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Acute-on chronic liver failure Rajiv Jalan 1,, Pere Gines 2 , Jody C Olson 3 , Rajeshwar P Mookerjee 1 , Richard Moreau 4 , Guadalupe Garcia-Tsao 5 , Vicente Arroyo 2 , Patrick S Kamath 3 1 Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom; 2 Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalunya, Spain, Institut d’Investigacions Biomèdiques August-Pi-Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas yDigestivas (CIBEREHED), Spain; 3 Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States; 4 INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Paris and Clichy, France; 5 Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States Summary Acute-on-chronic liver failure (ACLF) is an increasingly recogni- sed entity encompassing an acute deterioration of liver function in patients with cirrhosis, which is usually associated with a precipitating event and results in the failure of one or more organs and high short term mortality. Prospective data to define this is lacking but there is a large body of circumstantial evidence suggesting that this condition is a distinct clinical entity. From the pathophysiologic perspective, altered host response to injury and infection play important roles in its development. This review focuses upon the current understanding of this syndrome from the clinical, prognostic and pathophysiologic perspectives and indicates potential biomarkers and therapeutic targets for intervention. Ó 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. Introduction Acute-on-chronic liver failure (ACLF) is an increasingly recognised entity encompassing an acute deterioration of liver function in patients with cirrhosis, either secondary to superimposed liver injury or due to extrahepatic precipitating factors such as infection culminating in the end-organ dysfunction (Fig. 1). Occasionally, no specific precipitating event can be found. Although the exact path- ophysiology of the development of ACLF remains to be elucidated, unregulated inflammation is thought to be a major contributing factor. A characteristic feature of ACLF is its rapid progression, the requirement for multiple organ supports and a high incidence of short and medium term mortality of 50–90% [1]. The condition remains undefined but two consensus working definitions for this syndrome exist. The first was put forward by the Asia–Pacific association for the study of liver disease [2];‘Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease’; and a second at a EASL-AASLD single topic symposium [3];‘Acute deterioration of pre-existing, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3 months due to multi-system organ failure’. These definitions are too imprecise to allow homogeneous diagnostic criteria and clinical studies are cur- rently underway to reach an evidence-based definition. The latter definition implies that organ failure is a central component of this syndrome and leads to the hypothesis that the organs may behave differently to chronic decompensated liver disease. This review focuses upon the current understanding of this syndrome from the clinical, prognostic and pathophysiologic perspectives and indicates potential biomarkers and therapeutic targets for inter- vention. It is the second definition that will be used in the descrip- tion that follows unless otherwise stated. Epidemiology Data regarding the epidemiology of ACLF is rare. At the recently held EASL-AASLD Single Topic Symposium on the management of critically ill cirrhotic patients in the ICU (Atlanta, 2010), data were presented from the nationwide in-patient sample in the US for the year 2006. Using the parameters of the need for mechanical ventilation and/or invasive cardiovascular monitor- ing, 26,300 patients were identified. In-hospital mortality was found to be 53% and the mean length of hospitalization was about 14 days. The total charges associated with the ICU admissions alone were 3 billion US dollars with a suggestion that the ICU mortality in cirrhotic patients has remained unchanged [3]. It is likely that a significant proportion of these patients had ACLF but is difficult to confirm until evidence-based definition of ACLF is derived. Clinical and prognostic factors (P) Data on the natural history of patients with cirrhosis progressing to multiorgan failure and its outcome are limited. In a study reported in a preliminary form, the group at UCL hypothesized Journal of Hepatology 2012 vol. 57 j 1336–1348 Keywords: Acute-on chronic liver failure; Hepatorenal syndrome; Hepatic ence- phalopathy; Immune failure; Liver support; Liver transplantation. Received 3 April 2012; received in revised form 19 June 2012; accepted 19 June 2012 Corresponding author. Address: Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London NW3 2PF, United Kingdom. Tel.: +44 2074332795. E-mail address: [email protected] (R. Jalan). Review

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Review

Acute-on chronic liver failure

Rajiv Jalan1,⇑, Pere Gines2, Jody C Olson3, Rajeshwar P Mookerjee1, Richard Moreau4,Guadalupe Garcia-Tsao5, Vicente Arroyo2, Patrick S Kamath3

1Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London,United Kingdom; 2Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalunya, Spain, Institut d’Investigacions Biomèdiques

August-Pi-Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas yDigestivas (CIBEREHED), Spain; 3Division ofGastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States; 4INSERM, U773, Centre de Recherche

Biomédicale Bichat-Beaujon CRB3, Paris and Clichy, France; 5Section of Digestive Diseases, Yale University School of Medicine,New Haven, CT, United States

Summary manifesting as jaundice and coagulopathy, complicated within

Acute-on-chronic liver failure (ACLF) is an increasingly recogni-sed entity encompassing an acute deterioration of liver functionin patients with cirrhosis, which is usually associated with aprecipitating event and results in the failure of one or moreorgans and high short term mortality. Prospective data to definethis is lacking but there is a large body of circumstantial evidencesuggesting that this condition is a distinct clinical entity. Fromthe pathophysiologic perspective, altered host response to injuryand infection play important roles in its development. Thisreview focuses upon the current understanding of this syndromefrom the clinical, prognostic and pathophysiologic perspectivesand indicates potential biomarkers and therapeutic targets forintervention.� 2012 European Association for the Study of the Liver. Publishedby Elsevier B.V. All rights reserved.

Introduction

Acute-on-chronic liver failure (ACLF) is an increasingly recognisedentity encompassing an acute deterioration of liver function inpatients with cirrhosis, either secondary to superimposed liverinjury or due to extrahepatic precipitating factors such as infectionculminating in the end-organ dysfunction (Fig. 1). Occasionally, nospecific precipitating event can be found. Although the exact path-ophysiology of the development of ACLF remains to be elucidated,unregulated inflammation is thought to be a major contributingfactor. A characteristic feature of ACLF is its rapid progression,the requirement for multiple organ supports and a high incidenceof short and medium term mortality of 50–90% [1]. The conditionremains undefined but two consensus working definitions for thissyndrome exist. The first was put forward by the Asia–Pacificassociation for the study of liver disease [2]; ‘Acute hepatic insult

Journal of Hepatology 20

Keywords: Acute-on chronic liver failure; Hepatorenal syndrome; Hepatic ence-phalopathy; Immune failure; Liver support; Liver transplantation.Received 3 April 2012; received in revised form 19 June 2012; accepted 19 June 2012⇑ Corresponding author. Address: Liver Failure Group, UCL Institute for Liver andDigestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street,London NW3 2PF, United Kingdom. Tel.: +44 2074332795.E-mail address: [email protected] (R. Jalan).

4 weeks by ascites and/or encephalopathy in a patient with previouslydiagnosed or undiagnosed chronic liver disease’; and a second at aEASL-AASLD single topic symposium [3]; ‘Acute deterioration ofpre-existing, chronic liver disease, usually related to a precipitatingevent and associated with increased mortality at 3 months due tomulti-system organ failure’. These definitions are too imprecise toallow homogeneous diagnostic criteria and clinical studies are cur-rently underway to reach an evidence-based definition. The latterdefinition implies that organ failure is a central component of thissyndrome and leads to the hypothesis that the organs may behavedifferently to chronic decompensated liver disease. This reviewfocuses upon the current understanding of this syndrome fromthe clinical, prognostic and pathophysiologic perspectives andindicates potential biomarkers and therapeutic targets for inter-vention. It is the second definition that will be used in the descrip-tion that follows unless otherwise stated.

Epidemiology

Data regarding the epidemiology of ACLF is rare. At the recentlyheld EASL-AASLD Single Topic Symposium on the managementof critically ill cirrhotic patients in the ICU (Atlanta, 2010), datawere presented from the nationwide in-patient sample in theUS for the year 2006. Using the parameters of the need formechanical ventilation and/or invasive cardiovascular monitor-ing, 26,300 patients were identified. In-hospital mortality wasfound to be 53% and the mean length of hospitalization was about14 days. The total charges associated with the ICU admissionsalone were 3 billion US dollars with a suggestion that the ICUmortality in cirrhotic patients has remained unchanged [3]. It islikely that a significant proportion of these patients had ACLFbut is difficult to confirm until evidence-based definition of ACLFis derived.

Clinical and prognostic factors (P)

Data on the natural history of patients with cirrhosis progressingto multiorgan failure and its outcome are limited. In a studyreported in a preliminary form, the group at UCL hypothesized

12 vol. 57 j 1336–1348

0

Live

r fun

ctio

n (%

)

Months

100Acute insult

Threshold for organ failure

Chronic decompensationof cirrhosis

?Too late!

Fig. 1. Acute-on chronic liver failure: diagrammatic representation of theclinical concept. This figure describes the clinical concept of ACLF to distinguishit from chronic decompensated cirrhosis. The red line describes the course of apatient with chronic decompensation of cirrhosis that during evolution of theirliver disease will at some point develop organ dysfunction. This is usually inassociation with advanced liver disease where the only option for treatment isliver transplantation and the chances of reversibility of liver disease are verylimited. This is in contradistinction to the patient with acute-on chronic liverfailure (depicted by the blue line) who may often have a good liver reserve andcan deteriorate acutely over a short period, usually in association with aprecipitating illness that results in organ failure and high risk of death. Thepatient may also have advanced liver disease but be stable and deteriorateacutely following a precipitating event, and progress to organ failure. By contrast,this patient has a potential for reversibility and recovery to the state the patientwas in, prior to the acute event.

Table 1. SOFA scoring system.

Organ Measurement ScorePaO2 to FIO2 ratio ≥400 mmHg 0

300 to 399 mmHg 1200 to 299 mmHg 2100 to 199 mmHg 3<100 mmHg 4

Platelet count ≥150,000 per µl 0100,000 to 149,999 per µl 150,000 to 99,999 per µl 220,000 to 49,999 per µl 3<20,000 per µl 4

Serum bilirubin <1.2 mg/dl 01.2 to 1.9 mg/dl 12.0 to 5.9 mg/dl 26.0 to 11.9 mg/dl 3≥12.0 mg/dl 4

Hypotension MAP ≥70 mmHg 0MAP <70 mmHg, no pressor agents used

1

Dobutamine, any dose 2Dopamine 5 µg/kg/min 2Dopamine >5 to 15 µg/kg/min 3Dopamine >15 µg/kg/min 4Epinephrine ≤0.1 µg/kg/min 3Epinephrine >0.1 µg/kg/min 4Norepinephrine ≤0.1 µg/kg/min 3Norepinephrine >0.1 µg/kg/min 4

Glasgow coma score 15 013-14 110-12 26-9 33-5 4

Serum creatinine or urine output

Serum creatinine <1.2 mg/dl 0Serum creatinine 1.2 to 1.9 mg/dl 1Serum creatinine 2.0 to 3.4 mg/dl 2Serum creatinine 3.5 to 4.9 mg/dl 3Urine output 200 to 499 ml/day 3Serum creatinine >5.0 mg/dl 4Urine output <200 ml/day 4

MAP, mean arterial pressure.

JOURNAL OF HEPATOLOGY

that in patients with cirrhosis who present with acute deteriora-tion of cirrhosis due to a precipitating factor and progress todevelop a single organ dysfunction have significantly differentoutcome to those that do not develop a single organ dysfunction[4]. In a prospective study to explore this hypothesis, a group ofpatients with liver cirrhosis that were admitted to a single unitover a 5.5-year period and managed according pre-defined man-agement guidelines were analyzed. Organ failure was defined asthe need for support of any organ. The patients were followed-upclinically and biochemically until death or transplantation.Among the approximately 500 patients studied, about one thirddeveloped a single organ failure, of which 53% died during thefirst hospital admission, also indicating that the occurrence of asingle organ dysfunction was reversible in nearly 50% of cases.The study also showed that both the severity of inflammationand the occurrence of new infection were associated with ahigher risk of death [5].

The prognostic factors determining the outcome of patientswith cirrhosis and multiorgan failure are currently under evalua-tion, but it seems that the scoring systems addressing the sever-ity of liver disease, such as Child-Pugh score [6] or Model of EndStage Liver Disease (MELD) [7] perform less well than the scoringsystems addressing organ dysfunction such as the SequentialOrgan Failure Assessment (SOFA) (Table 1) [8] or the Acute Phys-iology, Age and Chronic Health Evaluation (APACHE) [9] scores.The available data describing the outcome of patients with cir-rhosis who develop organ failure and are admitted to the ICUare summarized in Table 2 and 3 [10–44]. Critical examinationof the data indicates two fundamentally important conclusions.First, the data suggest that the occurrence of an organ failure inpatients with cirrhosis with a defined severity of liver diseaseindicates a poor prognosis with very wide survival figures, whichis possibly related to criteria for ICU admission. This notion issupported by the second conclusion that it is not the severity of

Journal of Hepatology 2012

liver disease measured using conventional clinical and biochem-ical testing (Child-Pugh score) that is important, but the degree ofend-organ failure that determines outcome. In these complexpatients, a concept similar to the PIRO concept in sepsis (predis-position, infection/inflammation, response, organ failure) [45] mightbe useful in describing pathophysiology and clinical categories(Fig. 2).

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Table 2. Comparison of the current literature on mortality rates of patients with cirrhosis and organ failure.

Reference Number of patients Patient selection ICU mortality (%) Hospital mortality (%)Goldfarb et al., 1983 100 Cirrhosis on ICU, MV 89 -Shellman et al., 1988 100 Cirrhosis on ICU - 64Zauner et al., 1996 198 Cirrhosis on ICUZimmerman et al., 1996 117 Cirrhosis on ICU, MV 63Lee et al., 1997 47 Cirrhosis on ICU, MV 83 -Singh et al., 1998 54 Cirrhosis on ICU 43Kress et al., 2000 138 Cirrhosis on ICU 56Aggarwal et al., 2001 582 Cirrhosis on ICU 37 49Wehler et al., 2001 143 Cirrhosis on ICU 36 46Tsai et al., 2003 111 Cirrhosis on ICU 65Chen et al., 2003 76 Cirrhosis on ICU, bleeding 68Chen et al., 2004 67 Cirrhosis on ICU, renal failure 87Ho et al., 2003 135 Cirrhosis on ICU 67Tsai et al., 2004 160 Cirrhosis on ICUGildea et al., 2004 420 Cirrhosis on ICU 69 (1-yr mortality)Arabi et al., 2004 129 Cirrhosis on ICU 74 -Rabe et al., 2004 76 Cirrhosis on ICU, MV 59du Cheyron et al., 2005 73 Cirrhosis on ICU, renal failure 65, no renal failure 35Cholongitas et al., 2006 312 Cirrhosis on ICU 65Mackle et al., 2006 107 Alcoholic liver disease on ICU 58 88Chen et al., 2006 102 Cirrhosis on ICU 68Jenq et al., 2007 134 Cirrhosis on ICU 68Cholongitas et al., 2008 128 Cirrhosis on ICU after 48 h 55Fang et al., 2008 111 Cirrhosis on ICU, renal failure 82Juneja et al., 2009 104 Cirrhosis on ICU 42 56Cholongitas et al., 2009 412 Cirrhosis on ICU 61Thomson et al., 2010 137 Cirrhosis on ICU 38 47Filloux et al., 2010 86 Cirrhosis on ICU 37 48Juneja et al., 2011 73 Cirrhosis on ICU, MV 75 88Levesque et al., 2012 377 Cirrhosis on ICU 35 43Cavallazzi et al., 2012 441 Cirrhosis on ICUShawcross et al., 2012 660 Cirrhosis on ICU 51

ICU, intensive care unit; MV, mechanical ventilation.

Review

Pathophysiological basis

Precipitating event (I)

ACLF usually results following a precipitating event on the back-ground of established cirrhosis. The ‘event’ may directly exagger-ate liver injury such as alcoholic hepatitis, drug-induced liverinjury, superimposed viral hepatitis, portal vein thrombosis andischemic hepatitis or liver decompensation may be consequentupon extra-hepatic insults such as trauma, surgery, varicealbleeding or infection. In a proportion of patients, there may beno identifiable precipitating event. The best studied precipitatingevents are surgery and superimposed viral hepatitis in relation tothe development of ACLF. The most important predictors ofpost-operative mortality were severity of liver disease as

1338 Journal of Hepatology 2012

determined by the MELD score, age, and the American Societyof Anesthesiologists (ASA) score [46]. Patients with a low MELDscore who die immediately following surgery often had cerebraledema [47].

When HAV infection occurs in the setting of cirrhosis, there isa substantial risk of ACLF and death [48]. Hepatitis E virus (HEV)is an important cause of ACLF in Southern and Central Asia, China,Africa, and the Indian subcontinent and leads to rapid hepaticdecompensation and death. In a prospective study of 107 patientswith cirrhosis of varying severity, mortality was much higher inpatients with superimposed HEV infection vs. non-infected cir-rhotics. Mortality rate between HEV infected vs. non-infected cir-rhotics at 4 weeks was 43% vs. 22% (p = 0.001) respectively and70% vs. 30% (p = 0.001) at one year [49]. Patients who acquireacute HBV infection in the setting of chronic liver disease are

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Table 3. Comparison of data on prognostic accuracy of organ failure scores and liver disease scores in patients with liver cirrhosis and organ failure.

Reference Number of patients

Patient selection

APACHE II (AUROC)

APACHE III (AUROC)

SOFA (AUROC)

OFS (AUROC)

Child-Pugh score (AUROC)

Zauner et al., 1996 198 Cirrhosis on ICU 0.75 0.8 - - -Zimmerman et al., 1996 117 Cirrhosis on ICU,

MVAccurate for risk stratification

Singh et al., 1998 54 Cirrhosis on ICU Predicts mortality

Does not predict mortality

Kress et al., 2000 138 Cirrhosis on ICU Predicts mortality

Afessa et al., 2000 111 Cirrhosis on ICU, bleeding

0.78 0.76

Wehler et al., 2001 143 Cirrhosis on ICU 0.79 0.94 0.74Ho et al., 2003 135 Cirrhosis on ICU 0.833 0.75Tsai et al., 2003 111 Cirrhosis on ICU 0.901 0.748Chen et al., 2003 76 Cirrhosis on ICU,

bleeding0.887 0.900 0.706

Tsai et al., 2004 160 Cirrhosis on ICU 0.892 0.906 0.712Chen et al., 2004 67 Cirrhosis on ICU,

renal failure0.878 0.873

Rabe et al., 2004 76 Cirrhosis on ICU, MV

0.66 0.87

Gildea et al., 2004 420 Cirrhosis on ICU Predicts mortality

Cholongitas et al., 2006 312 Cirrhosis on ICU 0.78 0.83 0.72Chen et al., 2006 102 Cirrhosis on ICU 0.91 0.91Jenq et al., 2007 134 Cirrhosis and

renal failure on ICU0.92

Cholangitas et al., 2008 128 Cirrhosis on ICU after 48 h

0.78 0.88 0.85 0.78

Fang et al., 2008 111 Cirrhosis on ICU with renal failure

Juneja et al., 2009 104 Cirrhosis on ICU 0.90 0.93Cholangitas et al., 2009 412 Cirrhosis on ICU 0.84Thomson et al., 2010 137 Cirrhosis on ICUFilloux et al., 2010 86 Cirrhosis on ICUJuneja et al., 2011 73 Cirrhosis on ICU

requiring mechanical ventilation

0.77 0.94 0.83

Levesque et al., 2012 377 Cirrhosis on ICU 0.92 0.79Cavallazzi et al.,2012

441 Cirrhosis on ICU

ICU, intensive care unit; MV, mechanical ventilation.

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more likely to suffer decompensation, which is common in carri-ers who receive immunosuppressive therapy [50,51]. In a studyfrom India, patients with reactivation of HBV and ACLF wereshown to have improved survival if they were treated with ten-ofovir compared with no therapy [52]. Although the ethics of thisstudy can be questioned, it illustrates that early intervention mayprevent occurrence of multiorgan failure by aggressively target-ing the precipitating event. This principle is also illustrated bythe demonstration that survival of patients with variceal bleedingcan be improved by the prompt use of antibiotics, which reducesthe risk of infection [53]. Rapid control of the bleeding episodewith the insertion of a transjugular intrahepatic stent shunt inpatients with advanced liver disease or those with active

Journal of Hepatology 2012

bleeding saves lives [54,55]. It is likely that the common endpoint that leads from the precipitating event to the developmentof ACLF is an altered host response to injury, resulting in aninappropriate inflammatory response and immune dysfunctionincreasing the susceptibility to infection [56].

Inflammation and infection (R)

The role of a systemic inflammatory response (SIRS), which is acollection of simple and relatively crude clinical and hematolog-ical measure using heart and respiratory rate, white cell count,and temperature, in determining the outcome of patients withliver failure was first fully described in the acute liver failure,

vol. 57 j 1336–1348 1339

Response

Organ

Predisposition

The PIRO concept of acute-on chronic liver failure Assessment Intervention

Injury

Severity of cirrhosis

Precipitating event

Inflammation

Organ failure

• Aetiology• Pugh score• MELD• [Biomarkers]

• Hepatic• Extra-hepatic• [Therapies]

• Inflammation• Immune failure• [Biomarkers]

• SOFA• APACHE• [Biomarkers]

Early identificationRisk stratification Preventative strategies[Novel interventions]

Rapid intervention to treat eventBundles of care[Novel interventions]

Vigilance, monitoringGoal directed approaches[Biomarkers and novel interventions]

Intensive care, organ supportLiver transplantation[Liver support, stem cell therapies]

Fig. 2. The PIRO concept of acute-on chronic liver failure. In patients with ACLF, it is useful to think about the PIRO concept in determining pathogenesis and prognosis.Predisposition is indicated by the severity of the underlying illness. Injury by the nature and severity of the precipitating event. Response by host response to injury, whichdetermines the severity of inflammation and risk of infection. Organs by the extent of organ failure. Categorisation of patients into these entities allows definition ofinterventions and helps define prognosis at different levels.

Review

where the presence of SIRS was associated with more severeencephalopathy, associated infection, renal failure, and pooroutcome [57–59]. Elevated levels of multiple pro- and anti-inflammatory cytokines have been described in ACLF includingTNF-a, sTNF-aR1, sTNF-aR2, IL-2, IL-2R, IL-6, IL-8, IL-10, andIFN-! [60,61]. More recently, the mortality of patients presentingwith renal dysfunction of cirrhosis has been shown to be signifi-cantly higher in the group with SIRS [62,63]. It is not surprisingthat SIRS should be associated with increased inflammatory cyto-kine response but the use of anti-TNF alpha strategies in patientswith alcoholic hepatitis who demonstrate an inflammatoryresponse is associated with an increased risk of infection andmortality [64,65].

Infection is a common feature of ACLF, which complicates thenatural history and is associated with significant morbidity andmortality [66]. About 40–50% of hospital admissions of cirrhoticpatients are with sepsis and a further 20–40% will develop noso-comial infections. Overall in-hospital mortality rates of cirrhoticpatients with infection are about 15%, which is about twice thosewithout infection. The mortality rate of cirrhotic patients withsevere bacterial infection with septic shock is about 60–100%[66–70]. In cirrhotic patients, sepsis is a common precipitatingevent resulting in hepatic encephalopathy, renal dysfunctionand rebleeding, and mortality associated with variceal bleeding.Vigilance, repeated cultures from various sites, cautious use of

1340 Journal of Hepatology 2012

in-dwelling cannulas and very early treatment remain the cor-nerstones of therapy. The relationship between the SIRS responseand infection leads one to hypothesise that an inflammatoryresponse may lead to immune dysregulation, which may predis-pose to infection that would then further aggravate a pro-inflam-matory response resulting in a vicious cycle [56]. Thisimmunopathology of ACLF is reminiscent of the multimodalimmunological response observed in patients with severe sepsis,which is characterised by an initial SIRS response followed by amixed (MARS) and subsequently compensated anti-inflammatoryresponse (CARS) (Fig. 3 and 4).

The associated mechanisms of this phenomenon are not clearbut immune paresis has been suggested as a possible mechanism[71–73]. A recent study in cirrhotic patients suggested that agenetic predisposition may underlie the risk of infection. Theinvestigators focussed on Toll-like receptor (TLR) 2 and nucleo-tide-binding oligomerisation domain (NOD) 2 which recognizepathogen-associated molecular patterns (PAMS). In a multivari-ate analysis, they confirmed that TLR2 GT microsatellite polymor-phism and NOD2 variants were independent predictors ofspontaneous bacterial peritonitis (SBP) when both risk factorswere present, the risk of SBP was dramatically increased (oddsratio: 11.3; p = 0.00002) [74]. In alcoholic hepatitis patients,neutrophil activation indicated by increased resting burst andreduced phagocytic function was predictive of subsequent

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Liver failure/bacterial translocation

Immune paralysis

Innate immunity Adaptive immunity

• Endotoxemia• Reduced protein/complement synthesis• Reduced immune surveillance• Reduced albumin function

• Neutrophils: phagocytic defect• Monocytes: DR loss• NK cells

• T-cell exhaustion• Inability to profilerate• Increased apoptosis

Imm

une

resp

onse

SIRS: Systemic inflammatory response

CARS: Compensatory anti-inflammatory response

NormalACLF: survivorACLF: non-survivor

Fig. 3. Immune dysfunction of acute-on chronic liver failure. This figure describes the level of immune dysfunction that may be operative in patients with acute-onchronic liver failure and proposes the hypothesis that the immune status of patients during the illness may not be constant. Patients may move from a pro-inflammatory toan anti-inflammatory state, making them susceptible to infection. It is likely that the patients that do not resolve the compensated anti-inflammatory response are the onesthat will become infected and have the highest mortality rates.

Bacterial translocationBacterial infection

Compensatedcirrhosis

Multiorgan failure• Hypotension• Renal failure• Jaundice• Coagulopathy• Encephalopathy

Death

SIRS

Decompensatedcirrhosis

Increasing portalpressure, fibrosis and vasodilatation

Worsening systemic and hepatic hemodynamics/

liver function

• VH• Ascites• HE

Fig. 4. Role of bacterial translocation in acute-on chronic liver failure. In the transition from compensated to decompensated cirrhosis (marked by the development ofvariceal hemorrhage, ascites and/or hepatic encephalopathy) increasing portal pressure and liver fibrosis play a predominant role, while vasodilatation (and the resultanthyperdynamic circulatory state) is not as prominent. Conversely, the development of multiorgan failure is characterized by significant alterations in systemic and hepatichemodynamics and worsening of liver function. Bacterial translocation plays an important role in the transition of patients from compensated to decompensated cirrhosis,and together with bacterial infection is the most frequent precipitant of such deterioration via the systemic inflammatory response. VH, variceal hemorrhage; HE, hepaticencephalopathy.

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Journal of Hepatology 2012 vol. 57 j 1336–1348 1341

Review

infection, organ failure and mortality [72]. Importantly, data fromex vivo studies showed that this neutrophil dysfunction wasreversible and possibly due to a circulating humoral factor thatwas hypothesised to be endotoxin [72]. In another study,monocyte HLA-DR expression was significantly reduced in ACLFwho also showed an inability to produce TNF-a, the severity ofwhich correlated with survival [71–73]. These observationsprovide potential biomarkers to predict infection risk and allowindividualisation of therapy. Modulation of enteric microflorawith probiotic therapy has been shown to restore neutro-phil phagocytic capacity [75]. In a randomised clinical trial,administration of the granulocyte-colony stimulating factor wasassociated with improved survival of patients with ACLF [76].The study included 47 patients with ACLF using the APASL defini-tion and the investigators showed a very high 2-month mortalityof 71% in the untreated group compared with about 30% in thetreated group. Clearly, this study will need to be repeated withlarger numbers of patients but provides the proof of conceptthat modulation of immune paresis may prevent the progressionof ACLF.

The organs in ACLF (O)

Liver and hepatic hemodynamics

The hallmark of the liver manifestation of ACLF is hyperbilirubi-nemia and coagulopathy but the pathophysiological basis isunclear. It is likely that the histopathological characteristics ofthe liver during ACLF will be determined by the underlying causeof cirrhosis and the nature of the precipitating event. The occur-rence of ACLF due to a non-specific insults such as infection or avariceal bleeding is likely to be different from the effect of directhepatotoxins such as drugs or superimposed viral hepatitis.Recent studies in patients with acute deterioration of alcoholiccirrhosis and resultant ACLF showed presence of SIRS and biliru-binostatis as early markers to identify these high-risk patients[77,78]. The investigators made the important observation thatthe presence of bilirubinostasis was associated with an increasedrisk of subsequent infection. In another study, in a similar popu-lation, the role of bilirubinostasis was confirmed and the investi-gators also observed that K8/18 immunostaining was reducedsuggesting loss of cellular actin and microtubular structure,which was associated with important prognostic information[79]. At present, there is no clarity on the mechanism of cell-death or capacity for regeneration of ACLF livers. Early biopsymay help in both the management of patients and providing anunderstanding of the mechanisms involved, as new drugs, suchas pan-caspase inhibitors or stimulators of hepatic regeneration,may be useful [80].

Liver inflammation is an important determinant of portalpressure and prognosis in cirrhosis. Patients with ACLF thatoccurs on the background of alcoholic hepatitis have increasedplasma TNF-a level and also the highest portal pressures [81].Indeed anti-TNF-a therapy has been shown to reduce portalpressure in patients with severe alcoholic hepatitis and cirrhosis[81]. Several lines of evidence exist implicating gut-derivedendotoxemia in the pathogenesis of portal hypertension [82].Modulation of the portal bacterial load using antibiotics suchas quinolones and rifaxamin has been associated with areduction in inflammation and portal pressure [83,84]. Endotoxin

1342 Journal of Hepatology 2012

neutralisation with high density lipoprotein administration hasbeen associated with a reduction in portal pressure [85]. Anincrease in reactive oxidant species, in particular superoxide, isalso observed in ACLF, contributing to an increase in intrahepaticresistance by reducing nitric oxide bioavailability [86]. In patientswith ACLF, defined according to APASL criteria, no differences inthe portal hemodynamics between decompensated cirrhosis andACLF were observed [87], but using the EASL-AASLD definition,the portal pressure was markedly higher [88] in those with ACLFpointing to the need to carefully define the population understudy.

Hepatic eNOS activity has been shown to be reduced in thecontext of cirrhosis with superadded inflammation [89,90]. NOSactivity is subject to regulation by a number of inhibitors suchas asymmetric dimethylarginine (ADMA), which is increased dur-ing inflammation resulting in high ADMA levels [91]. This hasbeen suggested as both a prognostic marker and a possible targetof therapy. Evidence suggests that in addition to decreased nitricoxide generation, there is also a reduced response to nitric oxidein cirrhotic livers likely caused by dysfunction of the cyclic GMPsystem. Phosphodiesterase-5 inhibitors such as sildenafil, whichincrease cGMP, have been shown to have a beneficial effect onintrahepatic resistance [92]. Further studies are therefore neededin ACLF in whom both liver blood flow and intrahepatic resis-tance are altered.

Kidney dysfunction

HRS is thought to be a functional disorder secondary to circula-tory dysfunction in which there is splanchnic vasodilatation, alowering of arterial blood pressure, intense renal vasoconstric-tion, impaired cardiac function and marked activation of the sym-pathetic and neurohormonal systems [93–95]. However, inpatients with ACLF who present with renal dysfunction, the char-acteristics may be widely variable. Thus, in some patients the cir-culatory changes may predominate, and in other patients theremay be increased synthesis of pro-inflammatory mediators orboth. Administration of terlipressin and albumin remains the cur-rent gold standard for treatment of patients with HRS, but isunsuccessful in 54% of patients [96]. It is likely that in these latterpatients different factors predominate in the development ofrenal dysfunction. In about 30–40% of patients with cirrhosiswho develop renal dysfunction, a bacterial infection is the precip-itating cause (SBP) [94]. Indeed, the presence of SIRS in patientswith renal dysfunction was associated with infection in 56% ofthe subjects, which was a major independent prognostic factorfor mortality in these patients [63]. Traditionally, renal dysfunc-tion has been suggested to be reversible with transplantation.However, recent data suggests that patients that are transplantedwith evidence of renal tubular injury on the background of cir-rhosis are more likely to require renal replacement therapy aftertransplantation than patients undergoing transplantation withHRS, suggesting that the basis of renal dysfunction in ACLF isnot the same as HRS [97]. The important pathophysiological roleof inflammation in modulating renal dysfunction associated withACLF is highlighted by the benefit of anti-inflammatory agentssuch as albumin, pentoxifylline and N-acetylcysteine, whichdecreased the risk of renal dysfunction in patients with alcoholichepatitis [98,99]. Albumin in this situation probably acts as ananti-inflammatory agent and has been shown to protect the kid-ney during spontaneous bacterial peritonitis and is associated

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Acute on Chronic Liver Failure

Hyperammonemia

Astrocytic swelling

Activation of transcription factors

Oxidative stressiNOS; nitrotyrosine

Hepatic Encephalopathy

Inflammation

CytokinesActivation of NFkB

Fig. 5. Pathophysiological mechanisms of brain dysfunction in acute-onchronic liver failure. This figure describes the possible mechanisms underlyingthe pathogenesis of hepatic encephalopathy in acute-on chronic liver failure. It islikely that similar mechanisms are operative in other organs, where susceptibilityto an inflammatory insult is provided by organ characteristics that are a feature ofthat particular organ in cirrhosis.

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with improved survival in patients with renal failure [100,101].Administration of prophylactic norfloxacin, a selective gut decon-taminant reduced the incidence of renal failure and improvedsurvival [102]. The mechanism of the protective effect of norflox-acin was explored in animal models of cirrhosis and AKI andshown to result from modulation of renal NFkB and cytokinespossibly mediated through a TLR4-based mechanism. In a preli-minary observation, increased TLR4 has been shown in renaltubules in ACLF patients, which was not observed in HRS [103].These data provide potential novel insights into pathophysiologyand the potential for the development of novel biomarkers andtherapeutic approaches. Thus, the use of urinary biomarkers thatreflect renal injury may allow early diagnosis of renal dysfunctionof cirrhosis and allow the functional causes of renal dysfunctionto be better distinguished from the inflammatory causes. The bio-markers of interest are markers of tubular injury such as kidneyinjury molecule-1, pi and alpha glutathione S-transferase; mark-ers of inflammation such as NAG, NGAL, FABP, and IL-18 [104]. Itis possible that novel therapeutic approaches may be developed ifthis hypothesis can be confirmed.

Brain dysfunction

Hepatic encephalopathy (HE) is a common manifestation of ACLF[1,105–107]. Local and systemic changes have been implicated inthe pathophysiology of the development of this neurological syn-drome. From the pathophysiological perspective, like the situa-tion in acute liver failure, brain swelling is an important featureof ACLF also [105–108]. As the syndrome occurs on the back-ground of existing cirrhosis and chronic portacaval shunting, adegree of brain atrophy protects from this brain swelling, result-ing in an increase in intracranial pressure. There are, however,several reports of significant increases in intracranial pressurein patients with ACLF [105–107]. Studies using MRI have shownthat this increase in brain swelling can be reversed with livertransplantation supporting the notion that, like acute liver fail-ure, the brain manifestation of ACLF is a reversible disorder[109]. Ammonia is thought to play a key role in the developmentof HE but no direct relationship between the severity of hyperam-monemia and HE could be demonstrated [110]. On the back-ground of this hyperammonemia, an added hepatic insult and/or superimposed inflammation leads to the development of brainedema suggesting a synergy between ammonia and inflamma-tion. The synergy between ammonia and inflammation has beendemonstrated in animal models of cirrhosis where acute brainswelling was observed following administration of endotoxinmimicking the clinical situation seen in ACLF [108]. The mecha-nism is likely to be related to generation of cytokines in the brain,increased iNOS expression, oxidative stress and formation ofnitrated protein adducts [108,111]. Studies in animal modelshave suggested that ammonia may prime the brain to the delete-rious effects of superimposed inflammation by induction ofmicroglial cells, which have a huge repertoire for cytokine pro-duction; and a reduction in ammonia in cirrhotic models pre-vents the effect of superimposed inflammation [108,111–113].Conversely, reduction in bacterial translocation using a non-absorbable antibiotic, rifaximin was shown to prevent the occur-rence of HE, suggesting that reducing inflammation may be pro-tective as well [114]. Cerebral blood flow is known to beprogressively reduced in cirrhosis but in ACLF may be paradoxi-cally increased as seen in patients with acute liver failure. In a

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recent study, the acute effect of insertion of a transjugular intra-hepatic shunt, which is known to induce endotoxemia, was stud-ied in patients with cirrhosis. The study demonstrated that TIPSS-induced endotoxemia led to an increase in the rate of productionof nitric oxide, which was associated with endothelial dysfunc-tion and increased cerebral blood flow supporting the hypothesisthat multiple hits and brain swelling is a feature of ACLF [115](Fig. 5). However, the insertion of TIPSS in relatively well cirrho-tics without hepatic encephalopathy undergoing TIPSS was notassociated with a change in cerebral blood flow, stressing thepathophysiologically distinct nature of ACLF from otherwise sta-ble cirrhosis [116].

Cardiac and systemic hemodynamics

In patients with decompensated cirrhosis, a hyperdynamic cir-culation is the key hemodynamic feature. The increased cardiacoutput observed in this situation is mainly due to a vasodilatedsplanchnic bed but paradoxically, the blood flow in otherorgan, such as kidneys, brain and peripheral organs, isdecreased [117]. Additionally, patients with cirrhosis may havean underlying cirrhotic cardiomyopathy, which may makethem susceptible to cardiovascular collapse during an acuteinflammatory insult, but data supporting that hypothesis doesnot exist [118]. The hallmark of ACLF is cardiovascular collapseakin to the patients with acute liver failure and severe sepsis,often requiring large doses of inotropes. Unlike decompensatedcirrhosis, where the cardiac output remains elevated, in ACLF,

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despite splanchnic vasodilation, the cardiac output can bereduced and both systolic and diastolic functions are affected.This cardiovascular abnormality is associated with increasedrisk of death, particularly in those patients who present withrenal dysfunction [119]. In another study, where the definitionof ACLF was based upon the APASL criteria, no differences incardiac output were observed, highlighting the fact that thedesignation is crucial in defining which patients are beingdescribed. The mechanisms underlying the cardiac dysfunctionin ACLF are likely similar to those in severe sepsis, such as car-diovascular-active factors like TNF and nitric oxide which areincreased, and cortisol which is decreased [120]. The formercan further dilate the vasculature and the latter decreases thesensitivity to vasoconstrictors. However, no study has yet dem-onstrated the benefit of vasodilators/vasoconstrictors in themanagement of ACLF. It is important to monitor the cardiacsituation using appropriate methods to guide fluid replacementand inotrope support. The choice of inotropes is also unclearbut vasopressin analogue in this situation should be used cau-tiously as it may further reduce cardiac perfusion and analready compromised hepatic blood flow [121].

Coagulation

Routine diagnostic tests of coagulation are usually abnormalin patients with cirrhosis due to multiple defects. Anincreased bleeding tendency has been attributed to the degreeof abnormalities in these tests, but this has not been formallyproven [122]. Thrombin generation is normal in stable cirrho-tics with a rebalancing of pro- and anti-coagulant factors (pro-viding there are sufficient platelets >50,000 � 109/L). Sincehypercoagulation may exist [123], bleeding abnormalities arefar less frequent than it would be expected [124]. In cirrhosiswith sepsis, endogenous low-molecular weight heparinoids aredetected, and disappear with resolution of infection [68]. Anti-biotics are known to reduce early variceal rebleeding rates[125]. The use of prophylactic blood products to correctabnormalities to prevent bleeding is empirical and oftenguided by local protocols; virtually none of these are evi-dence-based [126]. Moreover, normalization of abnormal coag-ulation parameters is difficult to achieve, and creates volumeexcess, increasing the risk of transfusion-related acute lunginjury and other transfusion reactions. Even recombinant fac-tor VIIa, which corrects prothrombin time, does not reduceblood loss during variceal bleeding [127]. Conversely, antifibri-nolytic agents do reduce blood loss during liver transplanta-tion, but have not been evaluated prophylactically duringother procedures or for bleeding. Apart from increased fibrino-lysis, which is seen in ACLF, defective platelet function is theother major abnormality [128]. The thrombopoietin analogeltrombopag may be thrombogenic at least in stable cirrhosis(there has been a suspended trial in this area), probablybecause of the interaction with the very high levels of vWFin cirrhosis. The use of fresh frozen plasma is limited by thevolume of transfusions; safer prothrombin complex concen-trates which have 20 times the concentration of factors thanFFP are now available [129]. Currently, prophylactic transfu-sions of any coagulation products are difficult to justify andit is likely that more comprehensive, global tests of coagula-tion are needed to guide the correction of coagulation on anindividual basis [130].

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Hepato-adrenal axis

Adrenal insufficiency is reported in 51–68% of patients withcirrhosis and severe sepsis, particularly in patients with highChild-Pugh and MELD scores and hemodynamic instability.Adrenal insufficiency is associated with increased mortalitycompared to patients without adrenal insufficiency [131].Administration of hydrocortisone to patients with septic shockand adrenal insufficiency was shown to improve the circulatoryfunction but routine use of hydrocortisone during sepsis hasnot been confirmed to improve the outcome [132]. Interpreta-tion of response to synacthen test in cirrhosis and ACLF is dif-ficult due to methodological constraints, so no conclusions canbe made.

Intensive care management, organ support andtransplantation

Intensive care management of patients with ACLF has beenrecently reviewed and a full description is beyond the scopeof this review. The essential principles are those of multipleorgan support to allow the treatment of the precipitatingevent and the recovery of the liver. The two specific aspectsof treatment relevant to this group of patients are discussedbelow [3].

Liver support devices are intended to provide detoxificationfunctions to patients with ACLF until liver transplantation, recov-ery or futility. The overall efficacy of liver support devices havefailed to reach a level sufficient to gain approval for widespreaduse [133]. Liver support devices are of two main types; artificiallivers-acellular devices such as albumin dialysis and plasma-exchange/diafiltration, and bio-artificial livers, which incorporatecells from human, animal, or transformed sources. An unpub-lished study using the ELAD device which incorporates liver can-cer cells, C3A cells, into the device, was shown in a preliminarystudy to be useful in patients with ACLF, mainly induced byHBV reactivation in a small randomised controlled study [134].A pivotal clinical trial in USA and Europe has been stopped. Noneof the bioartificial liver devices as far as we know, are in clinicaltrials for ACLF patients at present.

The best studied artificial liver support devices are themolecular adsorbents recirculating system (MARS) and Prome-theus devices, which are based upon the principles of albumindialysis [135]. These devices are based on the concept that albu-min is a complex molecule with a plethora of physiologicalfunctions besides providing oncotic properties [136]. Studieshave demonstrated that during hepatic failure, the circulatingalbumin undergoes structural and functional modifications thatnegatively affect its biological activity [136]. These devices aredesigned to provide additional detoxification functions. Severalstudies have confirmed that the use of these devices can removeinflammatory molecules, reduce NO and improve systemic andhepatic hemodynamics, severe hepatic encephalopathy leadingto large clinical trials [61]. The randomised controlled trial ofthe Prometheus device in patients with ACLF has been recentlypublished [137]. The data show that the approach is safe andwell tolerated, although there is no overall significant survivalbenefit at 28 days. Subgroup analysis suggested that patientswith a MELD score of >30 and those with hepatorenal syndromemay have some benefit. MARS was tested in a similar cohort,

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the RELIEF trial, which has been reported in a preliminary com-munication and again failed to show any survival benefit [138].A better definition of ACLF would allow the study of a morehomogenous cohort, but it is likely that modifications to thecurrent devices will be necessary to improve their efficacy andcapacity.

Liver transplantation in patients with ACLF has not been sys-tematically analysed but a recent retrospective study was per-formed in 332 patients of whom 157 patients had ACLF and175 patients had no ACLF pre-transplant [139]. Thirty-fourpatients received a liver-kidney transplant, of whom 10(29.4%) had ACLF. The definition was based on a rapid increasein MELD by >5 points. The results showed that the group withACLF had a 26% mortality compared with a mortality of 17% inthe non-ACLF group. The difference was statistically different inunivariate analysis, but when only single organ transplantswere analysed, the results were not statistically different. Onmultivariate analysis, ACLF was not an independent predictorof post-transplant mortality, arguing strongly that this is agood indication for transplantation [139]. The timing of trans-plantation is crucial as patients with ACLF may provide a win-dow of opportunity. Therefore, living-donor transplantation isan attractive option, the experience of which has been reportedextensively from South-East Asia, mainly in patients with ACLFresulting from re-activation of hepatitis B virus infection. Thedata from Hong Kong suggests that although the patients withACLF and HRS had stormier post-operative course, living donortransplantation could be performed safely and overall therewere no significant differences in survival with 5-year survivalsof about 80% [140]. Similar observations have been maderegarding the safety and feasibility of living donor transplanta-tion from the Chinese groups [141]. Currently, in most coun-tries there is no priority for ACLF patients who havesignificantly higher short-term mortality. A better understand-ing of the natural history and prognostic criteria will allowACLF to be incorporated as a possible new indication for highurgency allocation.

Conclusions and future perspectives

In conclusion, ACLF is a devastating syndrome with inordinatelyhigh mortality, which is clinically, pathophysiologically andprognostically a distinct clinical entity, but the condition hasnot yet been defined. In order to fill this knowledge gap, groupsin Europe, US and Asia have started to study this entity as partof large consortia. One such consortium in Europe, the EASLCLIF-Consortium, has just finished the recruitment of 1400patients prospectively; the results of the study are eagerlyawaited [142]. It is likely that a better definition will requirenew biomarkers, which will allow the development of newdrugs and devices and, therefore, engagement with the industrywill be crucial to bring these emerging treatments to patients.The liver transplant community will need to be engaged todefine which patients with ACLF should be transplanted anddefine new allocation policy. Finally, it is likely that there willbe a resurgence of research activity in cirrhosis to allow thedetermination of modifiable factors that predispose to ACLF,and likely to personalise their management based on clinicaland genetic factors.

Journal of Hepatology 2012

Key Points

• Acute-on chronic liver failure is a syndrome that defines a subgroup of cirrhotic patients who develop organ failure following hospital admission with or without an identifiable precipitating event and have increased mortality rates

• Altered host response to injury such as deranged systemic inflammatory response plays an important pathophysiological role

• Bacterial infection that occurs on the background of varying degrees of immune paralysis plays an important role in determining the outcome of this syndrome

• Systemic, cardiac and hepatic hemodynamics are important determinants of outcome

• The end-organs such as the kidney and the brain show evidence of inflammation

• Survival of patients is dependent upon the severity of organ failure

• Treatment strategies are limited to organ support but better understanding of the pathophysiology is likely to lead to discovery of novel biomarkers and therapeutic strategies

Conflict of interest

The authors declared that they do not have anything to discloseregarding funding or conflict of interest with respect to thismanuscript.

Acknowledgements

A lot of the manuscript is based around the discussions during ameeting that took place at Atlanta, 2010; ‘Intensive Care of thePatient with Acute-on Chronic Liver Failure: Summary of anAmerican Association for the Study of Liver Diseases andEuropean Association for the Study of the Liver Single TopicConference.’

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