博文
肝硬化基础上慢加急性肝衰竭（二）
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四、治 疗
1. 药物治疗
ACLF的治疗包括早期识别、去除诱因和支持治疗8，14，118，119。早期治疗ACLF的诱因，如用替诺福韦治疗HBV感染复发的患者或用类固醇治疗酒精性肝炎患者，被证明可以降低患者死亡率75，117，119-121。然而，大多数ACLF治疗的重点是支持治疗 118。
（1）抗感染治疗：如上所述，约35％ACLF患者的诱因是细菌感染14（表4）。因此，患有细菌感染的肝硬化患者早期使用抗生素的界限较低。在脓毒性休克患者中，每延迟1小时，总死亡的校正优势比增加1.1 122，123。院内或者医疗措施相关感染的患者以及感染性休克的患者需要使用广谱抗生素，因为不恰当的初始抗微生物治疗会使死亡的校正优势比增加十倍122，123。和早期使用抗生素同样重要的是，一旦确定了病原体和/或患者临床症状改善，抗生素需要迅速降级。如果在使用广谱抗生素时，未能确定病原体且临床症状恶化，则应考虑抗真菌治疗123。此外，还需要预防ACLF患者双重感染（在原发感染上发生的继发性感染），应包括预防和控制呼吸机相关的肺炎、导管相关菌血症和尿道感染，做好手卫生、屏障预防措施和避免接触不必要的仪器124。
根据R.M.和CANONIC试验未发表的结果，无论是否合并感染的ACLF患者在院内均易新发细菌感染。的感染和非感染患者高度倾向于在住院期间发展新的细胞感染。 这些感染会成为该综合征的“第二次打击”。因此，预防、早期诊断和治疗这些继发感染是治疗ACLF的重要措施。
（2）HBV特异性治疗：HBV复发是亚洲患有ACLF的肝硬化患者的常见诱因。对HBV相关ACLF患者进行抗病毒治疗可改善肝功能、增加其短期和长期生存率119-121，125，126。因此，应尽快开始早期抗病毒治疗（如拉米夫定、替诺福韦、恩替卡韦或替比夫定）121，127。
（3）免疫调节：ACLF患者可能会受益于旨在恢复免疫功能的治疗，如白蛋白、N乙酰半胱氨酸和G-CSF117，128。事实上，近期的一个随机对照试验的结果表明，使用G-CSF可预防败血症并改善非重症（即败血症、脑衰竭或多器官衰竭）的ACLF患者的短期存活率128。目前认为G-CSF通过将干细胞从骨髓移动到外周（包括肝脏）从而促进肝再生来发挥作用的。
（4）肾功能不全和肾衰竭：急性肾损伤（AKI）是ACLF最常见的器官衰竭类型8，129。AKI的常见原因包括肾前性、内源性和HRS129。AKI的治疗取决于其病因，而尿生物标志有助于鉴定AKI的病因129，130。肾前性AKI的患者（即因过量利尿治疗而引起的低血容量相关的肾功能损伤）应使用晶体和/或白蛋白进行液体复苏。特利加压素或去甲肾上腺素是HRS的首选治疗，此外还应联合使用白蛋白扩容129。特利加压素或去甲肾上腺素拮抗HRS引起的内脏动脉血管舒张和肾血管收缩，前者可引起全身性循环功能障碍。最初认为白蛋白的作用是扩张血容量。但是目前发现白蛋白还存在调节ACLF患者全身性炎症的作用7，105。肾脏替代治疗用于重症AKI患者进行肝移植或肝肾移植的过度治疗，然而透析的剂量和时间尚未被充分研究。
（5）心血管循环衰竭：在处理败血症时，使用激进的液体复苏和血管收缩剂（即去甲肾上腺素）以维持足够的血压从而保证器官灌注对于拮抗与ACLF发生的血管扩张至关重要14，131。考虑到肝硬化患者易发生容量超负荷，目标平均动脉压应控制在>60 mmHg，同时应注意晶体的补充量118。胶体，包括白蛋白，也可能引起容量超负荷。特利加压素或加压素可与之联用。越来越多的证据表明ACLF中的肾上腺功能不全可进一步损害血液动力学132。可以通过测量清晨随机皮质醇水平来评估肾上腺功能不全，但这仍有争议。如果皮质醇水平不能明确，肾上腺皮质功能不全可以通过促肾上腺皮质激素（ACTH）试验（也称共刺激素、二十四酰化物或Synacthen试验）估计肾上腺对应激的反应来证实。
（6）脑功能障碍和脑衰竭：用自来水灌肠、乳果糖和口服非吸收性抗生素（如利福昔明和新霉素）治疗脑病，可通过提高意识程度从而预防吸入性支气管炎、吸入性肺炎和呼吸衰竭14。在预防由腹泻引起的低血容量以及预防由乳果糖引起的高钠血症（血钠水平升高）是控制适当的乳果糖滴定剂量和灌肠非常重要。一天目标粪排便次数应该为3-4次133。低排便量不足以减少肠道产氨及增加血氨清除率。高排便量可能诱发高钠血症性脱水。因为III-IV级脑病患者发生支气管吸入（唾液或胃液）的风险较高，故他们应该插管。不推荐这些患者采用颅内压监测及使用甘露醇，因为ACLF相关肝性脑病患者不易发生脑水肿和颅内高血压12。
（7）凝血异常：ACLF患者在血栓形成和无法止血状态之间的波动，故常难以控制ACLF的患者凝血异常134，135。在活动性出血和严重凝血异常情况下，应考虑输入血小板、冷沉淀物（从血浆中制备的用于增加纤维蛋白原水平的冷冻血液制品）和血液。然而，患者不应该预防性输血血浆以增加国际标准化比率。门静脉血栓形成的患者可能需要抗凝治疗以防止复发性静脉曲张出血。
2. 重症监护和肝支持设备
存在血管、呼吸道或大脑衰竭的患者必须转入重症监护病房，存在肾衰竭的患者建议转入。肝脏和凝血功能衰竭的患者仍然可以在常规病房中治疗，但需要密切监测。在CANONIC研究中8，50％的ACLF患者转入重症监护室（86％为ACLF 3级）。由于ACLF患者的死亡率高，急需能够支撑重症患者（ACLF 2级或入院后3-7天的3级患者）至接受肝移植治疗的治疗方法。
体外肝支持系统是ACLF的潜在治疗方法136，137。人工生物肝支持系统使用含有肝细胞的中空纤维生物组织来支持病肝的代谢和合成功能。目前，只能获取到肿瘤肝细胞或猪肝细胞系（Vital Therapies ELAD和Alliqua HepatAssist2000系统）。近期一项随机试验比较了ELAD与标准药物治疗，未发现两者对生存有显著影响136。 非生物系统由白蛋白透析技术组成，该分子能够去除因肝衰竭和全身性炎症反应引起的潴留于血浆中的非水溶性物质以及促炎分子（如PAMP和ROS）105。此外，在肝衰竭患者中，因其内源性ROS使分子发生严重氧化、分子结构以及与非水溶性物质（肝衰竭所产生或潴留的物质，如胆红素、胆盐和药物）的结合位点饱和情况的改变，其白蛋白的生理功能严重受损。目前有三种不同的白蛋白透析系统：Gambro分子吸附剂和再循环系统（MARS）、Prometheus分离血浆成分和吸收（FPSA）系统和Fresenius Medical Care单程白蛋白透析（SPAD）。MARS是在ACLF患者中被评估的最多的一个系统，它可改善全身性血液动力学和严重肝性脑病136，137。 然而，两项大型随机多中心研究未能表明MARS和FPSA可改善患者的生存138，139。最后，一项人工肝装置（伦敦大学的肝脏透析装置）旨在清除和代替肝硬化患者的白蛋白功能不全并减少循环内毒素血症目前正在评估140。血浆置换是一种增加急性肝功能衰竭患者生存率的解毒系统141，一项非随机研究中的结果表示它可改善ACLF患者的肝性脑病及其肝功能。
3. 肝移植
肝移植是ACLF患者唯一明确的治疗方法。然而，仅有少数几个研究评估了其可行性、选择标准（适应症和禁忌症）、时间点和疗效96，142-148。与急性肝衰竭患者相比，目前ACLF患者不能立即被列于高度紧急移植列表中。此外，由于ACLF的临床病程迅速进展，能够留给评估及将其置于移植列表上的时间通常很短。高龄、活动性酒精中毒、不能控制的感染和多器官功能衰竭是肝移植的主要禁忌症及除名的主要原因。目前普遍认为严重循环或呼吸衰竭和进行性脓毒症的患者必须避免移植。然而，对于大多数经验丰富的中心，器官支持（肾脏替代治疗和机械通气）使之不会成为ACLF患者进行肝移植的禁忌症。目前的数据表明，仅有不到一半的ACLF患者在列表上，且仅有10-25％的患者可进行肝移植，故而超过50-70％的患者在等候肝移植治疗是死亡147。美国最近的一项研究表明，具有高MELD评分（> 40）的肝硬化ACLF患者在等候肝移植时发生死亡的概率比1A级候选者（即急性肝衰竭患者）更高，几乎比后者高两倍145。确定移植列表上ACLF患者的选择标准及其优先级的标准将有助于通过及时的肝移植改善预后。几个研究表明活体供肝肝移植和尸体供肝肝移植的效果相似146-148。接受肝移植治疗的ACLF患者预后良好（图6），其5年生存率在74％和90％之间，与因其他指症而接受肝移植的患者相似96，144-148。
图6 肝移植增加了ACLF患者的生存率
慢加急性肝衰竭2级或3级（ACLF）患者确诊后3-7天的可能生存曲线，早期接受（<28天）肝移植的患者（红色曲线；n = 21），未接受肝移植的相同ACLF等级的患者（绿色曲线；n = 120）96。该曲线上的百分比显示了患者28天、90天和6个月的存活率。获得许可根据JohnWiley and Sons的参考文献96改编。
4. 管理策略
来自CANONIC研究的三个新的评分系统-CLIF-COF评分（或CLIF-SOFA评分）、CLIF-C ACLF评分和CLIF-C AD评分可用于对肝硬化和急性失代偿患者进行风险分层，以指示是否需要早期肝移植及评估重症监护治疗是否有效20，98（图7）。ACLF的预后不仅取决于器官衰竭的数量或诊断时的CLIF-C ACLF评分，还取决于其对早期治疗的反应96。 由于近20％的ACLF3级的患者在治疗后会好转，故具有三个或更多个器官衰竭的患者应该转人重症监护室，并接受短期（3-7天）接受无限制的器官支持治疗。如在此干预后持续存在三个或更多次器官衰竭，可考虑有限的生命支持治疗，因为在没有接受肝移植治疗的情况下，死亡几乎不可避免19。在无早期肝移植可能的患者中，如早期干预（在第3-7天）后CLIF-C ACLF评分仍较高（> 64分）也被认为无效96。但是，这些标准需要进一步验证。有希望进行早期肝移植（包括活体供肝移植）的患者不应限制其治疗。对于不可能进行肝移植的患者，应该根据评分和实用案例评估来制定治疗方案。
5. 再生治疗
一些研究评估了集落刺激因子治疗对少部分ACLF患者的效果128，149，150。该细胞因子动员骨髓来源的干细胞，恢复嗜中性粒细胞的功能并促进肝细胞再生。在非重症ACLF患者中使用G-CSF可降低发生器官衰竭（或衰竭）和败血症的风险，并提高患者的存活率。G-CSF疗法似乎在败血症患者和重症ACLF的患者中无效。肝细胞和干细胞移植也是ACLF的潜在治疗方法151。
6. 生活质量
ACLF好转的患者在出院后，可恢复社区活动能力、或者接受肝移植、或者被送到临时护理机构例如养老院或重新住院。患者30天内再入院率约为25％152。根据NACSELD研究153结果，在长期随访的6个月中，27％的患者死亡，14％的患者接受肝移植移植，59％的患者没有接受肝移植。患者出院后，45％随后发生感染。发生重复感染的患者年龄较大，更应该使用质子泵抑制剂、利福昔明或用诺氟沙星预防SBP 154，155。在上述三种情况下，患者易患细菌感染可能与肠道菌群紊乱或多耐药性细菌定植有关。更重要的是，感染相关的ACLF患者更有可能从肝移植列表中除名。
图7 ACLF或失代偿性肝硬化患者的管理策略
基于CANONIC研究8中患者死亡率的数据，提出了慢加急性肝衰竭（ACLF）患者的管理策略8。第一步是在开始接受医学治疗（包括器官支持）后3-7天评估ACLF等级。所有ACLF患者均应评估是否需要肝移植治疗，因为ACLF患者90天死亡率很高（>20％）。因为ACLF 2级和3级的患者短期（28天）死亡风险高，故应尽早对他们进行肝移植治疗。在存在肝移植禁忌症的情况下，在确诊后3-7天出现四个或更多器官衰竭（OFs）或慢性肝衰竭联盟（CLIF-C）ACLF评分> 64可能表示治疗无效。ICU：重症监护病房。获得许可根据John Wiley and Sons的参考文献 96改编。
五、展 望
1. ACLF定义
统一ACLF的定义是一个巨大的挑战。APASL和西方定义之间存在显著差异，不能通过协商解决。这些定义不仅在患者的特征、诊断标准和临床病程方面不同，最重要的是，它们对该疾病的整体认知也不同。APASL定义假设ACLF中的一系列事件均由肝损伤开始，肝损伤会引起急性肝衰竭以及肝外器官衰竭。而西方定义认为由于肝内及肝外发病机制的作用，肝功能发生急性损害（严重时称为肝衰竭）和其他器官功能不全（严重时称为器官衰竭）同时发展。这些机制包括来自病肝（如急性酒精性肝炎、病毒性肝炎或DILI）的DAMP或PAMP（通过侵袭脓毒血症中的细菌产生或来自于无明显诱因患者的肠道微生物菌群）大量释放相关的严重全身性炎症反应。这种争议只能通过进一步研究该综合征来解决。
2. 临床挑战
目前有关ACLF的研究都是在确诊ACLF后进行的，故有关ACLF发生前情况的数据很少。因此在该阶段进行前瞻性观察研究很有必要，尤其是评估全身性炎症反应的标志物，因为它们可能可以预测治疗的效果及预后。ACLF的肝脏病理学也未得到充分研究。在HBV感染相关的肝硬化患者中，ACLF存在亚大叶性肝坏死现象27。在酒精性肝硬化和活动性酒精中毒患者中，主要肝脏组织学特征是肝硬化基础上重叠严重酒精性肝炎。最后，最近的两项研究报道ACLF的特异性病变是严重胆管内胆红素沉积和胆汁淤积，该病变也可见于非肝硬化的脓毒症患者156，157。
3. 病理生理学
目前缺乏一系列关于ACLF发病前后的先天和适应性免疫系统功能的研究。这些研究对于了解ACLF的机制至关重要。此外，免疫系统功能可能在ACLF的临床病程中发生变化。在败血症中158，ACLF患者的免疫系统在被激活后可能存在一段免疫抑制期，这会进一步促进细胞易位和器官衰竭的进展。
ACLF中器官或系统衰竭的机制令人倍感兴趣。肝硬化中的肾衰竭被认为是继发于系统性循环功能障碍和肾脏灌注受损。然而，有关脓毒症研究的最新证据表明，肾衰竭也可能是肾脏炎症反应的直接作用的结果，肾脏炎症反应可损害肾微循环和细胞功能159。事实上，有证据表明，在肝硬化中，炎症反应可能与心功能障碍、脑病、肾上腺功能相对不全和肺功能障碍的发病机制有关7。
研究ACLF最大的困难是缺乏合适的动物模型。四氯化碳诱导的肝硬化大鼠模型是肝硬化的优良模型，但动物在出现肝外器官衰竭之前就已死亡160。胆管结扎的大鼠可作为急性肝衰竭和腹水模型，同时对该大鼠短期腹膜内使用LPS，该大鼠曾被用作ACLF的模型161。然而，该模型与肝硬化的人类患者显然不同，该模型不存在肝外器官衰竭。
4. 治 疗
对全身性炎症反应是ACLF的主要发病机制的认识在制定新的治疗方案中开辟了新的领域。这项认知将促进新的人工肝支持系统的发展，该系统能够去除由于器官衰竭而潴留的潜在的毒性分子，而且能够去除引起ACLF的促炎分子。全血浆置换141显然是去除PAMP、DAMP和自由基的另一种方法。
然而，ACLF管理的一个重要问题是预防。在这里有三种潜在的有效治疗方法需要探讨。第一种方法是通过长期口服施用难以吸收的抗生素预防细菌移位107，110，162。第二种是长期每周静脉内使用阿司匹林。在意大利的一项大型随机对照试验中的初步数据表明，该项技术可以预防失代偿性肝硬化患者发生细菌感染、AKI和肝性脑病，改善其生存163。最后，最近的研究表明，与ACLF发生有关的因子，缺陷性胆汁酸受体（也称为法尼酯衍生物X受体的特异性激动剂）参与的信号转导在肝脏炎症反应和肠道细菌移位中发挥核心作用164-166。奥贝胆酸是一种有效的胆汁酸受体激动剂。最近的动物实验的结果已经证明，奥贝胆酸可降低门静脉高压并改善细菌移位情况165，166，表明它可能对ACLF患者有益。
参考文献
1. Ginés，P. et al. Compensated cirrhosis：naturalhistory and prognostic factors. Hepatology 7，122–128 （1987）.
2. Schrier，R. W. et al. Peripheral arterial vasodilation hypothesis：a proposal for the initiation of renal sodium and water retention incirrhosis. Hepatology 8，1151–1157（1998）.
3. Fraser， C. L. & Arieff， A. I.Hepatic encephalopathy. N. Engl. J. Med. 313， 865–873 （1985）.
4. Polio， J. & Groszmann， R. J.Hemodynamic factors involved in the development and rupture of esophagealvarices： a pathophysiologic approach to treatment. Semin.Liver Dis. 6， 318–331 （1986）.
5. Ramachandran， P.， Iredale， J. P.& Fallowfield， J. A. Resolution of liver fibrosis： basic mechanisms and clinical relevance. Semin. Liver Dis. 35， 119–131 （2015）.
6. Qin， N. et al. Alterations of the human gut microbiome in livercirrhosis. Nature 513， 59–64 （2014）.
7. Bernardi， M.， Moreau， R.， Angeli， P.， Schnabl， B. & Arroyo， V.Mechanisms of decompensation and organ failure in cirrhosis： from peripheral arterial vasodilation to systemic inflammationhypothesis. J. Hepatol. 63， 1272–1284 （2015）.
8. Moreau， R. et al. Acute‑on‑chronic liver failure is a distinct syndrome that developsin patients with acute decompensation of cirrhosis. Gastroenterology 144， 1426–1437.e9 （2013）.
This article describes the firstprospective investigation assessing the diagnostic criteria （EASL-CLIF Consortium definition of ACLF）， prevalence， precipitating events， grading ofseverity and prognosis of ACLF in a large series of European patientshospitalized with decompensated cirrhosis using a pragmatic approach.
9. Wlodzimirow， K. A.， Eslami， S.， Abu-Hanna， A.， Nieuwoudt， M. & Chamuleau， R. A. F. M.A systematic review on prognostic indicators of acute on chronic liver failureand their predictive value for mortality. Liver Int. 33， 40–52 （2013）.
10. Jalan， R. & Williams， R. Acute‑on‑chronicliver failure： pathophysiological basis of therapeutic options. BloodPurif. 20， 252–261 （2002）.
11. Sarin， S. K. et al. Acute‑on‑chronic liver failure： consensusrecommendations of the Asian Pacific Association for the Study of the Liver （APASL）. Hepatol. Int. 3， 269–282 （2009）.
This article describes the resultsof a consensus conference promoted by the APASL aiming to assess the diagnosticdefinition of ACLF.
12. Sarin， S. K. et al. Acute‑on‑chronic liver failure： consensusrecommendations of the Asian Pacific Association for the Study of the Liver （APASL） 2014. Hepatol. Int. 8， 453–471 （2014）.
13. Bajaj， J. S. et al. Survival in infection-related acute‑on‑chronic liver failureis defined by extra-hepatic organ failures. Hepatology 60， 250–256 （2014）.
This study shows the prevalence ofACLF and associated mortality in a large series of patients with cirrhosis andbacterial infection from the United States.
14. Jalan， R. et al. Acute‑on chronic liver failure. J. Hepatol. 57， 1336–1348 （2012）.
15. Liver Failure and Artificial LiverGroup， Chinese Society of Infectious Diseases， Chinese Medical Association； SevereLiver Diseases and Artificial Liver Group， ChineseSociety of Hepatology， Chinese Medical Association.[Diagnostic and treatment guidelines for liver failure （2012 version）]. Zhonghua Gan Zang Bing Za Zhi 21， 177–183 （in Chinese）（2013）.
16. Vincent， J. L. et al. The SOFA （Sepsis-relatedOrgan Failure Assessment） score todescribe organ dysfunction/failure. On behalf of the Working Group onSepsis-Related Problems of the European Society of Intensive Care Medicine.Intensive Care Med. 22， 707–710 （1996）.
17. Wehler， M.， Kokoska， J.， Reulbach， U.， Hahn， E. G. & Strauss， R.Short-term prognosis in critically ill patients with cirrhosis assessed byprognostic scoring systems. Hepatology 34， 255–261 （2001）.
18. Das， V. et al. Cirrhotic patients in the medical intensive care unit： early prognosis and long-term survival. Crit. Care Med. 38， 2108–2116 （2010）.
19. Levesque， E. et al. Prospective evaluation of the prognostic scores for cirrhoticpatients admitted to an intensive care unit. J. Hepatol. 56， 95–102 （2012）.
20. Jalan， R. et al. Development and validation of a prognostic score to predictmortality in patients with acute on chronic liver failure. J. Hepatol. 61， 1038–1047 （2014）.
This study describes a prognosticscore specifically designed for patients with ACLF. The accuracy of this score （CLIF-C ACLF score）is significantly higher than thatof all scores currently used in clinical practice.
21. Bernal，W. et al. Acute‑on‑chronic liver failure. Lancet 386，1576–1587（2015）.
22. Bernsmeier，C. et al. Patients with acute‑on‑chronic liver failure have increasednumbers of regulatory immune cells expressing the receptor tyrosine kinaseMERTK. Gastroenterology 148，603–615.e14（2015）.
23. Zhang，Q. et al. Comparison of current diagnostic criteria for acute‑on‑chronicliver failure. PLoS ONE 10， e0122158（2015）.
24. Li，H. et al. Characteristics，diagnosisand prognosis of acute‑on‑chronic liver failure in cirrhosis associated tohepatitis B. Sci. Rep. 6，25487（2016）.
This study indicates that theEASL-CLIF Consortium definition of ACLF designed for European patients can alsobe used in Chinese patients with cirrhosis due to HBV infection with no majordifferences in prevalence，severityand prognosis.
25. Dirchwolf，M. et al. Immune dysfunction in cirrhosis：distinctcytokines phenotypes according to cirrhosis severity. Cytokine 77，14–25（2015）.
26. Amarapurkar，D. et al. Acute‑on‑chronic liver failure：aprospective study to determine the clinical profile， outcome，and factors predicting mortality. Indian J.Gastroenterol. 34，216–224（2015）.
27. Li，H. et al. Submassive hepatic necrosis distinguishes HBV-associated acuteon chronic liver failure from cirrhotic patients with acute decompensation. J.Hepatol. 63，50–59（2015）.
28. Singh，H. & Pai，C. G. Defining acute‑on‑chronicliver failure：east，west ormiddle ground? World J. Hepatol. 7，2571–2577（2015）.
29. Agrawal，S.，Duseja，A.，Gupta，T.，Dhiman，R. K. & Chawla，Y. Simpleorgan failure count versus CANONIC grading system for predicting mortality inacute‑on‑chronic liver failure. J. Gastroenterol. Hepatol. 30，575–581（2015）.
30. Lee，M. et al. CLIF-SOFA scoring system accurately predicts short-termmortality in acutely decompensated patients with alcoholic cirrhosis：a retrospective analysis. Liver Int. 35，46–57（2015）.
31. Dhiman，R. K.，Agrawal，S.，Gupta，T.，Duseja，A. & Chawla，Y. Chronic Liver Failure-SequentialOrgan Failure Assessment is better than the Asia-Pacific Association for theStudy of Liver criteria for defining acute‑on‑chronic liver failure andpredicting outcome. World J. Gastroenterol. 20，14934–14941 （2014）.
32. Kim，H. Y. et al. Characterization of acute‑on‑chronic liver failure andprediction of mortality in Asian patients with active alcoholism. J.Gastroenterol. Hepatol. 31，427–433（2016）.
33. Kim，T. Y. & Kim，D. J. Acute‑on‑chronic liverfailure. Clin. Mol. Hepatol. 19，349–359（2013）.
34. Jalan，R. et al. Toward an improved definition of acute‑on‑chronic liver failure.Gastroenterology 147，4–10 （2014）.
35. Kim，T. Y. et al. Characteristics and discrepancies in acute‑on‑chronic liverfailure：need for a unified definition. PLoS ONE 11，e0146745（2016）.
This study is the first to showthat the EASL-CLIF Consortium definition and the APASL definition of ACLFinclude different populations of patients.
36. Sarin，S. K. & Choudhury，A. Acute‑on‑chronicliver failure：terminology，mechanismsand management. Nat. Rev. Gastroenterol. Hepatol. 13，131–149（2016）.
37. Olson，J. C. & Kamath，P. S. Acute‑on‑chronicliver failure：concept，naturalhistory，and prognosis. Curr. Opin. Crit. Care 17，165–169 （2011）.
38. Singh，K. K.，Panda，S. K.，Shalimar & Acharya，S. K.Patients with diabetes mellitus are prone to develop severe hepatitis and liverfailure due to hepatitis virus infection. J. Clin. Exp. Hepatol. 3，275–280（2013）.
39. Verbeke，L.，Nevens，F. &Laleman，W. Bench‑to‑beside review：acute‑on‑chronicliver failure — linking the gut，liver andsystemic circulation. Crit. Care 15，233（2011）.
40. Suntharalingam， G. et al. Cytokine storm in a phase 1 trial of the anti‑CD28 monoclonalantibody TGN1412. N. Engl. J. Med. 355， 1018–1028 （2006）.
41. Medzhitov， R.， Schneider， D. S.& Soares， M. P. Disease tolerance as a defense strategy. Science335， 936–941 （2012）.
42. Medzhitov， R. Origin and physiological roles of inflammation. Nature 454， 428–435 （2008）.
43. Takeuchi， O. & Akira， S. Pattern recognition receptorsand inflammation. Cell 140， 805–820 （2010）.
44. Iwasaki， A. & Medzhitov， R. Controlof adaptive immunity by the innate immune system. Nat. Immunol. 16， 343–353 （2015）.
45. Wu， J. & Chen， Z. J. Innate immune sensing andsignaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32， 461–488 （2014）.
46. Xu， H. et al. Innate immune sensing of bacterial modifications of Rho GTPasesby the pyrin inflammasome. Nature 513， 237–241 （2014）.
47. Zhao， Y. et al. The NLRC4 inflammasome receptors for bacterial flagellin andtype III secretion apparatus. Nature 477， 596–600 （2011）.
48. Martinon， F.， Mayor， A. &Tschopp， J. The inflammasomes： guardiansof the body. Annu. Rev. Immunol. 27， 229–265 （2009）.
49. Kono， H. & Rock， K. L. How dying cells alert theimmune system to danger. Nat. Rev. Immunol. 8， 279–289 （2008）.
50. Rickard， J. A. et al. RIPK1 regulates RIPK3–MLKL-driven systemic inflammation andemergency hematopoiesis. Cell 157， 1175–1188 （2014）.
51. Angus， D. C. & van der Poll， T. Severesepsis and septic shock. N. Engl. J. Med. 369， 840–851 （2013）.
52. Medzhitov， R. Inflammation 2010： newadventures of an old flame. Cell 140， 771–776 （2010）.
53. Iwasaki， A. & Medzhitov， R.Regulation of adaptive immunity by the innate immune system. Science 327， 291–295 （2010）.
54. Chovatiya， R. & Medzhitov， R. Stress， inflammation， and defense of homeostasis. Mol.Cell 54， 281–288 （2014）.
55. Jalan， R. et al. Bacterial Infections in cirrhosis. A position statement basedon the EASL Special Conference 2013. J. Hepatol. 60， 1310–1324 （2014）.
56. Wiest， R.， Lawson，M. & Geuking， M. Pathological bacterial translocation in liver cirrhosis. J. Hepatol.60， 197–209 （2014）.
57. Byl， B.， Roucloux， I.， Crusiaux， A.， Dupont， E. & Devière， J. Tumor necrosis factor alpha andinterleukin 6 plasma levels in infected cirrhotic patients. Gastroenterology104， 1492–1497 （1993）.
58. Navasa， M. et al. Tumor necrosis factor and interleukin‑6 in spontaneousbacterial peritonitis in cirrhosis：relationship with the development of renal impairment and mortality. Hepatology27， 1227–1232 （1998）.
References 57 and 58 show for thefirst time an in vivo overproduction of pro-inflammatory cytokines in patientswith cirrhosis.
59. Gustot， T.， Durand， F.， Lebrec， D.， Vincent， J.‑L. & Moreau， R. Severesepsis in cirrhosis. Hepatology 50， 2022–2033 （2009）.
60. Devière， J. et al. Excessive in vitro bacterial lipopolysaccharide-inducedproduction of monokines in cirrhosis. Hepatology 11， 628–634 （1990）.
This paper shows for the first timethat the ex vivo innate immune response to LPS is deregulated in monocytes frompatients with alcoholic cirrhosis.
61. Le Moine， O. et al. Role of defective monocyte interleukin‑10 release in tumornecrosis factor-alpha overproduction in alcoholics cirrhosis. Hepatology 22， 1436–1439 （1995）.
62. Tazi， K. A. et al. Upregulation of TNF-alpha production signaling pathways inmonocytes from patients with advanced cirrhosis：possiblerole of Akt and IRAK‑M. J. Hepatol. 45，280–289（2006）.
This paper describes theintracellular mechanisms involved in the excessive innate immune response toLPS in monocytes from patients with decompensated cirrhosis.
63. Tazi，K. A. et al. Protein array technology to investigate cytokine productionby monocytes from patients with advanced alcoholic cirrhosis： an ex vivo pilot study. Hepatol. Res. 39，706–715（2009）.
64. Galbois，A. et al. Ex vivo effects of high-density lipoprotein exposure on thelipopolysaccharide-induced inflammatory response in patients with severecirrhosis. Hepatology 49，175–184（2009）.
65. Coant，N. et al. Glycogen synthase kinase 3 involvement in the excessiveproinflammatory response to LPS in patients with decompensated cirrhosis. J.Hepatol. 55，784–793 （2011）.
66. Gandoura，S. et al. Gene-and exon-expression profiling reveals an extensiveLPS-induced response in immune cells in patients with cirrhosis. J. Hepatol. 58，936–948（2013）.
67. Heller，J. et al. Effects of lipopolysaccharide on TNFα production，hepatic NOS2 activity，and hepatictoxicity in rats with cirrhosis. J. Hepatol. 33，376–381（2000）.
68. Moreau，R. et al. Terlipressin inhibits in vivo aortic iNOS expression induced bylipopolysaccharide in rats with biliary cirrhosis. Hepatology 36，1070–1078（2002）.
69. Urbanowicz，W. et al. Tezosentan，anendothelin receptor antagonist，limitsliver injury in endotoxin challenged cirrhotic rats. Gut 53，1844–1849（2004）.
70. Tazi，K. A. et al. In vivo altered unfolded protein response and apoptosis inlivers from lipopolysaccharide-challenged cirrhotic rats. J. Hepatol. 46，1075–1088（2007）.
This paper shows for the first timethat LPS-induced hepatic endoplasmic reticulum stress inhibits the accumulationof NF‑κB‑dependent anti-apoptotic proteins in livers from rats with cirrhosis.
71. Thabut，D. et al. High-density lipoprotein administration attenuates liverproinflammatory response，restoresliver endothelial nitric oxide synthase activity，and lowersportal pressure in cirrhotic rats. Hepatology 46，1893–1906（2007）.
72. Malhi，H. & Kaufman，R. J. Endoplasmic reticulum stressin liver disease. J. Hepatol. 54，795–809（2011）.
73. Chaisson，M. L.，Brooling，J. T.，Ladiges，W.，Tsai，S. & Fausto，N. Hepatocyte-specific inhibitionof NF‑κB leads to apoptosis after TNF treatment，but notafter partial hepatectomy. J. Clin. Invest. 110，193–202 （2002）.
74. Louvet，A. et al. Infection in patients with severe alcoholic hepatitis treatedwith steroids： early response to therapy is the key factor.Gastroenterology 137，541–548（2009）.
75. Lucey，M. R.，Mathurin，P. &Morgan， T. R. Alcoholic hepatitis. N. Engl. J. Med. 360，2758–2769 （2009）.
76. úbeda，M. et al. Obeticholic acid reduces bacterial translocation and inhibitsintestinal inflammation in cirrhotic rats. J. Hepatol. 64，1049–1057（2015）.
77. Du Plessis，J. et al. Activated intestinal macrophages in patients with cirrhosisrelease NO and IL‑6 that may disrupt intestinal barrier function. J. Hepatol.58，1125–1132（2013）.
78. Francés，R. et al. Bacterial translocation is downregulated by anti-TNFα monoclonalantibody administration in rats with cirrhosis and ascites. J. Hepatol. 46，797–803（2007）.
79. Dominguez，M. et al. Hepatic expression of CXC chemokines predicts portalhypertension and survival in patients with alcoholic hepatitis.Gastroenterology 136，1639–1650（2009）.
This paper shows thatneutrophil-attracting chemokines are overexpressed in livers from patients withsevere alcoholic cirrhosis.
80. Charo，I. F. & Ransohoff，R. M. Themany roles of chemokines and chemokine receptors in inflammation. N. Engl. J.Med. 354，610–621（2006）.
81. Kubes，P. & Mehal，W. Z. Sterile inflammation in theliver. Gastroenterology 143，1158–1172（2012）.
82. Larosche，I. et al. Prolonged ethanol administration depletes mitochondrial DNA inMnSOD-overexpressing transgenic mice，but not intheir wild type littermates. Toxicol. Appl. Pharmacol. 234，326–338（2009）.
83. Choumar，A. et al. Lipopolysaccharide-induced mitochondrial DNA depletion.Antioxid. Redox Signal. 15， 2837–2854（2011）.
84. West，A. P. et al. Mitochondrial DNA stress primes the antiviral innate immuneresponse. Nature 520， 553–557（2015）.
85. Dubuquoy，L. et al. Progenitor cell expansion and impaired hepatocyte regenerationin explanted livers from alcoholic hepatitis. Gut 64，1949–1960（2015）.
86. Brenner，D. A.，Paik，Y.‑H. &Schnabl，B. Role of gut microbiota in liver disease. J. Clin.Gastroenterol. 49， S25–S27（2015）.
87. Bajaj，J. S. et al. Altered profile of human gut microbiome is associated withcirrhosis and its complications. J. Hepatol. 60，940–947（2014）.
88. Bajaj，J. S. et al. Linkage of gut microbiome with cognition in hepaticencephalopathy. Am. J. Physiol. Gastrointest. Liver Physiol. 302，G168–G175（2012）.
89. Chen，Y. et al. Characterization of fecal microbial communities in patients withliver cirrhosis. Hepatology 54，562–572（2011）.
90. Chen，Y. et al. Gut dysbiosis in acute‑on‑chronic liver failure and itspredictive value for mortality. J. Gastroenterol. Hepatol. 30，1429–1437（2015）.
91. Pan，C. et al. Dynamic changes of lipopolysaccharide levels in different phasesof acute on chronic hepatitis B liver failure. PLoS ONE 7，e49460（2012）.
92. Bauer，T. M. et al. Small intestinal bacterial overgrowth in human cirrhosis isassociated with systemic endotoxemia. Am. J. Gastroenterol. 97，2364–2370（2002）.
This paper shows an associationbetween microbiota alterations and systemic endotoxaemia in patients withcirrhosis.
93. Zapater，P. et al. Serum and ascitic fluid bacterial DNA：a new independent prognostic factor in noninfected patients withcirrhosis. Hepatology 48，1924–1931（2008）.
94. McPhail，M. J. W. et al. Increased survival for patients with cirrhosis and organfailure in liver intensive care and validation of the Chronic LiverFailure-Sequential Organ Failure Scoring System. Clin. Gastroenterol. Hepatol.13，1353–1360.e8（2015）.
95. Silva，P. E. S. E. et al. Single-centre validation of the EASL-CLIF Consortiumdefinition of acute‑on‑chronic liver failure and CLIF-SOFA for prediction ofmortality in cirrhosis. Liver Int. 35，1516–1523（2015）.
96. Gustot，T. et al. Clinical course of acute‑on‑chronic liver failure syndrome andeffects on prognosis. Hepatology 62，243–252（2015）.
This study is the firstinvestigation defining the clinical course of ACLF within 28 days followingdiagnosis. It shows that ACLF is an extremely dynamic syndrome that may improve，worsen or follow a steady course. Prognosis is highly dependent on theclinical course within the first week after diagnosis.
97. Shi，Y. et al. Acute‑on‑chronic liver failure precipitated by hepatic injury isdistinct from that precipitated by extrahepatic insults. Hepatology 62，232–242（2015）.
This study confirms the results ofthe CANONIC study in European patients，showingthat short-term（28‑day and 90‑day）mortalityin Asian patients with ACLF depends on the number of organ failures and not onthe aetiology （the type of precipitating events）of the syndrome.
98. Jalan，R. et al. The CLIF Consortium Acute Decompensation score（CLIF‑C ADs）for prognosis of hospitalised cirrhotic patients withoutacute‑on‑chronic liver failure. J. Hepatol. 62，831–840（2015）.
99. Kamath，P. S. & Kim，W. R. The model for end-stage liverdisease（MELD）Hepatology45，797–805 （2007）.
100. Durand，F. & Valla，D. Assessment of the prognosis ofcirrhosis： Child-Pugh versus MELD. J. Hepatol. 42， S100–S107（2005）.
101. Biggins，S. W. Use of serum sodium for liver transplant graft allocation：a decade in the making，now is itready for primetime? Liver Transpl. 21，279–281（2015）.
102. Fernandez，J. & Arroyo，V. Bacterial infections incirrhosis：a growing problem with significant implications. Clin.Liver Dis. 2，102–105（2013）.
103. Sarin，S. K. et al. Asian-Pacific clinical practice guidelines on the managementof hepatitis B： a 2015 update. Hepatol. Int. 10，1–98（2016）.
104. Sort，P. et al. Effect of intravenous albumin on renal impairment and mortalityin patients with cirrhosis and spontaneous bacterial peritonitis. N. Engl. J.Med. 341，403–409（1999）.
This randomized controlled trialwas the first to show that intravenous albumin administration （1.5 g per kg of body weight at infection diagnosis and 1 g per kg of bodyweight at the third day） is highlyeffective in preventing type 1 HRS and mortality in patients with cirrhosis andspontaneous bacterial peritonitis.
105. Arroyo，V.，García-Martinez，R. &Salvatella，X. Human serum albumin，systemicinflammation，and cirrhosis. J. Hepatol. 61，396–407（2014）.
106. Guevara，M. et al. Albumin for bacterial infections other than spontaneousbacterial peritonitis in cirrhosis. A randomized，controlledstudy. J. Hepatol. 57，759–765（2012）.
107. Thévenot，T. et al. Effect of albumin in cirrhotic patients with infection otherthan spontaneous bacterial peritonitis. A randomized trial. J. Hepatol. 62，822–830（2015）.
108. Ginés，P. et al. Norfloxacin prevents spontaneous bacterial peritonitisrecurrence in cirrhosis：results ofa double-blind，placebo-controlled trial. Hepatology 12，716–724（1990）.
109. Soriano，G. et al. Norfloxacin prevents bacterial infection in cirrhotics withgastrointestinal hemorrhage. Gastroenterology 103，1267–1272（1992）.
110. Fernández，J. et al. Primary prophylaxis of spontaneous bacterial peritonitis delayshepatorenal syndrome and improves survival in cirrhosis. Gastroenterology 133，818–824（2007）.
This randomized controlled trialwas the first to show that long-term oral administration of norfloxacinprevents the development of spontaneous bacterial peritonitis and type 1 HRSand improves survival in patients with cirrhosis and severe liver and renaldysfunction.
111. Zapater，P. et al. Norfloxacin modulates the inflammatory response and directlyaffects neutrophils in patients with decompensated cirrhosis. Gastroenterology137，1669–1679.e1（2009）.
112. Gómez-Hurtado，I. et al. Interleukin‑10‑mediated heme oxygenase 1‑induced underlyingmechanism in inflammatory down-regulation by norfloxacin in cirrhosis.Hepatology 53，935–944（2011）.
113. Gómez-Hurtado，I. et al. Role of interleukin 10 in norfloxacin prevention of luminal freeendotoxin translocation in mice with cirrhosis. J. Hepatol. 61，799–808（2014）.
114. Akriviadis，E. et al. Pentoxifylline improves short-term survival in severe acutealcoholic hepatitis：a double‑blind，placebo-controlled trial. Gastroenterology 119，1637–1648（2000）.
115. Nguyen-Khac，E. et al. Glucocorticoids plus N‑acetylcysteine in severe alcoholichepatitis. N. Engl. J. Med. 365，1781–1789（2011）.
116. Thursz，M. R. et al. Prednisolone or pentoxifylline for alcoholic hepatitis. N.Engl. J. Med. 372，1619–1628 （2015）.
117. Kedarisetty，C. K. et al. Combination of granulocyte colony-stimulating factor anderythropoietin improves outcomes of patients with decompensated cirrhosis.Gastroenterology 148，1362–1370.e7（2015）.
118. Arroyo，V.，Moreau，R.，Jalan，R. & Ginès，P. Acute‑on‑chronicliver failure：a new syndrome that will re‑classify cirrhosis. J.Hepatol. 62，S131–S143（2015）.
119. Seto，W.‑K.，Lai，C.‑L. &Yuen，M.‑F. Acute‑on‑chronic liver failure in chronic hepatitisB. J. Gastroenterol. Hepatol. 27，662–669（2012）.
120. Garg，H. et al. Tenofovir improves the outcome in patients with spontaneousreactivation of hepatitis B presenting as acute‑on‑chronic liver failure.Hepatology 53，774–780（2011）.
121. Philips，C. A. & Sarin，S. K. Potent antiviral therapyimproves survival in acute on chronic liver failure due to hepatitis B virusreactivation. World J. Gastroenterol. 20，16037–16052（2014）.
The results of this study are aclear indication that potent antiviral therapy significantly improves theclinical course and survival of patients with ACLF due to reactivation of HBV.
122. Arabi，Y. M. et al. Antimicrobial therapeutic determinants of outcomes fromseptic shock among patients with cirrhosis. Hepatology 56，2305–2315（2012）.
123. Tandon，P. & Garcia-Tsao，G.Bacterial infections，sepsis，and multiorgan failure in cirrhosis. Semin. Liver Dis. 28，26–42（2008）.
124. Fernández，J.，Tandon，P.，Mensa，J. & Garcia-Tsao，G.Antibiotic prophylaxis in cirrhosis：good andbad. Hepatology 63，2019–2031（2016）.
125. Chen，T. et al. Nucleoside analogues improve the short-term and long-termprognosis of patients with hepatitis B virus-related acute‑on‑chronic liverfailure. Clin. Exp. Med. 12，159–164（2012）.
126. Xie，F. et al. Effects of nucleoside analogue on patients with chronichepatitis B‑associated liver failure： meta‑analysis.PLoS ONE 8，e54773（2013）.
127. Yang，J. et al. Initial combination anti-viral therapy with lamivudine andadefovir dipivoxil decreases short-term fatality rate of hepatitis-B‑virus-relatedacute‑on‑chronic liver failure. Virol. J. 12，97（2015）.
128. Garg，V. et al. Granulocyte colony-stimulating factor mobilizes CD34+ cells andimproves survival of patients with acute‑on‑chronic liver failure.Gastroenterology 142，505–512.e1（2012）.
129. Angeli，P. et al. Diagnosis and management of acute kidney injury in patients withcirrhosis：revised consensus recommendations of the InternationalClub of Ascites. J. Hepatol. 62，968–974（2015）.
This article provides the mostmodern clinical guidelines on the diagnosis and treatment of AKI in cirrhosis.
130. Belcher，J. M. et al. Urinary biomarkers and progression of AKI in patients withcirrhosis. Clin. J. Am. Soc. Nephrol. 9，1857–1867（2014）.
131. Rivers， E. et al. Early goal-directed therapy in the treatment of severe sepsisand septic shock. N. Engl. J. Med. 345， 1368–1377（2001）.
132. Fede，G. et al. Adrenocortical dysfunction in liver disease：asystematic review. Hepatology 55，1282–1291 （2012）.
133. Vilstrup，H. et al. Hepatic encephalopathy in chronic liver disease：2014 Practice Guideline by the American Association for the Study of LiverDiseases and the European Association for the Study of the Liver. Hepatology 60，715–735（2014）.
134. Bianchini，M.，De Pietri，L. &Villa，E. Coagulopathy in liver diseases：complicationor therapy? Dig. Dis. 32，609–614（2014）.
135. de Franchis，R. & Baveno VI Faculty. Expanding consensus in portal hypertension：report of the Baveno VI Consensus Workshop：stratifyingrisk and individualizing care for portal hypertension. J. Hepatol. 63，743–752（2015）.
This article provides the mostmodern clinical guidelines on the diagnosis management of portal hypertensionand gastrointestinal haemorrhage in cirrhosis. There is a detailed descriptionon the management of coagulopathy in patients with portal vein thrombosis.
136. Lee，S. Y.，Kim，H. J. &Choi，D. Cell sources，liversupport systems and liver tissue engineering：alternativesto liver transplantation. Int. J. Stem Cells 8，36–47（2015）.
137. Struecker，B.，Raschzok，N. &Sauer，I. M. Liver support strategies：cutting-edge technologies. Nat. Rev. Gastroenterol. Hepatol. 11，166–176（2014）.
This article contains acomprehensive review of the artificial liver support strategies in patientswith acute liver failure and ACLF.
138. Bañares，R. et al. Extracorporeal albumin dialysis with the molecular adsorbent recirculatingsystem in acute‑on‑chronic liver failure：the RELIEFtrial. Hepatology 57，1153–1162（2013）.
139. Kribben，A. et al. Effects of fractionated plasma separation and adsorption onsurvival in patients with acute‑on‑chronic liver failure. Gastroenterology 142，782–789.e3（2012）.
140. Lee，K. C. L. et al. Extracorporeal liver assist device to exchange albumin andremove endotoxin in acute liver failure：results ofa pivotal pre-clinical study. J. Hepatol. 63，634–642（2015）.
141. Larsen，F. S. et al. High-volume plasma exchange in patients with acute liverfailure：an open randomised controlled trial. J. Hepatol. 64，69–78（2016）.
142. Bahirwani，R.，Shaked，O.，Bewtra，M.，Forde，K. & Reddy，K. R. Acute‑on‑chronic liverfailure before liver transplantation：impact on posttransplantoutcomes. Transplantation 92，952–957（2011）.
143. Duan，B.‑W. et al. Liver transplantation in acute‑on‑chronic liver failurepatients with high model for end-stage liver disease（MELD）scores：a singlecenter experience of 100 consecutive cases. J. Surg. Res. 183， 936–943（2013）.
144. Finkenstedt，A. et al. Acute‑on‑chronic liver failure：excellentoutcomes after liver transplantation but high mortality on the wait list. LiverTranspl. 19，879–886（2013）.
145. Sharma，P.，Schaubel，D. E.，Gong，Q.，Guidinger，M. & Merion，R. M. End-stage liver diseasecandidates at the highest model for end-stage liver disease scores have higherwait-list mortality than status‑1A candidates. Hepatology 55，192–198（2012）.
146. Chan，A. C. et al. Liver transplantation for acute‑on‑chronic liver failure.Hepatol. Int. 3，571–581（2009）.
147. Chan，A. C. Y. & Fan，S. T.Criteria for liver transplantation in ACLF and outcome. Hepatol. Int. 9，355–359（2015）.
148. Reddy，M. S.，Rajalingam， R. &Rela，M. Liver transplantation in acute‑on‑chronic liverfailure：lessons learnt from acute liver failure setting. Hepatol.Int. 9，508–513（2015）.
149. Khanam，A. et al. Altered frequencies of dendritic cells and IFN‑γ‑secreting Tcells with granulocyte colony-stimulating factor（G‑CSF）therapy in acute‑on-chronic liver failure. Liver Int. 34，505–513（2014）.
150. Duan，X.‑Z. et al. Granulocyte-colony stimulating factor therapy improvessurvival in patients with hepatitis B virus-associated acute‑on‑chronic liverfailure. World J. Gastroenterol. 19，1104–1110（2013）.
151. Ma，X.‑R. et al. Transplantation of autologous mesenchymal stem cells forend-stage liver cirrhosis： ameta-analysis based on seven controlled trials. Gastroenterol. Res. Pract. 2015，908275（2015）.
152. Volk，M. L.，Tocco，R. S.，Bazick，J.，Rakoski，M. O. & Lok，A. S. Hospital readmissions amongpatients with decompensated cirrhosis. Am. J. Gastroenterol. 107，247–252（2012）.
153. Reddy，K. R. et al. High risk of delisting or death in liver transplantcandidates following infections：resultsfrom the North American Consortium for the Study of End-Stage Liver Disease.Liver Transpl. 21，881–888 （2015）.
154. O’Leary，J. G. et al. Long-term use of antibiotics and proton pump inhibitorspredict development of infections in patients with cirrhosis. Clin. Gastroenterol.Hepatol. 13，753–759.e2（2015）.
155. Battle，C. E.，Davies，G. &Evans，P. A. Long term health-related quality of life insurvivors of sepsis in south west Wales：anepidemiological study. PLoS ONE 9，e116304（2014）.
156. Vanwijngaerden，Y.‑M. et al. Critical illness evokes elevated circulating bile acidsrelated to altered hepatic transporter and nuclear receptor expression.Hepatology 54，1741–1752（2011）.
157. Katoonizadeh，A. et al. Early features of acute‑on‑chronic alcoholic liver failure： a prospective cohort study. Gut 59，1561–1569（2010）.
158. Hotchkiss，R. S.，Monneret，G. &Payen，D. Sepsis‑induced immunosuppression： from cellular dysfunctions to immunotherapy. Nat. Rev. Immunol. 13，862–874（2013）.
159. Gomez，H. et al. A unified theory of sepsis-induced acute kidney injury：inflammation，microcirculatory dysfunction，bioenergetics，and the tubular cell adaptation toinjury. Shock 41，3–11（2014）.
This article contains acomprehensive review of the mechanisms of AKI associated with systemicinflammation in sepsis. Concepts might be extended to AKI and other types oforgan failure in ACLF.
160. Jiménez，W.，Clária，J.，Arroyo，V. & Rodés，J. Carbontetrachloride induced cirrhosis in rats：a usefultool for investigating the pathogenesis of ascites in chronic liver disease. J.Gastroenterol. Hepatol. 7，90–97 （1992）.
161. Harry，D. et al. Increased sensitivity to endotoxemia in the bile duct-ligatedcirrhotic rat. Hepatology 30， 1198–1205（1999）.
162. Bass，N. M. et al. Rifaximin treatment in hepatic encephalopathy. N. Engl. J.Med. 362，1071–1081（2010）.
This article reports a randomizedcontrolled trial showing that oral rifaximin is highly effective in preventingthe recurrence of hepatic encephalopathy in cirrhosis.
163. Bernardi，M. et al. Long-term use of human albumin for the treatment of ascites inpatients with hepatic cirrhosis：the interimanalysis of the ANSWER study. Dig. Liv. Dis. 47（Suppl. 1），e6（2015）.
164. Neuschwander-Tetri，B. A. et al. Farnesoid X nuclear receptor ligand obeticholic acid fornon-cirrhotic， non‑alcoholic steatohepatitis（FLINT）：a multicentre，randomised，placebo-controlled trial. Lancet 385，956–965（2015）.
165. Verbeke，L. et al. Obeticholic acid，a farnesoidX receptor agonist，improves portal hypertension by twodistinct pathways in cirrhotic rats. Hepatology 59，2286–2298（2014）.
166. Verbeke，L. et al. The FXR agonist obeticholic acid prevents gut barrierdysfunction and bacterial translocation in cholestatic rats. Am. J. Pathol. 185，409–419（2015）.
This article reports a study inexperimental cirrhosis showing that oral obeticholic acid improves gutpermeability，intestinal inflammation and bacterial translocation.
167. Kayagaki，N. et al. Noncanonical inflammasome activation by intracellular LPSindependent of TLR4. Science 341，1246–1249（2013）.
168. Shi，J. et al. Inflammatory caspases are innate immune receptors forintracellular LPS. Nature 514，187–192 （2014）.
169. Broz，P. Immunology：caspase target drives pyroptosis.Nature 526，642–643（2015）.
170. Sargenti，K.，Prytz，H.，Nilsson，E. & Kalaitzakis，E.Predictors of mortality among patients with compensated and decompensated livercirrhosis：the role of bacterial infections and infection-relatedacute‑on‑chronic liver failure. Scand. J. Gastroenterol. 50，875–883（2015）.
171. Blei，A. T. & Córdoba，J. Hepaticencephalopathy. Am. J. Gastroenterol. 96，1968–1976（2001）.
Acknowledgements
The European Association for theStudy of the Liver-Chronic Liver Failure（EASL-CLIF）Consortium is endorsed by the European Association for the Study of theLiver and supported by an unrestricted grant from Grifols. The authors thank D.J. Kim for the supply of the published Korean data and the Data ManagementCentre of the EASL-CLIF Consortium for providing the unpublished European dataused in Figure 2.
Author contributions
Introduction（V.A.）； Epidemiology（P.S.K.）； Mechanisms/ pathophysiology （R.M. andB.S.）； Diagnosis， screeningand prevention（P.G.，V.A. andJ.F.）；Management（R.J.，G.G.‑T.，U.T. and J.F.）；Quality oflife （P.S.K.）；Outlook（F.N. and V.A.）；Overview of Primer（V.A.）. V.A. and R.M. contributed equally to this work.
Competing interests statement
V.A. has received research fundingfrom Grifols and has served on the scientific advisory board for Takeda. P.G.has received research funding from Grifols，served onthe scientific advisory board for Ferring and Squana Medical and receivedresearch funding from Sequana Medical. R.J. has received research funding fromVital Therapies，has served on the scientific advisory board for ConatusPharma and Takeda，has ongoing research collaborationswith Gambro and Grifiols and is the principal investigator of an industrysponsored study （Sequana Medical）. F.N. hasserved on the scientific advisory board of Center Fract，Croix Rouge Belgium， Intercept，Gore，Bristol-Myers Squibb，AbbVie，Novartis，MSD，Janssen-Cilag，Promethera Biosciences and Gilead，and hasreceived grants from Roche，Astellas，Ferring，Novartis，Janssen-Cilagand AbbVie. All other authors declare no competing interests.
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