The brain in acute on chronic liver failure

Acute-on-chronic liver failure (ACLF) is a newly defined clinical entity with significant morbidity and mortality (~40–90 % at 1 year dependent on need for organ support at presentation). It defines a presentation with acute severe liver injury, often with multiorgan dysfunction, on a background of previously known or unknown cirrhosis. In its severest form, it is almost indistinguishable from acute liver failure, as similarly in around 5 % may rapidly progress to intracranial hypertension and cerebral oedema culminating in coma and/or death. Our understanding of such cerebral sequelae is currently limited to clinical observation, though our knowledge base is rapidly expanding since recent consensus clinical definition and guidance. Moreover, there are now animal models of ACLF and imaging modalities to better characterize events in the brain that occur with ACLF. However, as yet there has been little in the way of interventional study of this condition which are much needed. In this review we dissect existing clinical and experimental data to better characterise the manifestations of ACLF on the brain and allow for the development of targeted therapy as currently the plethora of existing interventions were designed to treat either the effects of cirrhosis or acute liver injury independently.     

慢加急性乙型肝炎肝衰竭患者贫血特点分析

目的探索慢加急性肝衰竭患者贫血的发生、转归及对短期生存的影响。方法纳入2011年12月至2013年1月我院住院的乙型肝炎病毒感染导致的慢加急性肝衰竭患者,中心实验室常规检测血常规、血肌酐、谷丙转氨酶、谷草转氨酶、白蛋白、总胆红素、凝血功能指标等。与慢性乙型肝炎及HBV相关的肝硬化患者比较,观察慢加急性肝衰竭患者贫血的发生、转归。结果在纳入的171例肝病患者中,40例慢性乙型肝炎患者贫血发生率为2.5%,49例肝硬化患者为34.7%,82例慢加急性肝衰竭患者住院时贫血发生率为45.1%(其中26.8%为轻度贫血,17.1%为中度贫血,1.2%为重度贫血);慢加急性肝衰竭患者贫血程度在住院1周内加重(122.4 g/L对112.7 g/L,P0.001);长期生存患者(n=42)恢复期贫血情况显著改善(147.5 g/L对入院时的112.7 g/L,P=0.001);住院首日血红蛋白水平(截断点125.5 g/L)是90天生存率的预测因素(曲线下面积=0.735,P0.001)。结论慢加急性肝衰竭患者贫血发生率高,对短期生存不利,而生存者贫血情况可缓慢恢复;入院时血红蛋白水平能预测短期预后。     

Acute kidney injury in acute on chronic liver failure

Acute on chronic liver failure (ACLF) is a distinct clinical entity; however, there is still debate in the way it is defined in the East as compared to the West, especially with respect to incorporation of kidney dysfunction or failure in the definition of ACLF. Kidney dysfunction is defined as serum creatinine between 1.5 and 1.9 mg/dl and kidney failure as serum creatinine of more than 2 mg/dl or requirement of renal replacement therapy according to the EASL-CLIF Consortium. Kidney dysfunction or failure is universally present in patients with ACLF according to the definition by the EASL-CLIF Consortium while on the contrary the APASL definition of ACLF does not incorporate kidney dysfunction or failure in its definition. Recently, both the diagnosis and management of renal failure in patients with cirrhosis has changed with the advent of the acute kidney injury (AKI) criteria defined as an abrupt decline in renal functions, characterized by an absolute increase in serum creatinine of 0.3 mg/dl within 48 h or an increase of more than 50 % from baseline, which is known or presumed to have occurred in the previous 7 days. Further, recent studies in patients with cirrhosis have shown the utility of biomarkers for the diagnosis of AKI. The present review covers the pathogenetic mechanisms, diagnosis, prognosis as well as management of AKI in patients with ACLF from both a Western as well as an Eastern perspective. The review identifies an unmet need to diagnose AKI and prevent this ominous complication in patients with ACLF.     

Effect of acute on chronic liver failure over post-transplant survival

Introduction and ObjectivesAcute-on-chronic liver failure (ACLF) is associated with reduced short-term survival, and liver transplantation is frequently the only therapeutic option. Nonetheless, the post-transplantation prognosis seems to be worse in ACLF patients.Materials and MethodsThe databases of two university centers were retrospectively evaluated, and adult patients with cirrhosis who underwent transplantation between 2013 and 2020 were included. One-year survival of patients with ACLF was compared to that of patients without ACLF. Variables associated with mortality were identified.ResultsA total of 428 patients were evaluated, and 303 met the inclusion criteria; 57.1% were male, the mean age was 57.1 ± 10.2 years, 75 patients had ACLF, and 228 did not. The main etiologies of ACLF were NASH (36.6%), alcoholic liver disease (13.9%), primary biliary cholangitis (8.6%) and autoimmune hepatitis (7.9%). Mechanical ventilation, renal replacement therapy, the use of vasopressors and the requirement of blood product transfusion during liver transplantation were significantly more frequent in ACLF patients. Among those recipients without and with ACLF, survival at 1, 3 and 5 years was 91.2% vs. 74.7%, 89.1% vs. 72.6% and 88.3% vs. 72.6%, respectively (p=0.001). Among pre-transplantation variables, only the presence of ACLF was independently associated with survival (HR 3.2, 95% CI: 1.46-7.11). Post-transplantation variables independently associated with survival were renal replacement therapy (HR 2.8, 95% CI: 1.1-6.8) and fungal infections (HR 3.26, 95% CI: 1.07-9.9).ConclusionsACLF is an independent predictor of one-year post-transplantation survival. Importantly, transplant recipients with ACLF require the use of more resources than patients without ACLF.     

HBV感染所致慢加急性肝功能衰竭患者HBV变异的纵向研究

目的明确乙型肝炎病毒（HBV）变异与慢加急性肝功能衰竭（ACLF）发病之间的关系。方法采用纵向研究的方法 ,选取6例HBV感染者为研究对象,其中ACLF4例（P1～P4）,肝硬化（LC）2例（P5、P6）。分别留取每例患者不同疾病阶段血清2份,进行HBVDNA提取、扩增、克隆和测序,测序结果采用VectorNTISuite9.0软件分析,纵向对比HBV核苷酸序列变异情况。结果 6例患者均为基因C型。ACLF患者（P1～P4）在病程中HBV的核苷酸突变位点多于发生肝硬化患者（P5、P6）。ACLF患者中,nt53（C→T或T→C）、nt1846（A→T）、nt1896（G→A）的纵向突变见于2例或2例以上患者。C1913A或T突变可见于患者P1、P2,同时患者P2可见纵向突变。结论 nt53、nt1846、nt1896和nt1913四个核苷酸的突变可能与ACLF的发病相关。     

Acute liver injury,acute liver failure and acute on chronic liver failure: A clinical spectrum of poisoning due to Gyromitra esculenta

Gyromitra esculenta, also known as “false morel” is one of the most poisonous mushrooms. This species is found all over the world, growing in coniferous forest in early spring time. Common manifestation of poisoning includes gastrointestinal symptoms which include varied degrees of liver impairment.We describe three cases: acute liver injury, acute liver failure and acute-on-chronic liver failure due to G. esculenta poisoning. At admission patients presented with encephalopathy and features of liver failure. Two of them recovered completely following supportive management while the remaining patient who also had preexisting liver disease developed multiorgan failure and subsequently died.Although a rare occurrence, G. esculenta poisoning should be considered in the differential diagnosis of acute liver failure.     

CLIF-C OFs在乙型肝炎相关慢性肝病急性失代偿患者中鉴别慢加急性肝功能衰竭的临床研究

目的探究欧洲肝病学会提出的适用于以酒精为病因引起的慢加急性肝衰竭诊断标准(CLIF Consortium Organ Failure score,CLIF-C OF)是否适用于乙型肝炎相关的慢加急性肝衰竭。方法筛选并纳入2005年1月至2010年12月上海瑞金医院乙型肝炎相关慢性肝病急性失代偿患者854例,按CLIF-C OF标准分为ACLF组和非ACLF组。分析ACLF组和非ACLF组的临床和实验室指标、病情严重程度和短期病死率。结果 ACLF组262例和非ACLF组592例。ACLF组较非ACLF组年龄大,肝、肾、脑、凝血、循环、呼吸功能衰竭情况均显著高于入院非ACLF组(P0.01),28 d和90 d病死率均显著升高(27.1%比3.1%、39.6%比4.9%,P0.01),提示病情更重。结论欧洲肝病学会所提出的评分标准可从乙型肝炎相关慢性肝病合并急性失代偿患者中筛选出一组病情更为危重、病死率更高的慢加急性肝衰竭患者群体。乙型肝炎相关慢性肝病并发急性失代偿患者中确实存在一群疾病程度更严重的ACLF群体,CLIF-C OF标准可将ACLF患者从乙型肝炎相关慢性肝病并发急性失代偿患者中区分出来,以指导临床医生治疗决策。     

PE结合DPMAS对肝硬化并发慢加急性肝衰竭患者生存状况的影响

目的 探索血浆置换(plasma exchange,PE)结合双重血浆分子吸附系统(double plasma molecular absorbsystem,DPMAS)对肝硬化并发慢加急性肝衰竭患者生存状况的影响.方法 2017年1月—2019年1月我院共收治3684例肝脏疾病患者,按照纳入及排除标准最终确定248例...     

Hepatic and systemic haemodynamic changes after MARS in patients with acute on chronic liver failure

Abstract Hyperdynamic circulation and portal hypertension characterize acute on chronic liver failure (AoCLF), partially because of circulating mediators. Molecular Absorbents Recirculating System (MARS) may remove some of these substances. The objective of this study was to evaluate the effect of MARS on portal pressure, systemic haemodynamic and endogenous vasoactive systems. MARS treatment was performed in four patients with AoCLF (mean age 36.2 ± 3.1 years; Child–Pugh C 11 ± 1.8 points; three AAH and one NASH). Systemic and splanchnic haemodynamic measurements were performed before and after each session. Plasmatic renin activity (PRA) and NE were measured at baseline, at the end of the sessions and 10 days after MARS. All patients had severe portal hypertension (HVPG = 23 ± 7 mmHg) and pronounced hyperdynamic circulation (MAP 77.8 ± 11.7 mmHg; CO 11.2 ± 1.6 L/min; SVRI 478.5 ± 105 dyne s/cm⁵). HVPG decreased at the end of the first session in all patients (23 ± 7 mmHg vs 17.3 ± 9.9 mmHg; P = 0.05; mean decrease 32 ± 24%) because of a decrease in WHVP (40.7 ± 5.6 mmHg vs 34 ± 9.6 mmHg; P = 0.025; mean decrease 18 ± 19%). MARS significantly attenuated hyperdynamic circulation as shown by a decrease in CO (11.2 ± 1.6 L/min vs 9.4 ± 2.1 L/min; mean decrease 12.3%), with an increase in MAP (77.8 ± 11.7 mmHg vs 84.2 ± 8 mmHg; mean increase 9.2%) and in SVRI (478.5 ± 105 dyne s/cm⁵ vs 622 ± 198 dyne s/cm⁵; mean increase 41%). PRA and NE decreased significantly (14.2 ± 17.2 ng/mL/h vs 3.7 ± 3.4 ng/mL/h; 1319 ± 1002 pg/mL vs 617 ± 260 pg/mL, respectively). The NE decrease was correlated to HVPG decrease (r = 1, P = 0.01). MARS decreases portal hypertension and ameliorates hyperdynamic circulation in patients with AoCLF, probably mediated by clearance of vasoactive substances. Further studies are necessary to confirm these results.     

慢加急性乙型肝炎肝衰竭患者死亡危险因素和预后评分模型的构建

目的 分析慢加急性乙型肝炎肝衰竭(HBV-ACLF)患者死亡的危险因素,建立预后评分预测模型.方法 2016年1月～2019年9月我院收治的126例HBV-ACLF患者,记录临床资料,将各指标纳入多因素Logistic回归分析,并建立预后评分预测模型,采用Hosmer-Lemeshow检验评估模型拟合度,采用ROC检验...     

一级慢加急性肝衰竭是后续三级肝衰竭的预测因子

【据《Hepatology》2019年11月报道】题:一级慢加急性肝衰竭是后续三级肝衰竭的预测因子(作者Mahmud N等)慢加急性肝衰竭(ACLF)可升高潜在肝硬化患者的短期病死率。根据急性失代偿后发生的器官衰竭情况,欧洲肝病学会将ACLF的严重程度分为1级(最轻)至3级(最重)。然而,就随后发生的高等级ACLF的风险而言,幸存下来的低等级ACLF的意义尚不清楚。     

Safety and efficacy profile of G-CSF therapy in patients with acute on chronic liver failure

BACKGROUND/AIM: We aimed to evaluate safety and efficacy of granulocyte-colony stimulating factor treatment in patients with acute on chronic liver failure and the effect of granulocyte-colony stimulating factor on the expression level of CXCR4, vascular endothelial growth factor receptor and very late activation antigen 4. METHODS: Twenty-four patients with acute on chronic liver failure were randomised to receive standard therapy, standard therapy+granulocyte-colony stimulating factor (5 microg/kg/day for 6 days) and standard therapy+granulocyte-colony stimulating factor (15 microg/kg/day s.c. for 6 days). Data on CD34+cell mobilisation were compared to age-matched peripheral blood haematopoietic stem cell donors treated with granulocyte-colony stimulating factor. On day third of treatment, the expression level of CXCR4, vascular endothelial growth factor receptor and very late activation antigen 4 was analysed in mobilised CD34+ cells. RESULTS: CD34 cell count increased after the second day of granulocyte-colony stimulating factor injection in both treatment groups compared to the linear increase observed in control. After the fifth day the increase was significantly higher in healthy donors versus patients with acute on chronic liver failure. A decrease in the expression of CXCR4, very late activation antigen 4 and vascular endothelial growth factor receptor compared to premobilisation values was observed. No major side effects were observed. CONCLUSIONS: Granulocyte-colony stimulating factor treatment is able to induce CD34 mobilisation in patients with acute on chronic liver failure. The expression pattern of CXCR4, very late activation antigen 4 and vascular endothelial growth factor receptor suggests that these molecules are involved in the granulocyte-colony stimulating factor-induced stem cell mobilisation.     

Long-term therapy of acute chronic liver failure to successful transplantation with an extracorporeal liver support system

We report the case of a 38-year-old Caucasian male who was admitted because of end-stage liver failure due to primary sclerosing cholangitis. Because of the rapidly progressive severe hepatic encephalopathy and development of hepatorenal syndrome type I, the patient was immediately upgraded to a high priority status on the liver transplantation waiting list (T2 status according to Eurotransplant criteria). Intermittent therapy with an extracorporeal liver support system (Prometheus) was initiated in order to bridge the time period until the expected transplantation date. Under therapy with the extracorporeal liver support system, total serum bilirubin decreased significantly from 33 to 15 mg/dL after 8 sessions. Simultaneously the encephalopathy resolved gradually within 3 weeks (10 sessions) from initially grade 3 to grade 1. Extracorporeal detoxification therapy was continued for 51 days (23 sessions) until the patient underwent his successful liver transplantation in good general clinical condition. Prometheus, a new liver support system, seemed to sufficiently replace hepatic detoxification on a long-term basis in this patient with end-stage liver failure in order to bridge the time period until liver transplantation.     

慢加急性肝衰竭与慢性肝衰竭临床特征对比性分析

目的了解慢加急性肝衰竭(ACLF)与慢性肝衰竭(CLF)的临床特征及预后差异。方法 103例慢性重型肝炎患者按肝衰竭诊疗指南分为ACLF组(35例)和CLF组(68例),比较两组临床及实验室指标、常见并发症、MELD评分及预后。结果 CLF在慢性重型肝炎中占66.02%(68/103),患者年龄较大、病程较长;两组在血常规参数(WBC、HB、PLT、MPV)和凝血指标(PT、APTT、TT)均有差异(P<0.05,P<0.01);ACLF组肝功能AST、ALT、TBIL、ALB高于CLF组,GLO、TBA低于CLF组(P<0.05,P<0.01);两组腹水和肝性脑病发生率差异有统计学意义(P<0.01);ACLF组MELD分值低于CLF组,其预后优于CLF组(P<0.05,P<0.01)。结论 ACLF和CLF在好发年龄、病程、血常规参数、凝血功能、肝功能指标、并发症腹水和肝性脑病发生率、MELD评分及预后均有差异。肝衰竭指南符合国情,有重要的临床应用价值。     

The importance of immune dysfunction in determining outcome in acute liver failure

Acute liver failure (ALF) shares striking similarities with septic shock with regard to the features of systemic inflammation, progression to multiple organ dysfunction and functional immunoparesis. While the existence of opposing systemic pro- and anti-inflammatory profiles resulting in organ failure and immune dysfunction are well recognised in septic shock, characterization of these processes in ALF has only recently been described. This review explores the evolution of the systemic inflammation in acute liver failure, its relation to disease progression, exacerbation of liver injury and development of innate immune dysfunction and extra-hepatic organ failure as sequelae. Defects in innate immunity are described in hepatic and extra-hepatic compartments. Clinical studies measuring levels of pro- and anti-inflammatory cytokines and expression of the antigen presentation molecule HLA-DR on monocytes, in combination with ex-vivo experiments, demonstrate that the persistence of a compensatory anti-inflammatory response syndrome, leading to functional monocyte deactivation, is a central event in the evolution of systemic immune dysfunction. Accurate immune profiling in ALF may permit the development of immunomodulatory strategies in order to improve outcome in this condition.     

慢加急性肝衰竭患者血小板减少的可能原因

目的探讨引起慢加急性肝衰竭患者发生血小板减少的可能原因。方法选取南方医院肝病中心2011年12月至2014年8月住院的慢性乙型肝炎(CHB)、HBV相关肝硬化(CIR)、HBV相关慢加急性肝功能衰竭(ACLF)患者,收集患者相关临床资料,检测网织血小板比例、促血小板生成素水平、血小板活化比例(PAC-1、CD63、CD62p)、糖蕚素、可溶性CD163、凋亡血小板比例等指标,对以上指标进行相关和多元线性回归分析。结果研究共纳入191例患者,其中慢性乙型肝炎组68例,肝硬化组48例,慢加急性肝功能衰竭组75例。慢加急性肝功能衰竭患者血小板计数98(3~253)G/L较慢性乙型肝炎组172(24~327)G/L低(P0.01),与肝硬化患者88(22~244)G/L相当(P=0.913)。ACLF患者入院1周血小板计数71(4~208)G/L较入院当天97(21~267)G/L明显下降(P0.01)。慢加急性肝功能衰竭组患者脾脏厚度(40.4比35.1 mm,P=0.002)、D-二聚体(443.5比90 ug/L,P=0.002)、PT-INR(2.14比1.26,P0.01)、sCD163(5.33比1.81 ln mg/mL,P0.01)均高于慢性乙型肝炎组。但纤维蛋白原水平(1.24比2.25 g/L,P0.01)和血小板PAC-1(+)阳性率(3.33比10.7,P=0.002)均低于慢性乙型肝炎组。网织血小板比例、TPO、CD62p、CD63、糖蕚素、凋亡血小板比例在慢性乙型肝炎组与慢加急性肝功能衰竭组之间差异无统计学意义。血小板计数与脾脏厚度、PT-INR、总胆红素水平、血小板凋亡水平呈负相关,与纤维蛋白原水平、白蛋白水平、糖萼素水平呈正相关。多元线性回归分析显示,脾脏厚度、糖萼素水平,纤维蛋白原水平是ACLF患者血小板减少的独立危险因素(R2=0.597,P=0.011)。入院日的血小板计数可预测28天死亡(AUROC=0.72,P0.01)。结论慢加急性肝衰竭患者脾脏厚度、纤维蛋白原、糖萼素为血小板减少的独立危险因素。入院日血小板计数可预测患者的短期预后。