乙型肝炎病毒相关慢加急性肝衰竭预后相关因素的研究
发布时间：2018-09-11 21:26
【摘要】：目的:乙型肝炎病毒相关慢加急性肝衰竭(Hepatitis B virus associated Acute-on-chronic liver failure,HBV-ACLF)是一组复杂的临床症候群,病情危重,病死率高。本研究探索HBV-ACLF临床转归和预后预测的相关因素,寻找ACLF前期(pre-ACLF)高敏感性、高特异性的生物标志物,建立pre-ACLF早期预测预警系统,为pre-ACLF的早期识别提供新的特异生物标志物和/或预测体系,为临床阐明ACLF的早期病程演变及早期干预提供理论依据,从而降低ACLF的发生率和病死率,改善预后。方法:本研究包含两部分,回顾性研究(第一部分)和前瞻性队列研究(第二部分)。在第一部分里,回顾性研究湖北医药学院附属太和医院感染科2013.11-2016.10收治的HBV-ACLF患者共138例,按照其病情转归分为预后不良组(74例)和预后良好组(64例),分析预后良好组和预后不良组患者的性别、年龄、是否合并肝硬化、是否为停药反跳、是否合并腹水、是否联合人工肝支持治疗及人工肝治疗次数等一般信息,基线状态的临床指标以及CTP、MELD、MELD-Na、iMELD和ALBI评分等5种预后评分的差异,探索影响HBV-ACLF短期预后的相关因素。根据ROC曲线下面积评估预后评分系统对HBV-ACLF预后的预测能力;采用非条件二元Logistic回归分析采用向前似然比法得出独立危险因素并建立预测模型。第二部分,作为中国多中心ACLF队列研究的中心之一,建立ACLF多中心前瞻性队列。从中筛选28天内发生肝衰竭的HBV-ACLF患者,根据其病情转归分成存活组和死亡组,各10例,收集存活组和死亡组患者出现ACLF前后的血浆标本,使用iTRAQ技术筛选两组患者发生ACLF前、死亡组HBV-ACLF患者发生ACLF前后血浆中的显著差异蛋白,以差异1.5倍记为差异显著。然后从差异蛋白中筛选潜在的生物标志物,作为pre-ACLF和/或ACLF新的预测指标。结果:第一部分的研究结果显示:1)预后不同的两组HBV-ACLF患者一般信息中年龄、联合人工肝支持治疗及治疗次数的差异有统计学意义(P0.05),预后良好组患者较预后不良组患者平均年龄更低(43.16±12.44 vs.48.08±9.08),更多患者联合了人工肝支持治疗且平均治疗次数更多。两组患者的性别构成、是否合并肝硬化、是否为停药反跳以及入院时是否合并有腹水等基本情况均无统计学差异;2)预后不良组和预后良好组HBV-ACLF患者基线状态的LY、PLT、AST、Cr、PT、APTT、INR水平的差异均无统计学意义(P0.05),预后不良组患者基线状态的WBC、NE、NE/LY、TBil、Urea水平均明显高于预后良好组,但Alb和Na的水平前者低于后者,组间比较差异有统计学意义(P0.05);3)预后不良和预后良好组HBV-ACLF患者基线状态的CTP、MELD、MELD-Na、iMELD、ALBI五种预后评分系统的积分分别为11.2±1.68 vs.10.11±1.78、21.58±7.39vs.18.08±7.10、24.18±10.11 vs.18.95±7.7、40.75±9.90 vs.33.79±9.15、-1.01±0.54 vs.-1.34±0.52,预后不良组患者的5种预后评分均高于预后良好组,差异有统计学意义(P0.05);4)MELD、MELD-Na、CTP、ALBI和iMELD评分在预测对HBV-ACLF短期预后价值时ROC曲线下面积分别是0.639、0.656、0.672、0.682和0.699,差异无统计学意义。5)NE/LY、GGT、Alb、Na及是否联合人工肝支持治疗是HBV-ACLF短期预后的独立影响因素,非条件二分类logistic回归分析建立预测模型为logit(p)=3.068+1.003×NE/LY-0.892×GGT-1.138×Alb-1.364×Na+1.651×人工肝治疗(联合人工肝治疗记为1,否则记为0)。第二部分研究结果显示:1)与存活组相比,死亡组HBV-ACLF患者在pre-ACLF阶段血浆中24种蛋白显著升高,6种蛋白显著降低;2)死亡组HBV-ACLF患者ACLF阶段较pre-ACLF阶段4种蛋白升高,34种蛋白显著降低。3)筛选出25种蛋白/多肽因子,其在pre-ACLF和ACLF中的预测价值正在进一步研究中。结论:年龄、高水平WBC、NE、NE/LY、TBil、Urea、低Alb、低Na和高预后评分是HBV-ACLF预后不良的重要影响因素,早期多次联合人工肝支持治疗有利于改善HBV-ACLF的短期预后。在HBV-ACLF的发生发展过程中存在多种蛋白的变化,探索HBV-ACLF早期蛋白标志物,建立ACLF早期预警体系,可为该疾病的早期诊断和临床干预提供理论依据。
[Abstract]:Objective: Hepatitis B virus associated with Acute-on-chronic liver failure (HBV-ACLF) is a complex clinical syndrome with high mortality and critical condition. To establish a pre-ACLF early prediction and early warning system to provide new specific biomarkers and/or prediction system for early identification of pre-ACLF, and to provide theoretical basis for clinical elucidation of the early course of disease and early intervention of ACLF, so as to reduce the incidence and mortality of ACLF and improve prognosis. Retrospective study (Part 1) and prospective cohort study (Part 2). In the first part, 138 patients with HBV-ACLF were retrospectively studied in the Department of Infection, Taihe Hospital Affiliated to Hubei Medical College from November 2013 to October 2016. General information on sex, age, cirrhosis, withdrawal and rebound, ascites, combination of artificial liver support and artificial liver therapy, clinical indicators of baseline status, and differences in five prognostic scores, including CTP, MELD, MELD-Na, iMELD and ALBI, were explored to determine the short-term predictive value of HBV-ACLF. The prognostic predictive ability of the prognostic scoring system for HBV-ACLF was assessed according to the area under the ROC curve; independent risk factors were obtained using the forward likelihood ratio method using unconditional binary logistic regression analysis and a prediction model was established. The second part, as one of the centers of China's multicenter ACLF cohort study, established the ACLF multicenter front. Prospective cohort. Patients with HBV-ACLF who developed liver failure within 28 days were screened and divided into survival group and death group according to their prognosis. Plasma samples were collected before and after ACLF in survival group and death group. Significant differences in plasma were screened by iTRAQ before and after ACLF in death group. Results: The results of the first part of the study showed that: 1) There were significant differences in the age of general information, the number of times of combined therapy and the number of times of treatment between two groups with different prognosis of HBV-ACLF. The average age of the patients with good prognosis was lower than that of the patients with poor prognosis (43.16 [12.44] vs. 48.08 [9.08]). More patients were treated with artificial liver support and the average number of treatment was more. The sex composition of the patients in both groups, whether they had cirrhosis, whether they had withdrawal and rebound, and whether they had ascites at admission were associated with cirrhosis. There was no significant difference in baseline LY, PLT, AST, Cr, PT, APTT, and INR levels between the poor prognosis group and the good prognosis group (P 0.05). The levels of WBC, NE, NE/LY, TBil and Urea in the poor prognosis group were significantly higher than those in the good prognosis group, but the levels of Alb and Na in the former were lower than those in the latter. The scores of CTP, MELD, MELD-Na, iMELD and ALBI in the baseline status of HBV-ACLF patients with poor prognosis and good prognosis were 11.2 [1.68] vs. 10.11 [1.78], 21.58 [7.39] vs. 18.08 [7.10], 24.18 [10.11] vs. 18.95 [7.7], 40.75 [9.90] vs. 33.79 [-1.01] vs. 0.54 [-1.3], respectively. The five prognostic scores of the patients with poor prognosis were higher than those of the patients with good prognosis (P 0.05). 4) The scores of MELD, MELD-Na, CTP, ALBI and iMELD were 0.639, 0.656, 0.672, 0.682 and 0.699 under ROC curve when predicting the short-term prognostic value of HBV-ACLF, respectively. Artificial liver support therapy is an independent prognostic factor for short-term prognosis of HBV-ACLF. Unconditional binary logistic regression analysis established a predictive model of Logit (p) = 3.068 + 1.003 *NE/LY-0.892 *GGT-1.138 *Alb-1.364 *Na+1.651 * artificial liver therapy (combined with artificial liver therapy recorded as 1, otherwise recorded as 0). Compared with the pre-ACLF group, 24 proteins were significantly increased and 6 proteins were significantly decreased in the pre-ACLF stage in the death group; 2) ACLF stage in the death group was significantly higher than that in the pre-ACLF stage, and 34 proteins were significantly decreased. 3) 25 protein/peptide factors were screened and their predictive value in the pre-ACLF and ACLF is being further studied. Conclusion: Age, high levels of WBC, NE, NE/LY, TBil, Urea, low Alb, low Na and high prognostic score are important factors for poor prognosis of HBV-ACLF. Early multiple combination therapy with artificial liver support can improve the short-term prognosis of HBV-ACLF. The establishment of ACLF early warning system can provide a theoretical basis for early diagnosis and clinical intervention of the disease.
【学位授予单位】：湖北医药学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.62;R575.3
[Abstract]:Objective: Hepatitis B virus associated with Acute-on-chronic liver failure (HBV-ACLF) is a complex clinical syndrome with high mortality and critical condition. To establish a pre-ACLF early prediction and early warning system to provide new specific biomarkers and/or prediction system for early identification of pre-ACLF, and to provide theoretical basis for clinical elucidation of the early course of disease and early intervention of ACLF, so as to reduce the incidence and mortality of ACLF and improve prognosis. Retrospective study (Part 1) and prospective cohort study (Part 2). In the first part, 138 patients with HBV-ACLF were retrospectively studied in the Department of Infection, Taihe Hospital Affiliated to Hubei Medical College from November 2013 to October 2016. General information on sex, age, cirrhosis, withdrawal and rebound, ascites, combination of artificial liver support and artificial liver therapy, clinical indicators of baseline status, and differences in five prognostic scores, including CTP, MELD, MELD-Na, iMELD and ALBI, were explored to determine the short-term predictive value of HBV-ACLF. The prognostic predictive ability of the prognostic scoring system for HBV-ACLF was assessed according to the area under the ROC curve; independent risk factors were obtained using the forward likelihood ratio method using unconditional binary logistic regression analysis and a prediction model was established. The second part, as one of the centers of China's multicenter ACLF cohort study, established the ACLF multicenter front. Prospective cohort. Patients with HBV-ACLF who developed liver failure within 28 days were screened and divided into survival group and death group according to their prognosis. Plasma samples were collected before and after ACLF in survival group and death group. Significant differences in plasma were screened by iTRAQ before and after ACLF in death group. Results: The results of the first part of the study showed that: 1) There were significant differences in the age of general information, the number of times of combined therapy and the number of times of treatment between two groups with different prognosis of HBV-ACLF. The average age of the patients with good prognosis was lower than that of the patients with poor prognosis (43.16 [12.44] vs. 48.08 [9.08]). More patients were treated with artificial liver support and the average number of treatment was more. The sex composition of the patients in both groups, whether they had cirrhosis, whether they had withdrawal and rebound, and whether they had ascites at admission were associated with cirrhosis. There was no significant difference in baseline LY, PLT, AST, Cr, PT, APTT, and INR levels between the poor prognosis group and the good prognosis group (P 0.05). The levels of WBC, NE, NE/LY, TBil and Urea in the poor prognosis group were significantly higher than those in the good prognosis group, but the levels of Alb and Na in the former were lower than those in the latter. The scores of CTP, MELD, MELD-Na, iMELD and ALBI in the baseline status of HBV-ACLF patients with poor prognosis and good prognosis were 11.2 [1.68] vs. 10.11 [1.78], 21.58 [7.39] vs. 18.08 [7.10], 24.18 [10.11] vs. 18.95 [7.7], 40.75 [9.90] vs. 33.79 [-1.01] vs. 0.54 [-1.3], respectively. The five prognostic scores of the patients with poor prognosis were higher than those of the patients with good prognosis (P 0.05). 4) The scores of MELD, MELD-Na, CTP, ALBI and iMELD were 0.639, 0.656, 0.672, 0.682 and 0.699 under ROC curve when predicting the short-term prognostic value of HBV-ACLF, respectively. Artificial liver support therapy is an independent prognostic factor for short-term prognosis of HBV-ACLF. Unconditional binary logistic regression analysis established a predictive model of Logit (p) = 3.068 + 1.003 *NE/LY-0.892 *GGT-1.138 *Alb-1.364 *Na+1.651 * artificial liver therapy (combined with artificial liver therapy recorded as 1, otherwise recorded as 0). Compared with the pre-ACLF group, 24 proteins were significantly increased and 6 proteins were significantly decreased in the pre-ACLF stage in the death group; 2) ACLF stage in the death group was significantly higher than that in the pre-ACLF stage, and 34 proteins were significantly decreased. 3) 25 protein/peptide factors were screened and their predictive value in the pre-ACLF and ACLF is being further studied. Conclusion: Age, high levels of WBC, NE, NE/LY, TBil, Urea, low Alb, low Na and high prognostic score are important factors for poor prognosis of HBV-ACLF. Early multiple combination therapy with artificial liver support can improve the short-term prognosis of HBV-ACLF. The establishment of ACLF early warning system can provide a theoretical basis for early diagnosis and clinical intervention of the disease.
【学位授予单位】：湖北医药学院
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R512.62;R575.3
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