Nomogram prediction of individual prognosis of patients with acute-on-chronic hepatitis B liver failure

Background

The current definitions and etiologies of acute-on-chronic liver failure (ACLF) are clearly very different between East and West.

四种评分模型对慢加急性乙型肝炎肝衰竭患者短期预后的评价

目的比较终末期肝病模型（MELD）、MELD-Na、慢性重型肝炎预后指数（PI）和肝移植标准（LTS）模型对慢加急性乙型肝炎肝衰竭患者短期预后的预测价值.方法在138例慢加急性乙型肝炎肝衰竭患者入院24小时内进行MELD、MELD-Na、PI和LTS评分,并随访3个月.应用受试者工作特征曲线（ROC）下面积（AUC）判断四个模型的预测能力.结果在观察期内与肝病有关的死亡患者72例,生存者66例.死亡组LTS、MELD-Na、MELD和PI平均值明显高于生存组（P〈0.01）,四个模型的AUC分别为0.860、0.801、0.749、和0.749,差异无统计学意义;四个模型预测的正确率分别为82.61%、76.81%、75.36%和73.91%,差异无统计学意义.结论4种模型对慢加急性乙型肝炎肝衰竭患者短期预后均有较好的预测价值.     

Aberrant methylation of UBE2Q1 promoter is associated with poor prognosis of acute-on-chronic hepatitis B pre-liver failure

Acute-on-chronic hepatitis B liver failure (ACHBLF) is one severe liver disease with rapid progression and high mortality. Identification of specific markers for the prediction of ACHBLF has important clinical significance. We explored the feasibility of UBE2Q1 gene promoter methylation as an early prediction and prognosis biomarker of ACHBLF.UBE2Q1 promoter methylation frequency was detected in 60 patients with acute-on-chronic hepatitis B pre-liver failure (Pre-ACHBLF), 40 patients with chronic hepatitis B and 20 cases of healthy control (HC). The UBE2Q1 mRNA was detected by quantitative real-time polymerase chain reaction.The methylation frequency of the UBE2Q1 promoter in pre-ACHBLF patients was 38.33%, which was significantly lower than that in chronic hepatitis B patients (60.00%) and HCs (65.00%). The UBE2Q1 mRNA expression in pre-ACHBLF patients with UBE1Q1 non-methylation was significantly higher than that in patients with UBE1Q1 promoter methylation. Further analysis showed that hypomethylation of the UBE2Q1 promoter was positively correlated with total bilirubin and international normalized ratio levels in patients with pre-ACHBLF, but negatively correlated with PTA level. COX multivariate analysis showed that the model for end-stage liver disease score and UBE2Q1 promoter hypomethylation status were potential early warning factors that can predict the progression of pre-ACHBLF to ACHBLF. The sensitivity and specificity of UBE2Q1 promoter methylation status combined with the model for end-stage liver disease score for early diagnosis of ACHBLF were 92.9% and 75.0%, respectively. The area under the receiver-operating characteristic curve was 0.895.The hypomethylation of UBE2Q1 promoter is associated with severity of Pre-ACHBLF, which could serve as a potential prognostic biomarker for pre-ACHBLF.     

慢加急性/亚急性乙型肝炎肝衰竭患者发病诱因及影响临床转归因素分析*

目的 分析乙型肝炎相关性慢加急性(亚急性)肝衰竭(HBV-ACLF)患者发病诱因和影响临床转归的因素。方法 2019年1月～2021年12月我科收治的96例HBV-ACLF患者,接受内科综合治疗,观察90 d生存情况。应用单因素和多因素Logistic回归分析影响HBV-ACLF患者临床转归的因素。结果 本组HBV-ACLF患者发病诱因包括自行停用核苷(酸)类药物53例(55.2%)、并发HAV或HEV感染11例(11.4%)、并发细菌感染9例(9.4%)、劳累7例(7.3%)、饮酒6例(6.2%)、药物性肝损害5例(5.2%)和原因不明5例(5.2%);在治疗观察90 d,生存69例,死亡27例;死亡患者年龄为50(41,69)岁,显著大于生存患者【39(33,58),P<0.05】,并发消化道出血、肝性脑病和急性肾损伤的比率分别为14.8%、29.6%和44.4%,显著高于生存患者(分别为1.4%、5.8%和14.5%,P<0.05),血清总胆红素水平为532(204,780)μmol/L,显著高于生存组【302(80,416)μmol/L,P<0.05】,INR为3.0(2.0,3.4),显著大于生存患者【2.1(1.5,2.6),P<0.05】,MELD评分为26(18,37),显著大于生存患者【20(10,29),P<0.05】;多因素Logistic回归分析结果显示年龄【OR=1.04(95%CI:1.02～1.08)】、并发消化道出血【OR=1.51(95%CI:1.23～0.79)】、肝性脑病【OR=0.50(95%CI:0.22～0.78)】、INR【OR=1.52(95%CI:1.22～0.73)】和MELD评分【OR=2.44(95%CI:1.63～3.75)】均是影响HBV-ACLF患者死亡发生的独立危险因素。结论 熟知诱发HBV-ACLF患者发病的诱因有助于做好防治工作,而针对能引起患者死亡的因素做好临床救治可能提高肝衰竭患者生存率,临床和社会意义重大。     

Serum levels of miRNA in patients with hepatitis B virus-associated acute-on-chronic liver failure

Background: Hepatitis B virus(HBV)-associated acute-on-chronic liver failure(HBV-ACLF) is a lifethreatening condition and its exact pathophysiology and progression remain unclear. The present study aimed to assess the role of serum mi RNAs in the evaluation of HBV-ACLF and to develop a model to predict the outcomes for ACLF.Methods: Serum was collected from 41 chronic hepatitis B and 55 HBV-ACLF patients in addition to30 chronic asymptomatic HBV carriers as controls. The mi RNAs expressions were measured by real-time quantitative PCR(q-PCR). Statistical analyses were conducted to assess the ability of differentially expressed mi RNAs and other prognostic factors in identifying ACLF prognosis and to develop a new predictive model.Results: Real-time q-PCR indicated that serum miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p levels were significantly upregulated in ACLF patients compared to chronic hepatitis B and chronic asymptomatic HBV carriers patients. In addition, multivariate regression analyses indicated that Na+, INR, gastrointestinal bleeding and mi R-122-3 p are all independent factors that are reliable and sensitive to the prognosis of HBV-ACLF. Therefore, we developed a new model for the prediction of HBV-ACLF disease state: Y = 0.402 × Na+-1.72 × INR-4.963 × gastrointestinal bleeding(Yes = 0; No = 1)-0.278 ×(mi R-122-3 p) + 50.449. The predictive accuracy of the model was 95.3% and the area under the receiver operating characteristic curve(AUROC) was 0.847.Conclusions: Expression levels of these mi RNAs(miR-146 a-5 p, mi R-122-3 p and mi R-328-3 p) positively correlate with the severity of liver inflammation in patients with ACLF and may be useful to predict HBV-ACLF severity.     

HBV相关慢加急性肝衰竭患者预后及其影响因素分析*

目的 探讨影响乙型肝炎相关性慢加急性肝衰竭（ACLF）患者预后的因素。方法 2014年5月~2017年5月我院诊治的ACLF患者120例,给予内科综合治疗和人工肝治疗,回顾性分析其临床资料,应用二元多因素Logistic回归分析影响预后的因素。结果 经过3~6个月治疗,本组患者生存52例（43.3%）,死亡68例（56.7%）;两组患者性别、发病前病程、长期抗病毒和是否接受人工肝治疗等方面无显著性差异（P>0.05）,但生存组年龄≥50岁的比例和并发症发生率分别为40.4%和46.1%,均显著低于死亡组的61.8%和79.4%（P<0.05）;两组血清PAB、TBA、BUN、Cr和HBV DNA水平差异无显著性统计学意义（P>0.05）,但生存组患者血清TBIL和PT水平显著低于死亡组（P<0.05）,血清Alb、CHE、TC和AFP水平显著高于死亡组（P<0.05）;生存组肝性脑病、肝肾综合征、电解质紊乱和多种并发症发生率分别为7.7%、1.9%、15.4%和11.5%,显著低于死亡组的45.6%、14.7%、39.7%和26.5%（P<0.05）,而两组上消化道出血和自发性细菌性腹膜炎发生率比较,无显著性差异（P>0.05）;将血清TBIL、Alb、CHE、PT、TC、AFP、年龄和并发症作为自变量,预后结果作为应变量,经二元多因素Logistic回归分析发现,年龄、PT、肝性脑病、电解质紊乱和并发症发生是HBV相关的ACLF患者预后的独立影响因素。结论 了解影响乙型肝炎导致的ACLF患者预后的因素,做到早诊断,早治疗,把好可能导致死亡因素的治疗关,积极防治各种并发症,才能提高救治ACLF患者的成功率。     

HBV相关慢加急性肝衰竭不同分期的预后评价及影响因素分析

目的评价不同分期慢性HBV感染相关慢加急性肝衰竭的预后,并分析影响预后的因素。方法回顾性分析180例慢加急性肝衰竭（ACLF）患者的住院生存时间,通过Logistic回归与Cox回归分析不同预后的影响因素。结果 Kaplan-Meier显示不同分期ACLF患者累积生存率存在统计学差异（P〈0.001）,早期、中期、晚期ACLF患者住院期间生存期逐渐缩短（P〈0.001）;Lo-gistic多因素回归显示,有无结肠灌肠、是否并发肝性脑病和/或肝肾综合征、PTA、TBil及Alb水平是影响ACLF患者生存与否的独立因素（P〈0.05或P〈0.01）;Cox回归多因素分析显示,有无结肠灌肠、是否并发肝性脑病、疾病分期、WBC及CHE水平为ACLF住院生存期的独立影响因素（P〈0.05或P〈0.01）。结论早期ACLF患者较中晚期ACLF患者预后好,基线WBC、TBil、CHE及Alb水平为ACLF患者预后的影响因素,结肠灌肠可能对提高生存率延长生存期有积极治疗意义。     

慢加急性乙型肝炎肝衰竭患者血清聚集素水平变化及其临床意义探讨*

目的 探讨慢加急性乙型肝炎肝衰竭(HBV-ACLF)患者血清聚集素水平变化及其临床意义。方法 2019年1月～2021年1月我院收治住院的HBV-ACLF患者48例和同期入院诊治的慢性乙型肝炎(CHB)患者60例,采用ELISA法检测血清聚集素水平。结果 HBV-ACLF组外周血白细胞计数、血清ALT、AST、TBIL和MELD评分分别为(8.0±2.8)×10⁹/L、(418.2±163.5)U/L、(386.1±139.2)U/L、(226.6±74.4)μmol/L和(23.2±5.3),显著高于CHB组【分别为(6.0±2.3)×10⁹/L、(163.8±75.7)U/L、(118.7±73.3)U/L、(25.6±12.4)μmol/L和(9.6±3.6),P<0.05】,而外周血PLT计数为(101.8±42.0)×10⁹/L,血清Alb水平为(32.6±7.6)g/L,PTA为(35.3±5.3)%,血清聚集素水平为(51.0±5.9)μg/mL,显著低于CHB组【分别为(128.5±54.4)×10⁹/L、(38.1±8.5)g/L、(77.4±9.3)%和(185.9±13.5)μg/mL,P<0.05】;9例HBV-ACLF晚期患者血清凝集素水平为(28.5±3.8)μg/mL,显著低于20例早期【(72.6±7.2)μg/mL,P<0.05】或19例中期【(46.0±5.2)μg/mL,P<0.05】患者,13例感染患者血清凝集素水平为(36.6±4.6)μg/mL,显著低于35例无感染患者【(56.6±6.1)μg/mL,P<0.05】,15例死亡患者血清凝集素水平为(39.8±4.3)μg/mL,显著低于33例生存患者【(72.3±7.6)μg/mL, P<0.05】;死亡患者血清总胆红素水平更高,MELD评分更高,PTA更低,并发肝性脑病为46.7%,并发肝肾综合征为40.0%,与生存患者比,差异显著(P<0.05)。结论 HBV-ACLF患者血清聚集素降低,其降低程度与预后相关,是否可作为一种潜在的生物标志物用于评估HBV-ACLF患者病情的严重程度和预后,值得进一步研究。     

慢加急性肝衰竭患者血清二胺氧化酶水平及其临床意义探讨*

目的 探讨乙型肝炎相关的慢加急性肝衰竭（ACLF）患者血清二胺氧化酶（DAO）水平及其评估患者预后的价值。方法 2014年8月~2017年4月我院收治的104例ACLF患者,在治疗60 d内,生存64例,死亡40例。采用酶联免疫吸附法检测血清DAO水平,采用二元Logistic回归分析影响患者预后的因素。结果 生存患者血清DAO水平为（15.1±4.8） ng/mL,显著低于死亡患者[（68.4±25.4） ng/mL,P<0.05];单因素分析显示年龄、TBIL、AST、ALT、INR、ALB、Cr、MEID评分、WBC、自发性细菌腹膜炎、肝性脑病、腹水和肝硬化与患者预后结局相关,多因素回归分析显示,MELD评分、年龄和血清DAO水平为影响患者预后的独立危险因素;DAO≥48.7 ng/mL与DAO<48.7 ng/mL患者生存率分别为50.0%和77.3%,差异有统计学意义（P<0.05）,MELD≥26.1分与MELD<26.1分患者生存率分别为45.5%和79.6%,差异有统计学意义（P<0.05）,年龄≥40岁与年龄<40岁的患者生存率分别为50.8%和79.5%,差异有统计学意义（P<0.05）。结论 血清DAO水平也可以判断ACLF患者预后,为判断肝衰竭患者预后增加了一个可应用的指标,其作用还有待于进一步研究。     

Soluble mannose receptor as a predictor of prognosis of hepatitis B virus-related acute-on-chronic liver failure

BACKGROUND Hepatitis B virus-related acute-on-chronic liver failure(HBV-ACLF) is a syndrome with a high short-term mortality rate, and it is crucial to identify those patients at a high mortality risk clinically.AIM To investigate the clinical value of soluble mannose receptor(sMR) in predicting the 90-day mortality of HBV-ACLF patients.METHODS A total of 43 patients were diagnosed with HBV-ACLF between October 2017 and October 2018 at the Second Hospital of Anhui Medical University, and all of them were enrolled in this retrospective study. Their serum sMR levels were determined using an enzyme-linked immunosorbent assay. Demographic and clinical data, including gender, age, albumin level, total bilirubin(TBIL) level,international normalized ratio, HBV-DNA level, HBV serological markers,procalcitonin level, interleukin-6 level, and model for end-stage liver disease(MELD) score were accessed at the time of diagnosis of HBV-ACLF. A multivariate logistic regression analysis was used to analyze the independent risk factors for mortality.RESULTS Serum sMR level was significantly increased in HBV-ACLF patients compared with chronic hepatitis B patients and healthy controls(P 0.01). When compared with surviving patients, it was higher in those patients who succumbed to HBVACLF(P 0.05). Serum sMR level was positively correlated with MELD score(rs= 0.533, P = 0.001), HBV-DNA level(rs = 0.497, P = 0.022), and TBIL level(rs =0.894, P 0.001). Serum sMR level(odds ratio = 1.007, 95% confidence interval:1.004–1.012, P = 0.001) was an independent risk factor for the 90-day mortality inthe HBV-ACLF cases. The patients with HBV-ACLF were stratified into two groups in accordance with their serum sMR levels at the baseline(low risk: 99.84 pg/mL and high risk: ≥ 99.84 pg/mL). The 90-day mortality rates were27.3% in the low-risk group and 87.5% in the high-risk group. Furthermore, sMR level apparently improved the performance of MELD score for predicting the prognosis of patients with HBV-ACLF.CONCLUSION Serum sMR level may be a predictor of the prognosis of HBV-ACLF patients.     

恩替卡韦治疗慢加急性乙型肝炎肝衰竭近期疗效评价

目的探讨恩替卡韦治疗慢加急性乙型肝炎肝衰竭近期疗效。方法 68例慢加急性乙型肝炎肝衰竭患者被分成治疗组(42例)和对照组(26例),对照组采用常规内科治疗,治疗组在常规内科治疗基础上加用恩替卡韦0.5mg/d,比较两组治疗后血生化指标、凝血酶原活动度、HBV DNA水平、MELD分值变化及病死率。结果在治疗后12周,治疗组总胆红素和HBV DNA分别为89.7±42.5μmol/L和3.16±2.04log10copies/mL,显著低于对照组患者(145.6±64.2μmol/L和6.28±3.95log10copies/mL,P<0.01),凝血酶原活动度和白蛋白分别为48.5±15.6%和34.8±4.8g/L,显著高于对照组(40.5±12.4%和30.2±4.1g/L,P<0.05或P<0.01);治疗组早中期患者MELD分值和病死率分别为17.6±3.5和20.0%,显著低于对照组(22.4±4.1和52.9%,P<0.05或P<0.01),两组晚期患者MELD分值和病死率差异无统计学意义(P>0.05);治疗组有1例HBeAg阴转,1例HBeAg血清学转换,对照组HBVM无变化。结论恩替卡韦能有效抑制HBV复制,改善慢加急性乙型肝炎肝衰竭患者肝功能,降低早中期患者MELD分值和病死率。尽早抗病毒治疗可提高慢加急性乙型肝炎肝衰竭患者的生存率。     

慢加急性乙型肝炎肝衰竭临床特征及血浆置换治疗对其预后的影响

目的探讨乙型肝炎相关的慢加急性肝衰竭患者的临床特征,以及血浆置换（PE）对慢加急性肝衰竭治疗的疗效。方法按肝衰竭诊疗指南的诊断标准,收集2012年5月至2014年2月我科诊治的52例乙型肝炎相关慢加急性肝衰竭患者的住院临床资料。使用德国BE公司血液凝固分析仪检测凝血功能指标;使用美国 Beckman LH750 血球分析仪检测血细胞计数;使用日立7600全自动生化分析仪检测血清生化指标。结果16例死亡患者入院时凝血酶原时间（PT）为（48.8±11.7）s、活化部分凝血酶时间（APTT）为（65.8±19.0）s、凝血酶原时间国际标准化比率（INR）为（2.4±1.0）、血氨为（100.1±74.7）μmol/L,均显著高于36例生存患者[分别为（42.7±14.0）s、（48.0±11.4）s、（1.7±0.4）和（47.9±21.5）μmol/L,P<0.05];死亡组入院时凝血酶原活动度（PTA）为（31.8±12.9）%、血小板计数为（85.6±61.3）×10⁹/L、白蛋白为（29.2±4.1）g/L、血钾为（3.8±0.5）mmol/L,均显著低于生存组[分别为（47.9±21.2）%、（133.4±50.7）×10⁹/L、（32.8±4.7）g/L、（4.1±0.6）mmol/L,P<0.05];死亡组发生肝性脑病、腹水、自发性腹膜炎、电解质紊乱和发生2个以上并发症所占比例（分别为37.5%、68.75%、25%、62.5%、62.5%）显著高于生存组（分别为2.8%、30.35%、2.8%、11.11%、11.11%,P<0.05）;患者在接受PE治疗后PTA[（44.8±23.5）%]、白细胞计数[（8.0±3.6×10⁹）/L]、白蛋白[（36.4±3.6）g/L]、血尿素氮[（7.1±4.6）mmol/L]较治疗前显著升高[分别为（36.6±14.6）%、（5.9±2.8×10⁹）/L、（33.7±4.1）g/L、（5.4±3.8）mmol/L,P<0.05],红细胞计数[（3.9±0.7×10⁹）/L]、血红蛋白[（119.5±18.2）g/L]、ALT为[（100.6±67.9）U/L]、AST[（120.0±62.8）U/L]、总胆红素[（335.7±121.3）μmol/L]、间接胆红素[（226.3±77.9）μmol/L]较治疗前显著降低[分别为（4.2±0.8×10⁹）/L、（130.6±23.8）g/L、（300.0±302.3）U/L、（227.2±174.6）U/L,（410.8±129.8）μmol/L,（290.4±100.5）μmol/L,P<0.05]。结论凝血酶原时间、血小板和白蛋白是判断乙型肝炎相关的慢加急性肝衰竭患者预后的敏感的实验室指标,发生并发症的患者预后差,PE治疗可暂时改善患者的凝血功能及肝功能指标,却对其生存无影响。     

MELD评分联合血清降钙素原评估乙型肝炎相关慢加急性肝衰竭患者短期预后的价值

目的探讨MELD评分联合血清降钙素原(PCT)预测乙型肝炎慢加急性肝衰竭(ACLF)患者短期预后的临床价值。方法选取2012年1月至2015年12月于云南省第三人民医院住院的乙型肝炎相关ACLF患者331例,分为生存组(208例)和死亡组(123例),比较两组患者的血清TBil、肌酐(Cr)、国际标准化比值(INR)、血清钠(Na~+)、MELD评分和血清PCT。计量资料两组间比较采用独立样本Mann-Whitney U检验或t检验,计数资料组间比较采用χ~2检验,受试者工作特征曲线下面积(AUC)比较采用正态Z检验。结果死亡组患者的TBil(330.9±81.9)μmol/L比(245.5±67.7)μmol/L、Cr(94.9±23.8)μmol/L比(71.2±29.3)μmol/L、INR(2.5±1.0)μmol/L比(2.1±0.6)μmol/L、MELD评分(26.2±6.5)比(22.0±5.8)、血清PCT浓度(1.3±0.3)μg/L比(0.5±0.2)μg/L均高于生存组,血清Na~+水平(128.9±14.1)mmol/L比(133.8±9.3)mmol/L低于生存组,差异均有统计学意义(均P0.01)。MELD评分、血清PCT预测乙型肝炎相关ACLF患者近期死亡危险性的最佳临界值分别为24.8、0.65μg/L。MELD评分联合血清PCT判断乙型肝炎相关ACLF短期预后的AUC为0.880,高于单独MELD评分的AUC0.820和PCT的AUC0.803,差异均有统计学意义(均P0.01)。结论 MELD评分联合血清PCT对乙型肝炎相关ACLF患者短期预后的预测价值良好。     

Score model for predicting acute-on-chronic liver failure risk in chronic hepatitis B

AIM: To establish a clinical scoring model to predict risk of acute-on-chronic liver failure(ACLF) in chronic hepatitis B(CHB) patients.METHODS: This was a retrospective study of 1457 patients hospitalized for CHB between October 2008 and October 2013 at the Beijing Ditan Hospital, Capital Medical University, China. The patients were divided into two groups: severe acute exacerbation(SAE) group(n = 382) and non-SAE group(n = 1075). The SAE group was classified as the high-risk group based on the higher incidence of ACLF in this group than in the non-SAE group(13.6% vs 0.4%). Two-thirds of SAE patients were randomly assigned to risk-model derivation and the other one-third to model validation. Univariate risk factors associated with the outcome were entered into a multivariate logistic regression model for screening independent risk factors. Each variable was assigned an integer value based on the regression coefficients, and the final score was the sum of these values in the derivation set. Model discrimination and calibration were assessed using area under the receiver operating characteristic curve and the Hosmer-Lemeshow test. RESULTS: The risk prediction scoring model includedthe following four factors: age ≥ 40 years, total bilirubin ≥ 171 μmol/L, prothrombin activity 40%-60%, and hepatitis B virus DNA 107 copies/m L. The sum risk score ranged from 0 to 7; 0-3 identified patients with lower risk of ACLF, whereas 4-7 identified patients with higher risk. The Kaplan-Meier analysis showed the cumulative risk for ACLF and ACLF-related death in the two risk groups(0-3 and 4-7 scores) of the primary cohort over 56 d, and log-rank test revealed a significant difference(2.0% vs 33.8% and 0.8% vs 9.4%, respectively; both P 0.0001). In the derivation and validation data sets, the model had good discrimination(C index = 0.857, 95% confidence interval: 0.800-0.913 and C index = 0.889, 95% confidence interval: 0.820-0.957, respectively) and calibration demonstrated by the Hosmer-Lemeshow test(χ2 = 4.516, P = 0.808 and χ2 = 1.959, P = 0.923, respectively).CONCLUSION: Using the scoring model, clinicians can easily identify patients(total score ≥ 4) at high risk of ACLF and ACLF-related death early during SAE.     

IL-6基因多态性对HBV相关ACLF患者短期预后的影响

目的 研究白细胞介素6(IL-6)单核苷酸多态性(SNP)对慢加急性乙型肝炎肝衰竭(HBV-ACLF)患者短期预后的影响.方法 2017年4月～2020年4月我院收治的HBV-ACLF患者134例,采用imLDRTM多重SNP分型试剂盒检测血清IL-6基因rs1524107、rs2069837、rs2069840和rs...     

乙型肝炎病毒前C区/BCP区变异与慢加急性肝衰竭的关系

目的 探讨乙型肝炎病毒前C区/BCP区变异与乙型肝炎相关性慢加急性肝衰竭(ACLF)的关系. 方法 收集44例ACLF患者和28例慢性乙型肝炎患者(CHB)的血清及临床资料,并对其中10例ACLF患者进行随访,每周收集血清1次.依据MELD评分对患者的病情进行判断.采用巢氏PCR方法扩增HBV DNA,扩增产物直接测序.序列比对采用BioEdit (7.0.9.0)生物分析软件.采用荧光定量PCR法检测HBV DNA含量.数据采用SPSS13.0软件分析,两组间比较采用t检验及t'检验. 结果 44例ACLF患者基因型均为C型,28例CHB患者中仅两例基因型为B型,其余均为C型.ACLF组患者A1762T、G1764A、T1753V、G1896A、G1899A变异频率分别为88.6％(39/44)、93.2％(41/44)、61.4％(27/44)、63.6％(28/44)和29.5％(13/44),CHB组分别为64.3％(18/28)、67.9％(19/28)、14.3％(4/28)、21.4％(6/28)和3.6％(1/28),两组比较,x2值分别为6.152、7.901、15.468、12.331和7.370,P值均＜0.05,差异均有统计学意义.ACLF组内MELD评分＜ 20、20 ～ 25、＞25组间差异均无统计学意义.CHB组前C区、BCP区均未发生变异的频率为17.9％ (5/28),ACLF组为2.3％ (1/44),CHB组前C区、BCP区均未发生变异的频率高于ACLF组,x2=5.440,P=0.020,差异有统计学意义.ACLF组前C区、BCP区同时发生变异的频率为79.6％(35/44),CHB组为39.3％(11/28),两组比较,x2=12.021,P＜0.01,差异有统计学意义.CHB组仅BCP区有变异的发生频率为42.9％(12/28),ACLF组为20.5％(9/44),x2=4.157,P=0.041,差异有统计学意义.两组均未出现单独的前C区变异.10例ACLF患者均出现3个或3个以上的联合变异位点.G1896A、T1753C、A1846T变异随着病情好转而恢复.结论 乙型肝炎病毒前C区/BCP区变异可能与ACLF的发生相关.     

慢加急性乙型肝炎肝衰竭患者血清IFN-γ基因多态性分析

目的 探究慢加急性乙型肝炎肝衰竭(HBV-ACLF)患者血清γ-干扰素(IFN-γ)基因多态性分布特点。方法 2017年5月～2019年9月我院收治的HBV-ACLF患者60例,另选择同期健康体检者60例作为对照。采用Taqman探针荧光定量PCR法检测外周血IFN-γ基因多态性位点+874T/A和+2109A/G基因型,采用x²检验和Hardy-Weinberg平衡检验IFN-γ基因SNP位点+874T/A和+2109A/G基因型和等位基因频率分布差异。结果 在IFN-γ+874T/A位点,ACLF患者TT基因型为48.3%,显著低于健康人的56.7%,而AA基因型为31.7%,显著高于健康人的13.3%(P＜0.05),在等位基因频率分布方面,ACLF患者T等位基因频率为58.3%,显著低于健康人的71.7%,而A等位基因频率为41.7%,显著高于健康人的28.3%(P＜0.05);在IFN-γ+2109A/G位点,ACLF患者显性等位基因纯合子AA基因型频率为53.3%,显著低于健康人的66.7%,隐性等位基因纯合子GG基因型频率为28.3%,显著高于对照组的10.0%(P＜0.05),在等位基因频率分布方面,ACLF患者A等位基因频率为62.5%,显著低于对照组的78.3%,而G等位基因频率为37.5%,显著高于对照组的21.7%,差异具有统计学意义(P＜0.05)。结论 IFN-γ基因多态性与乙型肝炎患者发生ACLF可能存在某种关系,其中IFN-γ基因+874T/A位点中的A等位基因和+2109A/G位点中的G等位基因可能是患者发生HBV-ACLF的风险等位基因,监测外周血IFN-γ基因多态性对及时准确地预测ACLF的发生可能具有一定的临床意义。     

MHV-3诱导的暴发性肝炎小鼠肝脏和慢加急性肝衰竭患者外周血单个核细胞 TLR2表达的变化

目的：研究慢性乙型肝炎患者和慢加急性乙型肝炎肝衰竭（HBV-ACLF）患者外周血单个核细胞（PBMC）Toll 样受体2（TLR2）表达,以及鼠三型肝炎病毒（MHV-3）诱导的暴发性肝炎小鼠肝脏 TLR2表达的变化。方法收集慢性乙型肝炎和 HBV-ACLF 患者外周血,分离 PBMC,采用实时定量 PCR 法检测 PBMC 中 TLR2 mRNA;给 Balb/cJ 小鼠腹腔注射MHV-3（100 pfu）,建立小鼠暴发性肝炎模型,观察感染0、24、48和72 h 后肝脏TLR2水平变化。结果 BALB/cJ 小鼠在感染 MHV-3后,与0 h[（0.39±0.06）%]比,肝细胞 TLR2 mRNA 水平在感染48和72 h 均显著升高[分别为（9.06±1.60）%和（6.42±2.42）%,P＜0.05）],并于48 h 达最高水平,且两时间点细胞 TLR2 mRNA 水平均与血清 ALT 和 AST 水平呈正相关（r=0.804,P＜0.01;r=0.797,P＜0.01）;HBV-ACLF患者 PBMC 中 TLR2 mRNA 水平显著高于慢性乙型肝炎患者[（5.92±5.26）%对（1.15±1.59）%,P＜0.05）]。结论 TLR2参与了 MHV-3诱导的暴发性肝炎小鼠以及 HBV-ACLF 患者肝脏损伤的发病过程。     

乙型肝炎相关慢加急性肝衰竭患者的预后因素分析

目的 探讨影响乙型肝炎相关慢加急性肝衰竭患者预后的危险因素.方法 记录263例乙型肝炎相关慢加急性肝衰竭患者治疗基线时血清胆碱酯酶、白蛋白及胆固醇等反应肝脏储备功能的临床指标及重要并发症的发生情况,并计算其MELD评分.所有患者随访满1年.通过Cox比例风险回归模型筛选出影响预后的独立危险因素.结果 在1年的随访时间内,67例死亡,病死率为25.5％.死亡组血清胆碱酯酶、白蛋白、胆固醇水平均较存活组低.血清胆固醇水平随着MELD值的升高而下降.Cox比例风险回归模型分析得出,肝性脑病、肝肾综合征、上消化道出血、胆固醇≤2.5 mmol/L、MELD评分≥30是影响乙型肝炎相关慢加急性肝衰竭患者预后的独立危险因素,RR分别为6.286、2.983、2.272、2.168及1.853.结论 胆固醇≤2.5 mmol/L、肝性脑病、肝肾综合征、上消化道出血及MELD评分≥30是决定乙型肝炎相关慢加急性肝衰竭患者预后的主要危险因素.