本文選題：重型肝炎 + 肝衰竭��； 參考：《第三軍醫(yī)大學(xué)》2013年碩士論文

【摘要】：背景和目的 肝衰竭(liver failure，LF)是由多種病因引起的嚴(yán)重肝臟損害，以黃疸、肝性腦病、凝血機(jī)制障礙及肝腎綜合征等為主要臨床表現(xiàn)的嚴(yán)重肝病癥候群。在我國LF的主要病因是病毒性肝炎，尤其是乙型病毒性肝炎感染所致的重型肝炎肝衰竭(severe hepatitisB-induced liver failure，SHBLF)；在歐美等西方國家，LF主要病因是藥物(尤其是對乙酰氨基酚)及酒精性肝損害。SHBLF病情危重，預(yù)后兇險，病死率高，內(nèi)科治療生存率不足30%，而施行肝臟移植(liver transplantation，LTx)后1個月和1年的生存率分別為90%和70%，LTx已被國際上公認(rèn)為治療SHBLF最有效的方法。 世界范圍內(nèi)的供肝短缺對LTx的發(fā)展是一項極大的挑戰(zhàn)，且SHBLF患者病情進(jìn)展迅速，LTx的手術(shù)時機(jī)稍縱即逝；因此如何及時、準(zhǔn)確、客觀的評估LF的嚴(yán)重程度并預(yù)測其行LTx的預(yù)后，據(jù)此選擇最佳的手術(shù)時機(jī)，合理化分配供肝，對挽救患者生命、提高其生存率至關(guān)重要。目前國外多采用英國皇家學(xué)院(King’s College Hospital，KCH)標(biāo)準(zhǔn)、終末期肝病模型(model for end-stage liver disease，MELD)評分等評估系統(tǒng)進(jìn)行LF患者行LTx手術(shù)時機(jī)的選擇、受體的篩選及預(yù)后的預(yù)測；但不論是在受體病因及分類的構(gòu)成方面，還是在患者的LTx指征與手術(shù)時機(jī)的選擇方面，我國都與歐美等西方國家有很大的不同，且KCH標(biāo)準(zhǔn)及MELD評分對預(yù)后的預(yù)測效能尚存在爭議。 本課題選擇我中心近10年來因SHBLF行LTx的受者為研究對象，對其臨床病歷及術(shù)后隨訪資料進(jìn)行回顧性研究，利用生存分析、受試者工作特征曲線等統(tǒng)計學(xué)方法確定影響預(yù)后的危險因素，建立預(yù)后評估模型，評估其預(yù)測能力，探討行LTx的最佳手術(shù)時機(jī)，為我國SHBLF肝移植受體的選擇及手術(shù)時機(jī)的決斷提供科學(xué)依據(jù)。 方法 1．研究對象：根據(jù)相關(guān)納入、排除及診斷標(biāo)準(zhǔn)，篩選出第三軍醫(yī)大學(xué)第一附屬醫(yī)院肝移植中心自1999年1月至2010年12月收治的病因為SHBLF而行LTx的受者共98例，收集整理在院及術(shù)后隨訪數(shù)據(jù)，建立數(shù)據(jù)資料庫。隨訪截止日期為2011年12月31日。 2．根據(jù)文獻(xiàn)資料結(jié)合臨床經(jīng)驗，提出可能與SHBLF行LTx預(yù)后相關(guān)的因素；先利用單因素Cox比例風(fēng)險回歸模型(簡稱Cox模型)分析初篩，再行多因素Cox模型逐步回歸分析得到影響預(yù)后的主要變量。 3．利用篩選出的變量及其回歸系數(shù)構(gòu)建HBV感染所致重型肝炎肝衰竭肝移植預(yù)后評估模型(severe hepatitis B-induced liver failure prognosis model，SHBLFPM)。 4．利用受試者工作特征(receiver-operating-characteristic，ROC)曲線下面積(theareas under the curves，AUCs)的比較評估SHBLFPM、KCH標(biāo)準(zhǔn)及MELD評分的預(yù)測能力。 5．根據(jù)SHBLF的ROC曲線最佳診斷閾值(cut-off value)分組，繪制兩組Kaplan-Meier生存曲線，并用log-rank檢驗比較兩組差異，探討最佳手術(shù)時機(jī)。 6．本研究中的計量資料用均數(shù)±標(biāo)準(zhǔn)差(mean±SD)表示，，除三個模型AUCs的比較使用MedCalc統(tǒng)計軟件進(jìn)行外，所有統(tǒng)計采用SPSS13.0統(tǒng)計軟件處理，P0.05被認(rèn)為差異有統(tǒng)計學(xué)意義。 結(jié)果 1．受者一般情況及總體生存分析：入選98例SHBLF受者，其中男性88例，女性10例，平均年齡42±9歲。到隨訪截止日時，無一例患者失訪，其中64例存活，34例死亡，總死亡率為34.7%；LTx術(shù)后1個月、6個月和1年受體的生存率分別為76.5%、70.4%和67.3%。 2．HBV所致重型肝炎肝衰竭肝移植預(yù)后評估模型的構(gòu)建。 (1)單因素Cox模型初篩結(jié)果：共8個因素對SHBLF移植受體預(yù)后的影響有統(tǒng)計學(xué)意義，分別是：年齡(AGE，P=0.036)、肝腎綜合征(HRS, P=0.003)、肝性腦病(HE, P=0.016)、白細(xì)胞(WBC, P=0.037)、總膽紅素(TBiL, P0.001)、凝血酶原時間國際標(biāo)準(zhǔn)化比值(INR,P0.001)、肌酐(Cr, P=0.008)及尿素氮(UN, P=0.032)。 (2)多因素Cox模型逐步回歸結(jié)果：最終有4個變量進(jìn)入方程，分別是：AGE(P=0.017)、HE(P=0.013)、TBiL(P0.001)及INR(P=0.001)。 (3)利用篩選出的變量及其回歸系數(shù)，構(gòu)建得到HBV感染所致重型肝炎肝衰竭肝移植預(yù)后評估模型(SHBLFPM)： SHBLFPM=1.806×loge[AGE(歲)]+2.221×loge[TBiL(μmol/L)]+1.951×logeINR+0.318×HE(無肝性腦病時取0；肝性腦�、�-Ⅳ級分別對應(yīng)1-4)。 3．新模型SHBLFPM預(yù)測效能的評估 (1)SHBLFPM、 KCH標(biāo)準(zhǔn)及MELD評分ROC曲線下面積(AUC)的比較：SHBLFPM、KCH標(biāo)準(zhǔn)及MELD評分的AUC分別為0.881、0.596及0.783；SHBLFPM的預(yù)測效能明顯優(yōu)于KCH標(biāo)準(zhǔn)及MELD評分，MELD評分有一定的臨床應(yīng)用價值，而KCH標(biāo)準(zhǔn)預(yù)測價值差。 (2)SHBLFPM評分在23.57時有最好的預(yù)測效能；根據(jù)此值將受體分為高分組和低分組，比較兩組生存時間及生存曲線，低分組預(yù)后明顯好于高分組(P0.001)。 結(jié)論 1．AGE、HE、TBiL及INR是影響SHBLF受體行LTx預(yù)后的主要危險因素。 2．根據(jù)我中心資料構(gòu)建得到HBV感染所致重型肝炎肝衰竭肝移植預(yù)后評估模型SHBLFPM=1.806×loge[AGE(歲)]+2.221×loge[TBiL(μmol/L)]+1.951×logeINR+0.318×HE(無肝性腦病時取0；肝性腦病Ⅰ-Ⅳ級分別對應(yīng)1-4)。 3．新模型SHBLFPM能準(zhǔn)確預(yù)測SHBLF受體行LTx的預(yù)后，其預(yù)測效能明顯優(yōu)于KCH標(biāo)準(zhǔn)及MELD評分，MELD評分有一定的臨床應(yīng)用價值，而KCH標(biāo)準(zhǔn)預(yù)測價值差。 4．術(shù)前SHBLFPM評分≤23.57組行LTx的預(yù)后明顯好于術(shù)前SHBLFPM評分23.57組。 5．對術(shù)前SHBLFPM評分≤23.57的受者，在積極內(nèi)科支持治療的基礎(chǔ)上擇期行LTx；對術(shù)前SHBLFPM評分23.57的受者，應(yīng)在嚴(yán)密監(jiān)護(hù)及強(qiáng)化支持治療的基礎(chǔ)上急診行LTx。
[Abstract]:Background and purpose
Liver failure (LF) is a serious liver damage caused by a variety of causes, with jaundice, hepatic encephalopathy, coagulation mechanism and hepatorenal syndrome as the major symptoms of liver disease. In China, the main cause of LF is viral hepatitis, especially severe hepatitis B caused by hepatitis B virus infection (severe HepatitisB-induced liver failure, SHBLF); in western countries such as Europe and America, the main cause of LF is drug (especially acetaminophen) and alcoholic liver damage,.SHBLF is critical, the prognosis is dangerous, the mortality rate is high, the survival rate of medical treatment is less than 30%, and the survival rate of 1 months and 1 years after the liver transplantation (liver transplantation, LTx). For 90% and 70%, LTx has been internationally recognized as the most effective way to treat SHBLF.
The shortage of donor liver in the world is a great challenge for the development of LTx, and the patient's condition of SHBLF is progressing rapidly and the timing of LTx's operation is fleeting. Therefore, how to evaluate the severity of LF and predict the prognosis of LTx in a timely, accurate and objective way, so as to choose the best operation time, rationalize the distribution of donor liver, and save the life of the patient. It is very important to improve the survival rate. At present, many foreign countries adopt the King 's College Hospital (KCH) standard, the end stage liver disease model (model for end-stage liver disease, MELD) scoring system for the selection of the timing of the operation, the selection of the recipient and the prognosis, but whether it is in the receptor cause and the prognosis. The composition of the classification, or indications and timing of surgery in patients with LTx in our country are very different from the western countries, and the forecasting performance of KCH standard and MELD score for the prognosis is still controversial.
This topic selected our center for the last 10 years for the study of SHBLF line LTx recipients. The clinical records and postoperative follow-up data were reviewed. The risk factors affecting the prognosis were determined by the survival analysis, the working characteristic curve of the subjects and other statistical methods. The prognosis evaluation model was established, the prediction ability was evaluated, and the most LTx was discussed. The best timing of operation is to provide scientific evidence for the selection of SHBLF liver transplant recipients and the timing of operation.
Method
1. research object: according to the inclusion and exclusion criteria, selected transplantation center, the First Affiliated Hospital of Third Military Medical University from January 1999 to December 2010 were liver disease due to SHBLF and LTx in 98 cases, collected in the hospital and postoperative follow-up data, establishment of data database. The deadline for follow-up in December 31, 2011.
2. according to the literature and clinical experience, the factors that may be related to the prognosis of SHBLF LTx were proposed. First, a single factor Cox proportional risk regression model (Cox model) was used to analyze the initial screening, and the stepwise regression analysis of the multi factor Cox model was used to get the main prognostic variables.
3. variables were selected by regression coefficient and construction of HBV infection in liver failure caused by severe hepatitis (severe hepatitis B-induced transplantation evaluation model of liver failure prognosis model, SHBLFPM).
4. using the receiver operating characteristic (receiver-operating-characteristic, ROC) and area under the curve (theareas under the curves, AUCs) of the evaluation and comparison of SHBLFPM, KCH and MELD score standard prediction ability.
5. according to the ROC curve of the best diagnostic threshold SHBLF (cut-off value) group, two Kaplan-Meier group draw survival curves, and use log-rank test to compare the difference between the two groups, to explore the optimal timing of surgery.
The mean and standard deviation of measurement data used in this study 6. (mean + SD) said, in addition to the three AUCs model compared with statistical software MedCalc, SPSS13.0 statistical software was used for statistical processing of all, P0.05 was considered statistically significant.
Result
1. the general situation and overall survival analysis: 98 cases of SHBLF recipients were selected, including 88 men and 10 women, with an average age of 42 9 years. When the follow-up deadline, none of the patients were lost, 64 of them survived, 34 died, and the total mortality was 34.7%; 1 months after LTx, the survival rates of 1 and 1 years were 76.5%, 70.4% and 67.3%., respectively.
Construction of a prognostic model for severe hepatitis liver failure caused by 2.HBV.
(1) preliminary screening results of single factor Cox model: a total of 8 factors have significant effects on the prognosis of SHBLF transplant recipients: age (AGE, P=0.036), HRS (P=0.003), hepatic encephalopathy (HE, P=0.016), leukocyte (WBC, P=0.037), total bilirubin (TBiL, P0.001), Prothrombin time international standardization ratio Anhydride (Cr, P=0.008) and urea nitrogen (UN, P=0.032).
(2) stepwise regression results of multivariate Cox models: finally, 4 variables entered the equation, namely: AGE (P=0.017), HE (P=0.013), TBiL (P0.001) and INR (P=0.001).
(3) using the selected variables and their regression coefficients, we constructed a liver transplantation prognosis assessment model for severe hepatitis caused by HBV infection (SHBLFPM):
SHBLFPM=1.806 * loge[AGE (age)]+2.221 x loge[TBiL (U mol/L)]+1.951 * logeINR+0.318 * HE (0 without hepatic encephalopathy); hepatic encephalopathy I - IV corresponding to 1-4 respectively.
Evaluation of predictive effectiveness of 3. new model SHBLFPM
(1) the comparison of area (AUC) under SHBLFPM, KCH standard and MELD score ROC curve: SHBLFPM, KCH standard and MELD score AUC are 0.881,0.596 and 0.783 respectively; SHBLFPM predictive efficiency is obviously superior to KCH standard and score score.
(2) the SHBLFPM score is the best forecast performance in 23.57; according to this value the receptors are divided into high and low groups, compared two groups of survival time and survival curve, low packet prognosis is significantly better than the high score group (P0.001).
conclusion
1.AGE, HE, TBiL and INR are the major risk factors affecting the prognosis of SHBLF receptor LTx.
2. according to the data of our center, the prognosis evaluation model of liver failure of severe hepatitis caused by HBV infection was established, SHBLFPM=1.806 x loge[AGE (year old)]+2.221 x loge[TBiL (mu mol/L)]+1.951 x logeINR+0.318 x HE (0 in the absence of hepatic encephalopathy), and 1-4 of hepatic encephalopathy grade I - IV respectively.
3. new SHBLFPM model can accurately predict the prognosis of SHBLF receptor for LTx, its forecast performance is better than the standard KCH and MELD score, MELD score has certain clinical application value, and the predictive value of KCH standard deviation.
4. the prognosis of LTx before operation in group SHBLFPM was significantly better than that in group SHBLFPM before operation (23.57) in group SHBLFPM.
5. of the preoperative SHBLFPM score less than 23.57 of the subjects in support of active medical treatment on the basis of elective LTx; the preoperative SHBLFPM score by 23.57, should be in strict monitoring and strengthening support treatment on the basis of emergency LTx.
【學(xué)位授予單位】：第三軍醫(yī)大學(xué)
【學(xué)位級別】：碩士
【學(xué)位授予年份】：2013
【分類號】：R575.3

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