第九章 乙型肝炎重症化的早期预警和乙型重型肝炎(肝衰竭)的临床诊断

内容提要

1.应用于乙型肝炎重症化早期预警指标筛选的技术方法主要如下：基因诊断技术，包括聚合酶链反应、基因序列分析、基因芯片、全基因组关联分析等；蛋白质水平上的双向凝胶电泳技术和质谱分析技术；以DNA甲基化和组蛋白修饰为代表的表观遗传学；用于微生物序列和功能分析的生物信息学技术及系统生物学方法。

2.目前已应用于临床，且与乙型肝炎重症化相关的检测指标主要如下：谷丙转氨酶与谷草转氨酶、血清总胆红素、凝血酶原时间与凝血酶原活动度、血清白蛋白与前白蛋白、血清胆碱酯酶及血氨等。近年来的大量研究又发掘了一系列新的可能与乙型肝炎重症化相关的指标，包括基因变异(HBV 1896位点突变及1762/1764双突变等)，遗传分子靶标(CXCL10-201G/A、IL10-592T/C、ESR1 IVS1-401T/C、TBX21-1993T/C、ICAM1 R241-E469等)、免疫因素(TNF-α、活性氧簇和活性氮簇、sCD163分子、hfgl2分子、HLA-DR、NK细胞、CTL、Th17细胞、Treg细胞、PD-1/PD-L等)、宿主代谢性因素(溶血卵磷脂、脂肪酰胺及胆汁酸等)。

3.乙型重型肝炎临床诊断的主要依据包括临床表现(如黄疸、凝血功能障碍、肝性脑病和腹水等)及实验室检查(如凝血酶原时间、凝血酶原活动度、国际标准化比值、血清白蛋白、血清总胆红素、AST/ALT值、胆碱酯酶、胆固醇、乳酸、甲胎蛋白等)。

4.对于肝衰竭的诊断标准国内外学术界尚存在分歧。我国既往将肝衰竭诊断为重型肝炎，而西方国家将这类由病毒导致的肝衰竭诊断为暴发性肝炎，且仅指其中的急性肝衰竭。我国将急性暴发性肝炎的概念扩展到非脑病患者，而欧美和日本等把肝性脑病Ⅱ期以上作为重型肝炎诊断的必要条件。

5.肝衰竭主要分为急性肝衰竭和慢性肝衰竭，其中急性肝衰竭包括急性和亚急性肝衰竭，慢性肝衰竭包括慢加急性肝衰竭和慢性失代偿性肝衰竭。目前认为肝性脑病是诊断急性肝衰竭的必要条件，但慢性肝衰竭不一定会发生肝性脑病，而主要表现为肝脏的失代偿。

6.现有的评价乙型肝炎进展的方法主要包括Child-Turcotte-Pugh(CTP)评分、终末期肝病模型(model for end-stage liver disease，MELD)、英国皇家学院标准(KCC)、序贯器官衰竭估计(sequential organ failure assessment，SOFA)评分，急性生理学和慢性健康状况评价Ⅱ(acute physiology and chronichealth evaluation Ⅱ，APACHE Ⅱ)、Clichy-Villejuif标准、慢性肝衰竭联盟器官衰竭（CLIF-COF）评分、慢性肝衰竭联盟慢加急性肝衰竭（CLIF-C ACLF）评分、亚太肝脏研究学会慢加急性肝衰竭联盟（AARC）-ACLF评分、中国乙型重型肝炎研究组（COSSH）-ACLF评分以及同济预测模型（TPPM）评分等。(https://www.daowen.com)

Abstract 9

1.Technologies used for early screening of severehepatitis B include gene-based diagnostic techniques，such as the polymerase chain reaction，gene sequence analysis，gene chips，and GWAS.Protein-based methods include two-dimensional gel electrophoresis and mass spectrometry；and epigenetic-based methods include assays of DNA methylation andhistone modification.In addition，meta-genomics and systematic biologyhave been used to analyze microbial sequence and function.

2.Early-warning parameters for severehepatitis B mainly include serum concentrations of ALT，AST，total bilirubin，albumin and prealbumin，and cholinesterase；and measurements of blood ammonia，prothrombin time and prothrombin activity.Several new parameters related to severehepatitis Bhave been identified，including gene mutations(e.g.HBV 1896 site mutation and 1762/1764 double mutation)，genetic molecular targets(e.g.CXCL10-201 G/A，IL10-592T/C，ESR1 IVS1-401T/C，TBX21-1993T/C，and ICAM1 R241-E469)，immune factors(e.g.TNF-α，reactive oxygen species，reactive nitrogen species，sCD163，hfgl2，HLA-DR，NK cells，CTL，Th17 cells，Treg cells，PD-1/PD-L)，and metabolic factors(e.g.lecithin，fat amides and bile acids).

3.The clinical diagnosis of severehepatitis B is mainly based on clinical manifestations，including jaundice，coagulation disorders，hepatic encephalopathy and ascites，and laboratory tests，including prothrombin time，prothrombin activity，international normalized ratio，AST/ALT ratio，and serum concentrations of albumin，total bilirubin，cholinesterase，cholesterol，lactic acid，and alpha-fetoprotein.

4.At present，there are differences among countries in terms of the standard for diagnosing liver failure.In China，liver failure is diagnosed as severehepatitis，whereas，in western counties，liver failure caused by viruses is diagnosed as fulminanthepatitis and refers only to acute liver failure.The main difference is that，in China，the concept of acute fulminanthepatitishas been extended to patients without encephalopathy.However，hepatic encephalopathy Ⅱ is a necessary condition to diagnose severehepatitis in the United States，Europe and Japan.

5.Liver failure can be subdivided into acute and chronic liver failure.Acute liver failure includes acute and sub-acute liver failure，chronic liver failure includes acute-on-chronic and chronic decompensated liver failure.At present，hepatic encephalopathyhas been considered necessary for the diagnosis of acute liver failure，but not chronic liver failure，which is characterized by decompensated liver.

6.Several methodshave been used to evaluate the progression of chronic liver diseases，including Child-Turcotte-Pugh(CTP)score，MELD，King’s College Criteria(KCC)，Sequential Organ Failure Assessment(SOFA)score，APACHEⅡ，Clichy-Villejuif criteria，Chronic Liver Failure Consortium organ failure(CLIF-COF)score、CLIF-C acute-on-chronic liver failure(CLIF-C ACLF)score、Asia-pacific Association for the Study of Liver ACLF Research Consortium ACLF Research Consortium (AARC- ACLF)score、Chinese Group on the Study of Severe Hepatitis B-ACLF(COSSH-ACLF)score and Tongji prognostic predictor model(TPPM)score.