乙型肝炎病毒相關(guān)慢加急性肝衰竭預(yù)后相關(guān)因素的研究
發(fā)布時間：2018-09-11 21:26
【摘要】：目的:乙型肝炎病毒相關(guān)慢加急性肝衰竭(Hepatitis B virus associated Acute-on-chronic liver failure,HBV-ACLF)是一組復(fù)雜的臨床癥候群,病情危重,病死率高。本研究探索HBV-ACLF臨床轉(zhuǎn)歸和預(yù)后預(yù)測的相關(guān)因素,尋找ACLF前期(pre-ACLF)高敏感性、高特異性的生物標(biāo)志物,建立pre-ACLF早期預(yù)測預(yù)警系統(tǒng),為pre-ACLF的早期識別提供新的特異生物標(biāo)志物和/或預(yù)測體系,為臨床闡明ACLF的早期病程演變及早期干預(yù)提供理論依據(jù),從而降低ACLF的發(fā)生率和病死率,改善預(yù)后。方法:本研究包含兩部分,回顧性研究(第一部分)和前瞻性隊列研究(第二部分)。在第一部分里,回顧性研究湖北醫(yī)藥學(xué)院附屬太和醫(yī)院感染科2013.11-2016.10收治的HBV-ACLF患者共138例,按照其病情轉(zhuǎn)歸分為預(yù)后不良組(74例)和預(yù)后良好組(64例),分析預(yù)后良好組和預(yù)后不良組患者的性別、年齡、是否合并肝硬化、是否為停藥反跳、是否合并腹水、是否聯(lián)合人工肝支持治療及人工肝治療次數(shù)等一般信息,基線狀態(tài)的臨床指標(biāo)以及CTP、MELD、MELD-Na、iMELD和ALBI評分等5種預(yù)后評分的差異,探索影響HBV-ACLF短期預(yù)后的相關(guān)因素。根據(jù)ROC曲線下面積評估預(yù)后評分系統(tǒng)對HBV-ACLF預(yù)后的預(yù)測能力;采用非條件二元Logistic回歸分析采用向前似然比法得出獨立危險因素并建立預(yù)測模型。第二部分,作為中國多中心ACLF隊列研究的中心之一,建立ACLF多中心前瞻性隊列。從中篩選28天內(nèi)發(fā)生肝衰竭的HBV-ACLF患者,根據(jù)其病情轉(zhuǎn)歸分成存活組和死亡組,各10例,收集存活組和死亡組患者出現(xiàn)ACLF前后的血漿標(biāo)本,使用iTRAQ技術(shù)篩選兩組患者發(fā)生ACLF前、死亡組HBV-ACLF患者發(fā)生ACLF前后血漿中的顯著差異蛋白,以差異1.5倍記為差異顯著。然后從差異蛋白中篩選潛在的生物標(biāo)志物,作為pre-ACLF和/或ACLF新的預(yù)測指標(biāo)。結(jié)果:第一部分的研究結(jié)果顯示:1)預(yù)后不同的兩組HBV-ACLF患者一般信息中年齡、聯(lián)合人工肝支持治療及治療次數(shù)的差異有統(tǒng)計學(xué)意義(P0.05),預(yù)后良好組患者較預(yù)后不良組患者平均年齡更低(43.16±12.44 vs.48.08±9.08),更多患者聯(lián)合了人工肝支持治療且平均治療次數(shù)更多。兩組患者的性別構(gòu)成、是否合并肝硬化、是否為停藥反跳以及入院時是否合并有腹水等基本情況均無統(tǒng)計學(xué)差異;2)預(yù)后不良組和預(yù)后良好組HBV-ACLF患者基線狀態(tài)的LY、PLT、AST、Cr、PT、APTT、INR水平的差異均無統(tǒng)計學(xué)意義(P0.05),預(yù)后不良組患者基線狀態(tài)的WBC、NE、NE/LY、TBil、Urea水平均明顯高于預(yù)后良好組,但Alb和Na的水平前者低于后者,組間比較差異有統(tǒng)計學(xué)意義(P0.05);3)預(yù)后不良和預(yù)后良好組HBV-ACLF患者基線狀態(tài)的CTP、MELD、MELD-Na、iMELD、ALBI五種預(yù)后評分系統(tǒng)的積分分別為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,預(yù)后不良組患者的5種預(yù)后評分均高于預(yù)后良好組,差異有統(tǒng)計學(xué)意義(P0.05);4)MELD、MELD-Na、CTP、ALBI和iMELD評分在預(yù)測對HBV-ACLF短期預(yù)后價值時ROC曲線下面積分別是0.639、0.656、0.672、0.682和0.699,差異無統(tǒng)計學(xué)意義。5)NE/LY、GGT、Alb、Na及是否聯(lián)合人工肝支持治療是HBV-ACLF短期預(yù)后的獨立影響因素,非條件二分類logistic回歸分析建立預(yù)測模型為logit(p)=3.068+1.003×NE/LY-0.892×GGT-1.138×Alb-1.364×Na+1.651×人工肝治療(聯(lián)合人工肝治療記為1,否則記為0)。第二部分研究結(jié)果顯示:1)與存活組相比,死亡組HBV-ACLF患者在pre-ACLF階段血漿中24種蛋白顯著升高,6種蛋白顯著降低;2)死亡組HBV-ACLF患者ACLF階段較pre-ACLF階段4種蛋白升高,34種蛋白顯著降低。3)篩選出25種蛋白/多肽因子,其在pre-ACLF和ACLF中的預(yù)測價值正在進(jìn)一步研究中。結(jié)論:年齡、高水平WBC、NE、NE/LY、TBil、Urea、低Alb、低Na和高預(yù)后評分是HBV-ACLF預(yù)后不良的重要影響因素,早期多次聯(lián)合人工肝支持治療有利于改善HBV-ACLF的短期預(yù)后。在HBV-ACLF的發(fā)生發(fā)展過程中存在多種蛋白的變化,探索HBV-ACLF早期蛋白標(biāo)志物,建立ACLF早期預(yù)警體系,可為該疾病的早期診斷和臨床干預(yù)提供理論依據(jù)。
[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.
【學(xué)位授予單位】：湖北醫(yī)藥學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：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.
【學(xué)位授予單位】：湖北醫(yī)藥學(xué)院
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2017
【分類號】：R512.62;R575.3
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