(fù)相關(guān)性。 5.激素治療前,ACHBLF患者TBIL水平明顯高于健康對(duì)照(P0.05),PTA水平明顯低于健康對(duì)照；ACHBLF患者生存組與死亡組TBIL及PTA水平無(wú)明顯差別(P0.05)。激素治療第28天,生存組患者TBIL水平明顯下降,PTA明顯上升；而死亡組無(wú)明顯改善。在90天隨訪結(jié)束時(shí)采用激素治療的ACHBLF患者死亡率為52.3%。采用小樣本生存率估計(jì)(Kaplan-Meier法)對(duì)最初存在甲基化及無(wú)甲基化的患者分別進(jìn)行生存分析,發(fā)現(xiàn)激素治療能夠明顯提高SOCS1非甲基化患者的生存率(P0.05)。 6.激素治療前有34%的ACHBLF患者存在SOCS1基因的甲基化情況,而30例健康對(duì)照中均未發(fā)現(xiàn)SOCS1啟動(dòng)子區(qū)的甲基化。激素治療第3天MSP檢測(cè)ACHBLF患者未發(fā)現(xiàn)甲基化狀態(tài)明顯改變,激素治療第28天檢測(cè)發(fā)現(xiàn),8名最初存在SOCSl基因啟動(dòng)子甲基化的患者未檢測(cè)至SOCS1的甲基化狀態(tài),其中全部6名最初存在甲基化的生存組患者中有5人出現(xiàn)去甲基化,而l0例死亡組患者中僅有3例出現(xiàn)了去甲基化情況。結(jié)論慢加急性乙型肝炎肝衰竭患者中,早期應(yīng)用糖皮質(zhì)激素能夠明顯改善患者肝功能,提高SOCS1基因非甲基化者的生存率,而出現(xiàn)SOCS1甲基化的ACHBLF患者對(duì)糖皮質(zhì)激素治療效果反應(yīng)較差,死亡率明顯高于無(wú)甲基化的患者,預(yù)后不良。通過(guò)檢測(cè)ACHBLF患者SOCS1基因甲基化狀態(tài),或許可以成為使用糖皮質(zhì)激素治療ACHBLF篩選條件。
[Abstract]:Expression of SOCSl gene in the first part of Chinese abstract in chronic hepatitis B liver failure and its methylation status
Research background
Chronic liver failure in patients with acute hepatitis B (Acute-on-chronic hepatitis B liver failure, ACHBLF) is defined by the hepatitis B virus (Hepatitis B, virus, HBV) of chronic infection, acute hepatic decompensation, severe.ACHBLF syndrome secondary to severe liver damage in patients with chronic hepatitis B in China in high incidence the blood coagulation dysfunction, jaundice, hepatic encephalopathy, ascites as the main performance, resulting in multiple organ dysfunction syndrome, patients who a high mortality rate. At present, the role of cytokines in the pathogenesis of liver failure has attracted more and more attention on the one hand, cytokines can make lymphocyte activation, the immune response is involved in the clearance of the virus; the evolution of the other on the one hand, cytokines and direct participation of the aggravation of liver failure, caused by the pathological immune response leading to liver cell necrosis.
Suppressor of cytokine signaling (Suppressor of cytokine signaling SOCS, 1) belongs to SOCS protein family, is a kind of feedback produced by cells and blocking negative cytokine signal transduction factor. The study found that SOCS1 can be inhibited by the negative feedback loop of inflammatory cytokine signal transduction, play an important role in variety immune response. HBV may lead to host gene methylation, SOCS1 expression decreased, decreased inhibition of inflammatory factor, inflammation may aggravate the liver damage.
Studies show that inflammation and methylation of SOCS1 gene in chronic viral hepatitis, fibrosis and antiviral therapy, there is a certain correlation. But the relationship in chronic liver failure acute hepatitis B SOCS1 and inflammatory cytokines gene expression and promoter methylation of the not yet studied.
research objective
The expression of ACHBLF was detected by peripheral blood mononuclear cells of patients with SOCS1 in the mRNA, starting state and hypermethylation in plasma inflammatory cytokines interleukin -6 (interleukin-6, IL-6), interferon gamma (interferon- y, IFN- y) and tumor necrosis factor alpha (tumor alpha factor- alpha necrosis, TNF-) level and with chronic hepatitis B (CHB) patients and normal people were compared, analysis of the relationship between SOCS1 methylation and liver immune injury, and investigate the acute on chronic hepatitis B liver failure patients with the pathogenesis and clinical relevance.
research method
The object of the study is from June 2009 to March 2013. In 60 cases of ACHBLF patients in Qilu Hospital of Shandong University and Yantai infectious disease hospital and treatment, 60 cases of CHB patients, and 30 cases of healthy volunteers as control patients with.ACHBLF diagnosis in line with the Asia Pacific Association for the study of the liver (APASL) annual meeting standard. By using real-time quantitative PCR (real-time quantitative PCR, RT-PCR methods both ACHBLF and CHB) patients and healthy controls SOCSl in peripheral blood mononuclear cells of the expression, and by methylation specific PCR (Methylation-specific PCR, MSP SOCSl) to detect the methylation status of the promoter region. The application of enzyme linked immunosorbent assay (Enzyme linked immunosorbent assay, ELISA) method for detection of ACHBLF CHB patients and healthy controls, plasma IL-6, IFN- y and TNF- a level. And the SOCS1 expression of IL-6, IFN- and TNF- level with the severity of gamma alpha severity index, total cholesterol Red pigment (Total bilirubin, TBIL), prothrombin activity (Prothrombin, activity, PTA), serum alanine aminotransferase (Alanine, aminotransferase, ALT), HBV-DNA and MELD score were analyzed. Comparison of SOCS1 gene promoter methylation in patients with clinical parameters and prognosis. The data were analyzed by SPSS13.0 software, the results were standard deviation (x + s) said, the differences between groups using two independent samples t test or chi square test and correlation analysis using Pearson correlation analysis.P0.05 was statistically significant difference.
Research results
1.ACHBLF patients and CHB patients. Plasma IL-6 and TNF- levels were significantly higher than those in healthy control group (P0.05); IL-6 and TNF- levels in patients with ACHBLF group is the highest in the three group, was significantly higher than that in the group of CHB (P0.05).ACHBLF plasma IFN- in patients with gamma levels were significantly higher than that in CHB group, but compared with the healthy control group no statistically significant difference.
The expression of SOCS1mRNA in the patients with 2.ACHBLF and CHB was significantly higher than that in the healthy control group (P0.01), and the SOCS1 expression in the ACHBLF group was significantly higher than that in the CHB group (P0.05).
The level of cytokine IL-6/IFN- gamma /TNF- alpha in patients with 3.ACHBLF was positively correlated with TBIL, ALT and MELD scores, negatively correlated with PTA, and had no significant correlation with HBV-DNA load.
The mRNA level of SOCS1 gene in 4ACHBLF patients was negatively correlated with TBIL and ALT, and positively correlated with PTA. There was a negative correlation between SOCS1 expression level and IL-6/IFN- gamma /TNF- alpha level in ACHBLF patients. There was no significant correlation between IL-6/IFN- level and IL-6/IFN- score.
The methylation rate of SOCS1 gene promoter in 5ACHBLF group (35%) was significantly higher than that in CHB group (16.7%, 2=3.52, P=0.003), and no methylation in SOCS1 promoter region was found in 30 healthy controls.
6. in ACHBLF and CHB patients, the methylation of SOCS1 gene expression group was significantly lower than the non methylation group of.ACHBLF patients with SOCS1 promoter methylation group IL-6/IFN- gamma /TNF- levels, TBIL and ALT were significantly higher than those in non methylation group, while the level of PTA was significantly lower than that of non methylation group. In addition, MELD integral and mortality in patients with ACHBLF methylation group was higher than that in non methylation group.
conclusion
The expression level of SOCS1 is negatively correlated with the severity of the disease. The methylation of SOCS1 promoter region may be involved in the immune damage of inflammatory factors related to liver function in patients with chronic hepatitis B and liver failure.
Study on the methylation and expression of SOCS1 gene in second parts of Chinese abstract and glucocorticoid therapy for chronic hepatitis B liver failure
Research background
Acute on chronic liver failure and the time dependent undergo immune injury, three against ischemia injury and endotoxemia, the immune inflammatory factors involved in the injury plays a crucial role in liver failure. Liver disease especially in patients with liver failure exists in adrenal insufficiency, so early the use of corticosteroids is the treatment of acute on chronic liver failure in recent years, with the increase of glucocorticoid adverse reaction and complication prevention and treatment, the use of corticosteroids and regulating the immune function of patients, inhibiting the inflammatory reaction has become a choice for the treatment of acute on chronic liver failure.
The first part of the study has confirmed that the SOCS1 gene promoter methylation in liver damage related inflammatory factors in the patients with ACHBLF. But the effect of glucocorticoid on patients with ACHBLF and SOCS1 on the prognosis of patients have suggested a role has not been studied. Previous studies have confirmed that glucocorticoids in vivo and in vitro environment can promote the expression of SOCS1 gene and cause the methylation status change. So we presumed that the ACHBLF patients were treated by glucocorticoid therapy may affect SOCS1 on inflammation related regulation. Help our understanding of glucocorticoid expression and methylation status of ACHBLF SOCS1 in this study revealed that the SOCS1 of suggesting the role of sugar corticosteroids in the treatment of ACHBLF, in order to provide theoretical basis for clinical treatment and new ways.
research objective
Objective to investigate the correlation between SOCS1 expression, methylation status and related genes and cytokines in patients with ACHBLF after glucocorticoid treatment, and further explore the correlation between SOCS1 expression and prognosis of glucocorticoid treatment.
research method
The object of the study is from December 2007 to May 2013 in Qilu Hospital of Shandong University and 47 cases of ACHBLF patients, and 30 cases of healthy volunteers as control patients with.ACHBLF diagnosis in line with the Asia Pacific Association for the study of the liver (APASL) annual meeting standard. All ACHBLF patients were treated with glucocorticoid treatment for 4 weeks. The application of RT-PCR method of detecting ACHBLF patients before treatment, after treatment for third days and 28 days after SOCSl and interferon regulatory receptor (interferon regulatory factors, IRF -1), chemokine ligand (C-X-C motif ligand, CXCL 9, CXCL10), the expression of CXCL11, ELISA was used to detect ACHBLF patients and healthy controls IL-6 and serum TNF- level in plasma, combined with clinical indicators patients with MELD score correlation analysis of specific PCR (Methylation Specific PCR, methyl MSP) determination of methylation status of SOCSl gene promoter and analysis of sugar Effect of promoter methylation status of SOCSl gene promoter of the cortical hormone, to investigate the correlation between SOCSl expression and glucocorticoid treatment. The data were analyzed by SPSSl3.0 software, the standard deviation (x + s), t group difference test using two independent sample data, correlation analysis using Pearson.P0.05 linear correlation analysis for the difference was statistically significant.
Research results
After 1. hormone treatment, the symptoms of hepatic encephalopathy and ascites in ACHBLF patients were obviously improved and the.MELD score was obviously decreased.
2. hormone therapy before ACHBLF gene in patients with SOCS1 gene expression level of mRNA was significantly higher than that of healthy controls (P0.05); the expression of ACHBLF in the survival group SOCS1mRNA was significantly higher than that of death group (P=0.007). Hormone therapy for third days, the survival group SOCS1 expression increased; on the twenty-eighth day of treatment, the survival group SOCSl gene (?) the expression of mRNA was significantly decreased however, the death group during treatment and after treatment of SOCS1 gene mRNA expression had no obvious change.
3. hormone therapy before IL-6 and TNF- levels in plasma of patients with ACHBLF was significantly higher than that of healthy controls (P0.05); third days after hormone therapy in patients with ACHBLF, IL-6 and TNF- levels decreased significantly, the death group TNF- levels were significantly higher than the survival group, but the level of IL-6 in the two groups for third days. No significant differences in hormone therapy the twenty-eighth day survival group IL-6 and TNF- alpha levels were significantly lower than the death group (P0.05) and gamma STATl related gene expression of IFN- and healthy controls increased in varying degrees of.ACHBLF patients, and in 3 days of hormone treatment decreased significantly, reduced more than 30%. in the twenty-eighth world
There was a significant negative correlation between the expression level of 4.SOCS1 and the MELD score before the treatment of the hormone.
5. hormones before treatment, the level of TBIL in patients with ACHBLF was significantly higher than that of healthy controls (P0.05), the level of PTA was significantly lower than the healthy control group; no significant difference in survival of patients with ACHBLF and TBIL and PTA level in the death group (P0.05). The twenty-eighth day survival hormone therapy, patients in group TBIL were decreased and PTA increased significantly; and the death group had no obvious improved. At the end of the 90 day follow-up with mortality in patients with hormone therapy for ACHBLF 52.3%. using the small sample survival rate (Kaplan-Meier method) for initial methylation and non methylation were survival analysis, found that hormone therapy can significantly improve the survival rate of SOCS1 methylation in patients (P0.05).
6. hormone therapy before 34% ACHBLF patients have the methylation status of SOCS1 gene, and 30 healthy controls were not found in methylation of SOCS1 promoter region. Hormone therapy third days MSP detection of ACHBLF patients found no methylation changes obviously, hormone therapy twenty-eighth days detected 8 initial SOCSl gene promoter hypermethylation of patients not detected to SOCS1 methylation, in which all 6 initial methylation in patients with survival group 5 showed demethylation, and l0 cases of death in patients with only 3 cases appeared demethylation. Conclusion patients with acute on chronic hepatitis B liver failure in early stage glucocorticoids can significantly improve the liver function of patients, improve the survival rate of SOCS1 gene in non methylation, and SOCS1 methylation of ACHBLF in patients with poor response to glucocorticoid treatment, mortality was significantly higher than those without Patients with methylation have poor prognosis. By detecting the methylation status of the SOCS1 gene in ACHBLF patients, it may be possible to be used as a glucocorticoid 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】：2014
【分類(lèi)號(hào)】：R512.62;R575.3

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本文編號(hào)：1525320