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Acute-on chronic liver failure

  • Rajiv Jalan
    Correspondence
    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.
    Affiliations
    Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom
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  • Pere Gines
    Affiliations
    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
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  • Jody C Olson
    Affiliations
    Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States
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  • Rajeshwar P Mookerjee
    Affiliations
    Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London, United Kingdom
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  • Richard Moreau
    Affiliations
    INSERM, U773, Centre de Recherche Biomédicale Bichat-Beaujon CRB3, Paris and Clichy, France
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  • Guadalupe Garcia-Tsao
    Affiliations
    Section of Digestive Diseases, Yale University School of Medicine, New Haven, CT, United States
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  • Vicente Arroyo
    Affiliations
    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
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  • Patrick S Kamath
    Affiliations
    Division of Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States
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Open AccessPublished:June 29, 2012DOI:https://doi.org/10.1016/j.jhep.2012.06.026

      Summary

      Acute-on-chronic liver failure (ACLF) is an increasingly recognised 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.

      Keywords

      Linked Article

      • Acute-on-chronic liver failure – Its definition remains unclear
        Journal of HepatologyVol. 59Issue 1
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          We have read with interest the review by Jalan et al. [1] in which they focus on the current understanding of acute-on-chronic liver failure (ACLF) from the clinical, prognostic and pathophysiologic perspectives. In addition, they indicate potential biomarkers and therapeutic targets for intervention. The authors confirm that the condition remains undefined, but that two consensus working definitions for this syndrome exist: one put forward by the Asia-Pacific association for the study of liver disease (APASL) and the other based on an EASL-AASLD single topic symposium.
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      • Reply to: “Acute-on-chronic liver failure – Its definition remains unclear”
        Journal of HepatologyVol. 59Issue 1
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          We would like to thank Dr. Wlodzimirow and colleagues for their comments. We agree with them that a uniform definition of Acute on Liver Failure (ACLF) is essential [1]. It is with this aim that the CLIF Consortium initiated the CANONIC study, the results of which provide the framework for a definition of ACLF and its diagnostic criteria on the background of cirrhosis [2,3]. The issue of liver failure that occurs on the background of chronic hepatitis is more difficult and without more data that include biopsies in this group of patients, will remain very difficult to define.
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      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 pathophysiology 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% [
      • Jalan R.
      • Williams R.
      Acute-on-chronic liver failure: pathophysiological basis of therapeutic options.
      ]. 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 [
      • Sarin S.K.
      • Kumar A.
      • Almeida J.A.
      • Chawla Y.K.
      • Fan S.T.
      • Garg H.
      • et al.
      Acute-on-chronic liver failure: consensus recommendations of the Asian Pacific Association for the Study of the Liver (APASL).
      ]; ‘Acute hepatic insult manifesting as jaundice and coagulopathy, complicated within 4weeks 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 [
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • Vicente A.
      • Jalan R.
      • Garcia-Tsao G.
      • et al.
      Intensive care of the patient with cirrhosis.
      ]; ‘Acute deterioration of pre-existing, chronic liver disease, usually related to a precipitating event and associated with increased mortality at 3months due to multi-system organ failure’. These definitions are too imprecise to allow homogeneous diagnostic criteria and clinical studies are currently 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 intervention. It is the second definition that will be used in the description that follows unless otherwise stated.
      Figure thumbnail gr1
      Fig. 1Acute-on chronic liver failure: diagrammatic representation of the clinical concept. This figure describes the clinical concept of ACLF to distinguish it from chronic decompensated cirrhosis. The red line describes the course of a patient with chronic decompensation of cirrhosis that during evolution of their liver disease will at some point develop organ dysfunction. This is usually in association with advanced liver disease where the only option for treatment is liver transplantation and the chances of reversibility of liver disease are very limited. This is in contradistinction to the patient with acute-on chronic liver failure (depicted by the blue line) who may often have a good liver reserve and can deteriorate acutely over a short period, usually in association with a precipitating illness that results in organ failure and high risk of death. The patient may also have advanced liver disease but be stable and deteriorate acutely following a precipitating event, and progress to organ failure. By contrast, this patient has a potential for reversibility and recovery to the state the patient was in, prior to the acute event.

      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 monitoring, 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 [
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • Vicente A.
      • Jalan R.
      • Garcia-Tsao G.
      • et al.
      Intensive care of the patient with cirrhosis.
      ]. 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 that in patients with cirrhosis who present with acute deterioration of cirrhosis due to a precipitating factor and progress to develop a single organ dysfunction have significantly different outcome to those that do not develop a single organ dysfunction [
      • Jalan R.
      • Stadlbauer V.
      • Sen S.
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      • Davies N.
      • Hodges S.
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      ]. In a prospective study to explore this hypothesis, a group of patients with liver cirrhosis that were admitted to a single unit over a 5.5-year period and managed according pre-defined management guidelines were analyzed. Organ failure was defined as the need for support of any organ. The patients were followed-up clinically and biochemically until death or transplantation. Among the approximately 500 patients studied, about one third developed a single organ failure, of which 53% died during the first hospital admission, also indicating that the occurrence of a single organ dysfunction was reversible in nearly 50% of cases. The study also showed that both the severity of inflammation and the occurrence of new infection were associated with a higher risk of death [
      • Jalan R.
      • Sen S.
      • Williams R.
      Prospects for extracorporeal liver support.
      ].
      The prognostic factors determining the outcome of patients with cirrhosis and multiorgan failure are currently under evaluation, but it seems that the scoring systems addressing the severity of liver disease, such as Child-Pugh score [
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      ] perform less well than the scoring systems addressing organ dysfunction such as the Sequential Organ Failure Assessment (SOFA) (Table 1) [
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      The SOFA (Sepsis-related Organ Failure Assessment) score to describe organ dysfunction/failure. On behalf of the Working Group on Sepsis-Related Problems of the European Society of Intensive Care Medicine.
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      ]. Critical examination of the data indicates two fundamentally important conclusions. First, the data suggest that the occurrence of an organ failure in patients with cirrhosis with a defined severity of liver disease indicates a poor prognosis with very wide survival figures, which is possibly related to criteria for ICU admission. This notion is supported by the second conclusion that it is not the severity of liver disease measured using conventional clinical and biochemical testing (Child-Pugh score) that is important, but the degree of end-organ failure that determines outcome. In these complex patients, a concept similar to the PIRO concept in sepsis (predisposition, infection/inflammation, response, organ failure) [
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      SAPS 3 Investigators. Sepsis mortality prediction based on predisposition, infection and response.
      ] might be useful in describing pathophysiology and clinical categories (Fig. 2).
      Table 1SOFA scoring system.
      MAP, mean arterial pressure.
      Table 2Comparison of the current literature on mortality rates of patients with cirrhosis and organ failure.
      ICU, intensive care unit; MV, mechanical ventilation.
      Table 3Comparison of data on prognostic accuracy of organ failure scores and liver disease scores in patients with liver cirrhosis and organ failure.
      ICU, intensive care unit; MV, mechanical ventilation.
      Figure thumbnail gr2
      Fig. 2The 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, which determines the severity of inflammation and risk of infection. Organs by the extent of organ failure. Categorisation of patients into these entities allows definition of interventions and helps define prognosis at different levels.

      Pathophysiological basis

      Precipitating event (I)

      ACLF usually results following a precipitating event on the background of established cirrhosis. The ‘event’ may directly exaggerate liver injury such as alcoholic hepatitis, drug-induced liver injury, superimposed viral hepatitis, portal vein thrombosis and ischemic hepatitis or liver decompensation may be consequent upon extra-hepatic insults such as trauma, surgery, variceal bleeding or infection. In a proportion of patients, there may be no identifiable precipitating event. The best studied precipitating events are surgery and superimposed viral hepatitis in relation to the development of ACLF. The most important predictors of post-operative mortality were severity of liver disease as determined by the MELD score, age, and the American Society of Anesthesiologists (ASA) score [
      • Plataki M.
      • Hubmayr R.D.
      The physical basis of ventilator-induced lung injury.
      ]. Patients with a low MELD score who die immediately following surgery often had cerebral edema [
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      Risk factors for mortality after surgery in patients with cirrhosis.
      ].
      When HAV infection occurs in the setting of cirrhosis, there is a substantial risk of ACLF and death [
      • Keeffe E.B.
      Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases?.
      ]. 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 hepatic decompensation and death. In a prospective study of 107 patients with cirrhosis of varying severity, mortality was much higher in patients with superimposed HEV infection vs. non-infected cirrhotics. Mortality rate between HEV infected vs. non-infected cirrhotics at 4 weeks was 43% vs. 22% (p = 0.001) respectively and 70% vs. 30% (p = 0.001) at one year [
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      Hepatitis E virus (HEV) infection in patients with cirrhosis is associated with rapid decompensation and death.
      ]. Patients who acquire acute HBV infection in the setting of chronic liver disease are more likely to suffer decompensation, which is common in carriers who receive immunosuppressive therapy [
      • Loomba R.
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      Fulminant reactivation of hepatitis B due to envelope protein mutant that escaped detection by monoclonal HBsAg ELISA.
      ]. In a study from India, patients with reactivation of HBV and ACLF were shown to have improved survival if they were treated with tenofovir compared with no therapy [
      • Garg H.
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      • Kumar M.
      • Garg V.
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      ]. Although the ethics of this study can be questioned, it illustrates that early intervention may prevent occurrence of multiorgan failure by aggressively targeting the precipitating event. This principle is also illustrated by the demonstration that survival of patients with variceal bleeding can be improved by the prompt use of antibiotics, which reduces the risk of infection [
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      ]. It is likely that the common end point that leads from the precipitating event to the development of ACLF is an altered host response to injury, resulting in an inappropriate inflammatory response and immune dysfunction increasing the susceptibility to infection [
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      ].

      Inflammation and infection (R)

      The role of a systemic inflammatory response (SIRS), which is a collection of simple and relatively crude clinical and hematological measure using heart and respiratory rate, white cell count, and temperature, in determining the outcome of patients with liver failure was first fully described in the acute liver failure, where the presence of SIRS was associated with more severe encephalopathy, associated infection, renal failure, and poor outcome [
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      ]. Elevated levels of multiple pro- and anti-inflammatory cytokines have been described in ACLF including TNF-α, sTNF-αR1, sTNF-αR2, IL-2, IL-2R, IL-6, IL-8, IL-10, and IFN-ϒ [
      • Gustot T.
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      ]. More recently, the mortality of patients presenting with renal dysfunction of cirrhosis has been shown to be significantly higher in the group with SIRS [
      • Cazzaniga M.
      • Dionigi E.
      • Gobbo G.
      • Fioretti A.
      • Monti V.
      • Salerno F.
      The systemic inflammatory response syndrome in cirrhotic patients: relationship with their in-hospital outcome.
      ,
      • Thabut D.
      • Massard J.
      • Gangloff A.
      • Carbonell N.
      • Francoz C.
      • Nguyen-Khac E.
      • et al.
      Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure.
      ]. It is not surprising that SIRS should be associated with increased inflammatory cytokine response but the use of anti-TNF alpha strategies in patients with alcoholic hepatitis who demonstrate an inflammatory response is associated with an increased risk of infection and mortality [
      • Naveau S.
      • Chollet-Martin S.
      • Dharancy S.
      • Mathurin P.
      • Jouet P.
      • Piquet M.A.
      • et al.
      Foie-alcool group of the association Française pour l’Etude du Foie. A double-blind randomized controlled trial of infliximab associated with prednisolone in acute alcoholic hepatitis.
      ,
      • Boetticher N.C.
      • Peine C.J.
      • Kwo P.
      • Abrams G.A.
      • Patel T.
      • Aqel B.
      • et al.
      A randomized, double-blinded, placebo-controlled multicenter trial of etanercept in the treatment of alcoholic hepatitis.
      ].
      Infection is a common feature of ACLF, which complicates the natural history and is associated with significant morbidity and mortality [
      • Linderoth G.
      • Jepsen P.
      • Schonheyder H.C.
      • et al.
      Short-term prognosis of community-acquired bacteremia in patients with liver cirrhosis or alcoholism: a population-based cohort study.
      ]. About 40–50% of hospital admissions of cirrhotic patients are with sepsis and a further 20–40% will develop nosocomial infections. Overall in-hospital mortality rates of cirrhotic patients with infection are about 15%, which is about twice those without infection. The mortality rate of cirrhotic patients with severe bacterial infection with septic shock is about 60–100% [
      • Linderoth G.
      • Jepsen P.
      • Schonheyder H.C.
      • et al.
      Short-term prognosis of community-acquired bacteremia in patients with liver cirrhosis or alcoholism: a population-based cohort study.
      ,
      • Borzio M.
      • Salerno F.
      • Piantoni L.
      • et al.
      Bacterial infection in patients with advanced cirrhosis: a multicentre prospective study.
      ,
      • Montalto P.
      • Vlachogiannakos J.
      • Cox D.J.
      • Pastacaldi S.
      • Patch D.
      • Burroughs A.K.
      Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study.
      ,
      • Arvaniti V.
      • D’Amico G.
      • Fede G.
      • Manousou P.
      • Tsochatzis E.
      • Pleguezuelo M.
      • et al.
      Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.
      ,
      • Gustot T.
      • Durand F.
      • Lebrec D.
      • Vincent J.L.
      • Moreau R.
      Severe sepsis in cirrhosis.
      ]. In cirrhotic patients, sepsis is a common precipitating event resulting in hepatic encephalopathy, renal dysfunction and rebleeding, and mortality associated with variceal bleeding. Vigilance, repeated cultures from various sites, cautious use of in-dwelling cannulas and very early treatment remain the cornerstones of therapy. The relationship between the SIRS response and infection leads one to hypothesise that an inflammatory response may lead to immune dysregulation, which may predispose to infection that would then further aggravate a pro-inflammatory response resulting in a vicious cycle [
      • Malik R.
      • Mookerjee R.P.
      • Jalan R.
      Infection and inflammation in liver failure: two sides of the same coin.
      ]. This immunopathology of ACLF is reminiscent of the multimodal immunological response observed in patients with severe sepsis, which is characterised by an initial SIRS response followed by a mixed (MARS) and subsequently compensated anti-inflammatory response (CARS) (Fig. 3, Fig. 4).
      Figure thumbnail gr3
      Fig. 3Immune dysfunction of acute-on chronic liver failure. This figure describes the level of immune dysfunction that may be operative in patients with acute-on chronic 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 to an 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 ones that will become infected and have the highest mortality rates.
      Figure thumbnail gr4
      Fig. 4Role of bacterial translocation in acute-on chronic liver failure. In the transition from compensated to decompensated cirrhosis (marked by the development of variceal hemorrhage, ascites and/or hepatic encephalopathy) increasing portal pressure and liver fibrosis play a predominant role, while vasodilatation (and the resultant hyperdynamic circulatory state) is not as prominent. Conversely, the development of multiorgan failure is characterized by significant alterations in systemic and hepatic hemodynamics 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, hepatic encephalopathy.
      The associated mechanisms of this phenomenon are not clear but immune paresis has been suggested as a possible mechanism [
      • Wasmuth H.E.
      • Kunz D.
      • Yagmur E.
      • et al.
      Patients with acute on chronic liver failure display “sepsis-like” immune paralysis.
      ,
      • Mookerjee R.P.
      • Stadlbauer V.
      • Lidder S.
      • Wright G.A.
      • Hodges S.J.
      • Davies N.A.
      • et al.
      Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts outcome.
      ,
      • Berry P.A.
      • Antoniades C.G.
      • Carey I.
      • McPhail M.J.
      • Hussain M.J.
      • Davies E.T.
      • et al.
      Severity of the compensatory anti-inflammatory response determined by monocyte HLA-DR expression may assist outcome prediction in cirrhosis.
      ]. A recent study in cirrhotic patients suggested that a genetic predisposition may underlie the risk of infection. The investigators focussed on Toll-like receptor (TLR) 2 and nucleotide-binding oligomerisation domain (NOD) 2 which recognize pathogen-associated molecular patterns (PAMS). In a multivariate analysis, they confirmed that TLR2 GT microsatellite polymorphism and NOD2 variants were independent predictors of spontaneous bacterial peritonitis (SBP) when both risk factors were present, the risk of SBP was dramatically increased (odds ratio: 11.3; p = 0.00002) [
      • Nischalke H.D.
      • Berger C.
      • Aldenhoff K.
      • Thyssen L.
      • Gentemann M.
      • Grünhage F.
      • et al.
      Toll-like receptor (TLR) 2 promoter and intron 2 polymorphisms are associated with increased risk for spontaneous bacterial peritonitis in liver cirrhosis.
      ]. In alcoholic hepatitis patients, neutrophil activation indicated by increased resting burst and reduced phagocytic function was predictive of subsequent infection, organ failure and mortality [
      • Mookerjee R.P.
      • Stadlbauer V.
      • Lidder S.
      • Wright G.A.
      • Hodges S.J.
      • Davies N.A.
      • et al.
      Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts outcome.
      ]. Importantly, data from ex vivo studies showed that this neutrophil dysfunction was reversible and possibly due to a circulating humoral factor that was hypothesised to be endotoxin [
      • Mookerjee R.P.
      • Stadlbauer V.
      • Lidder S.
      • Wright G.A.
      • Hodges S.J.
      • Davies N.A.
      • et al.
      Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts outcome.
      ]. In another study, monocyte HLA-DR expression was significantly reduced in ACLF who also showed an inability to produce TNF-α, the severity of which correlated with survival [
      • Wasmuth H.E.
      • Kunz D.
      • Yagmur E.
      • et al.
      Patients with acute on chronic liver failure display “sepsis-like” immune paralysis.
      ,
      • Mookerjee R.P.
      • Stadlbauer V.
      • Lidder S.
      • Wright G.A.
      • Hodges S.J.
      • Davies N.A.
      • et al.
      Neutrophil dysfunction in alcoholic hepatitis superimposed on cirrhosis is reversible and predicts outcome.
      ,
      • Berry P.A.
      • Antoniades C.G.
      • Carey I.
      • McPhail M.J.
      • Hussain M.J.
      • Davies E.T.
      • et al.
      Severity of the compensatory anti-inflammatory response determined by monocyte HLA-DR expression may assist outcome prediction in cirrhosis.
      ]. These observations provide potential biomarkers to predict infection risk and allow individualisation of therapy. Modulation of enteric microflora with probiotic therapy has been shown to restore neutrophil phagocytic capacity [
      • Stadlbauer V.
      • Mookerjee R.P.
      • Hodges S.
      • Wright G.A.
      • Davies N.A.
      • Jalan R.
      Effect of probiotic treatment on deranged neutrophil function and cytokine responses in patients with compensated alcoholic cirrhosis.
      ]. In a randomised clinical trial, administration of the granulocyte-colony stimulating factor was associated with improved survival of patients with ACLF [
      • Garg V.
      • Garg H.
      • Khan A.
      • Trehanpati N.
      • Kumar A.
      • Sharma B.C.
      • et al.
      Granulocyte colony-stimulating factor mobilizes CD34(+) cells and improves survival of patients with acute-on-chronic liver failure.
      ]. The study included 47 patients with ACLF using the APASL definition and the investigators showed a very high 2-month mortality of 71% in the untreated group compared with about 30% in the treated group. Clearly, this study will need to be repeated with larger numbers of patients but provides the proof of concept that modulation of immune paresis may prevent the progression of ACLF.

      The organs in ACLF (O)

      Liver and hepatic hemodynamics

      The hallmark of the liver manifestation of ACLF is hyperbilirubinemia and coagulopathy but the pathophysiological basis is unclear. It is likely that the histopathological characteristics of the liver during ACLF will be determined by the underlying cause of cirrhosis and the nature of the precipitating event. The occurrence of ACLF due to a non-specific insults such as infection or a variceal bleeding is likely to be different from the effect of direct hepatotoxins such as drugs or superimposed viral hepatitis. Recent studies in patients with acute deterioration of alcoholic cirrhosis and resultant ACLF showed presence of SIRS and bilirubinostatis as early markers to identify these high-risk patients [
      • Katoonizadeh A.
      • Laleman W.
      • Verslype C.
      • Wilmer A.
      • Maleux G.
      • Roskams T.
      • et al.
      Early features of acute-on-chronic alcoholic liver failure: a prospective cohort study.
      ,
      • Jalan R.
      • Mookerjee R.P.
      Acute-on-chronic liver failure: an early biopsy is essential?.
      ]. The investigators made the important observation that the presence of bilirubinostasis was associated with an increased risk of subsequent infection. In another study, in a similar population, the role of bilirubinostasis was confirmed and the investigators also observed that K8/18 immunostaining was reduced suggesting loss of cellular actin and microtubular structure, which was associated with important prognostic information [
      • Mookerjee R.P.
      • Lackner C.
      • Stauber R.
      • Stadlbauer V.
      • Deheragoda M.
      • Aigelsreiter A.
      • et al.
      The role of liver biopsy in the diagnosis and prognosis of patients with acute deterioration of alcoholic cirrhosis.
      ]. At present, there is no clarity on the mechanism of cell-death or capacity for regeneration of ACLF livers. Early biopsy may help in both the management of patients and providing an understanding of the mechanisms involved, as new drugs, such as pan-caspase inhibitors or stimulators of hepatic regeneration, may be useful [
      • Adebayo D.
      • Mookerjee R.P.
      • Jalan R.
      Mechanistic biomarkers in acute liver injury: are we there yet?.
      ].
      Liver inflammation is an important determinant of portal pressure and prognosis in cirrhosis. Patients with ACLF that occurs on the background of alcoholic hepatitis have increased plasma TNF-α level and also the highest portal pressures [
      • Mookerjee R.P.
      • Sen S.
      • Davies N.A.
      • Hodges S.J.
      • Williams R.
      • Jalan R.
      Tumour necrosis factor α is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.
      ]. Indeed anti-TNF-α therapy has been shown to reduce portal pressure in patients with severe alcoholic hepatitis and cirrhosis [
      • Mookerjee R.P.
      • Sen S.
      • Davies N.A.
      • Hodges S.J.
      • Williams R.
      • Jalan R.
      Tumour necrosis factor α is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.
      ]. Several lines of evidence exist implicating gut-derived endotoxemia in the pathogenesis of portal hypertension [
      • Benten D.
      • Wiest R.
      Gut microbiome and intestinal barrier failure – The “Achilles heel” in hepatology?.
      ]. Modulation of the portal bacterial load using antibiotics such as quinolones and rifaxamin has been associated with a reduction in inflammation and portal pressure [
      • Vlachogiannakos J.
      • Saveriadis A.S.
      • Viazis N.
      • Theodoropoulos I.
      • Foudoulis K.
      • Manolakopoulos S.
      • et al.
      Intestinal decontamination improves liver haemodynamics in patients with alcohol-related decompensated cirrhosis.
      ,
      • Rasaratnam B.
      • Kaye D.
      • Jennings G.
      • Dudley F.
      • Chin-Dusting J.
      The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial.
      ]. Endotoxin neutralisation with high density lipoprotein administration has been associated with a reduction in portal pressure [
      • Thabut D.
      • Tazi K.A.
      • Bonnefont-Rousselot D.
      • Aller M.
      • Farges O.
      • Guimont M.C.
      • et al.
      High-density lipoprotein administration attenuates liver proinflammatory response, restores liver endothelial nitric oxide synthase activity, and lowers portal pressure in cirrhotic rats.
      ]. An increase in reactive oxidant species, in particular superoxide, is also observed in ACLF, contributing to an increase in intrahepatic resistance by reducing nitric oxide bioavailability [
      • Laviña B.
      • Gracia-Sancho J.
      • Rodríguez-Vilarrupla A.
      • Chu Y.
      • Heistad D.D.
      • Bosch J.
      • et al.
      Superoxide dismutase gene transfer reduces portal pressure in CCl4 cirrhotic rats with portal hypertension.
      ]. In patients with ACLF, defined according to APASL criteria, no differences in the portal hemodynamics between decompensated cirrhosis and ACLF were observed [
      • Kumar A.
      • Das K.
      • Sharma P.
      • Mehta V.
      • Sharma B.C.
      • Sarin S.K.
      Hemodynamic studies in acute-on-chronic liver failure.
      ], but using the EASL-AASLD definition, the portal pressure was markedly higher [
      • Jalan R.
      • Mookerjee R.P.
      Systemic hemodynamics, hepatic blood flow and portal pressure in patients with cirrhosis and multiorgan failure: the role of sympathetic activation.
      ] in those with ACLF pointing to the need to carefully define the population under study.
      Hepatic eNOS activity has been shown to be reduced in the context of cirrhosis with superadded inflammation [
      • Mookerjee R.P.
      • Wiesenthal A.
      • Icking A.
      • Hodges S.J.
      • Davies N.A.
      • Schilling K.
      • et al.
      Increased gene and protein expression of the novel eNOS regulatory protein NOSTRIN and a variant in alcoholic hepatitis.
      ,
      • Shah V.
      • Haddad F.G.
      • Garcia-Cardena G.
      • Frangos J.A.
      • Mennone A.
      • Groszmann R.J.
      • et al.
      Liver sinusoidal endothelial cells are responsible for nitric oxide modulation of resistance in the hepatic sinusoids.
      ]. NOS activity is subject to regulation by a number of inhibitors such as asymmetric dimethylarginine (ADMA), which is increased during inflammation resulting in high ADMA levels [
      • Mookerjee R.P.
      • Malaki M.
      • Davies N.A.
      • Hodges S.J.
      • Dalton R.N.
      • Turner C.
      • et al.
      Increasing dimethylarginine levels are associated with adverse clinical outcome in severe alcoholic hepatitis.
      ]. This has been suggested as both a prognostic marker and a possible target of therapy. Evidence suggests that in addition to decreased nitric oxide generation, there is also a reduced response to nitric oxide in cirrhotic livers likely caused by dysfunction of the cyclic GMP system. Phosphodiesterase-5 inhibitors such as sildenafil, which increase cGMP, have been shown to have a beneficial effect on intrahepatic resistance [
      • Lee K.C.
      • Yang Y.Y.
      • Wang Y.W.
      • Hou M.C.
      • Lee F.Y.
      • Lin H.C.
      • et al.
      Acute administration of sildenafil enhances hepatic cyclic guanosine monophosphate production and reduces hepatic sinusoid resistance in cirrhotic patients.
      ]. Further studies are therefore needed in ACLF in whom both liver blood flow and intrahepatic resistance are altered.

      Kidney dysfunction

      HRS is thought to be a functional disorder secondary to circulatory dysfunction in which there is splanchnic vasodilatation, a lowering of arterial blood pressure, intense renal vasoconstriction, impaired cardiac function and marked activation of the sympathetic and neurohormonal systems [
      • Gines P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      ,
      • Martín-Llahí M.
      • Guevara M.
      • Torre A.
      • Fagundes C.
      • Restuccia T.
      • Gilabert R.
      • et al.
      Prognostic importance of the cause of renal failure in patients with cirrhosis.
      ,
      • Stadlbauer V.
      • Wright G.
      • Banaji M.
      • Mukhopadhyay A.
      • Mookerjee R.
      • Moore K.
      • et al.
      Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.
      ]. However, in patients with ACLF who present with renal dysfunction, the characteristics may be widely variable. Thus, in some patients the circulatory changes may predominate, and in other patients there may be increased synthesis of pro-inflammatory mediators or both. Administration of terlipressin and albumin remains the current gold standard for treatment of patients with HRS, but is unsuccessful in 54% of patients [
      • Nazar A.
      • Pereira G.H.
      • Guevara M.
      • Martín-Llahi M.
      • Pepin M.N.
      • Marinelli M.
      • et al.
      Predictors of response to therapy with terlipressin and albumin in patients with cirrhosis and type 1 hepatorenal syndrome.
      ]. It is likely that in these latter patients different factors predominate in the development of renal dysfunction. In about 30–40% of patients with cirrhosis who develop renal dysfunction, a bacterial infection is the precipitating cause (SBP) [
      • Martín-Llahí M.
      • Guevara M.
      • Torre A.
      • Fagundes C.
      • Restuccia T.
      • Gilabert R.
      • et al.
      Prognostic importance of the cause of renal failure in patients with cirrhosis.
      ]. Indeed, the presence of SIRS in patients with renal dysfunction was associated with infection in 56% of the subjects, which was a major independent prognostic factor for mortality in these patients [
      • Thabut D.
      • Massard J.
      • Gangloff A.
      • Carbonell N.
      • Francoz C.
      • Nguyen-Khac E.
      • et al.
      Model for end-stage liver disease score and systemic inflammatory response are major prognostic factors in patients with cirrhosis and acute functional renal failure.
      ]. Traditionally, renal dysfunction has been suggested to be reversible with transplantation. However, recent data suggests that patients that are transplanted with evidence of renal tubular injury on the background of cirrhosis are more likely to require renal replacement therapy after transplantation than patients undergoing transplantation with HRS, suggesting that the basis of renal dysfunction in ACLF is not the same as HRS [
      • Nadim M.K.
      • Genyk Y.S.
      • Tokin C.
      • Fieber J.
      • Ananthapanyasut W.
      • Ye W.
      • et al.
      Impact of etiology of acute kidney injury on outcomes following liver transplantation: acute tubular necrosis versus hepatorenal syndrome.
      ]. The important pathophysiological role of inflammation in modulating renal dysfunction associated with ACLF is highlighted by the benefit of anti-inflammatory agents such as albumin, pentoxifylline and N-acetylcysteine, which decreased the risk of renal dysfunction in patients with alcoholic hepatitis [
      • Holt S.
      • Goodier D.
      • Marley R.
      • Patch D.
      • Burroughs A.
      • Fernando B.
      • et al.
      Improvement in renal function in hepatorenal syndrome with N-acetylcysteine.
      ,
      • Akriviadis E.
      • Bolta R.
      • Briggs W.
      • et al.
      Pentoxifylline improves short-term survival in severe alcoholic hepatitis: a double-blind, placebo-controlled trial.
      ]. Albumin in this situation probably acts as an anti-inflammatory agent and has been shown to protect the kidney during spontaneous bacterial peritonitis and is associated with improved survival in patients with renal failure [
      • Sort P.
      • Navasa M.
      • Arroyo V.
      • Aldeguer X.
      • Planas R.
      • Ruiz-del-Arbol L.
      • et al.
      Effect of intravenous albumin on renal impairment and mortality in patients with cirrhosis and spontaneous bacterial peritonitis.
      ,
      • Ortega R.
      • Ginès P.
      • Uriz J.
      • Cárdenas A.
      • Calahorra B.
      • De Las Heras D.
      • et al.
      Terlipressin therapy with and without albumin for patients with hepatorenal syndrome: results of a prospective, nonrandomized study.
      ]. Administration of prophylactic norfloxacin, a selective gut decontaminant reduced the incidence of renal failure and improved survival [
      • Fernàndez J.
      • Navasa M.
      • Planas R.
      • et al.
      Primary prophylaxis of spontaneous bacterial peritonitis delays hepatorenal syndrome and improves survival in cirrhosis.
      ]. The mechanism of the protective effect of norfloxacin was explored in animal models of cirrhosis and AKI and shown to result from modulation of renal NFkB and cytokines possibly mediated through a TLR4-based mechanism. In a preliminary observation, increased TLR4 has been shown in renal tubules in ACLF patients, which was not observed in HRS [
      • Shah N.
      • Dhar D.
      El Zahraa Mohammed F, Habtesion A, Davies NA, Jover-Cobos M, et al. Prevention of acute kidney injury in a rodent model of cirrhosis following selective gut decontamination is associated with reduced renal TLR4 expression.
      ]. These data provide potential novel insights into pathophysiology and the potential for the development of novel biomarkers and therapeutic approaches. Thus, the use of urinary biomarkers that reflect renal injury may allow early diagnosis of renal dysfunction of cirrhosis and allow the functional causes of renal dysfunction to be better distinguished from the inflammatory causes. The biomarkers of interest are markers of tubular injury such as kidney injury molecule-1, pi and alpha glutathione S-transferase; markers of inflammation such as NAG, NGAL, FABP, and IL-18 [
      • Cárdenas A.
      • Ginès P.
      Acute-on-chronic liver failure: the kidneys.
      ]. It is possible that novel therapeutic approaches may be developed if this hypothesis can be confirmed.

      Brain dysfunction

      Hepatic encephalopathy (HE) is a common manifestation of ACLF [
      • Jalan R.
      • Williams R.
      Acute-on-chronic liver failure: pathophysiological basis of therapeutic options.
      ,
      • Crippin J.S.
      • Gross Jr., J.B.
      • Lindor K.D.
      Increased intracranial pressure and hepatic encephalopathy in chronic liver disease.
      ,
      • Jalan R.
      • Dabos K.
      • Redhead D.N.
      • Lee A.
      • Hayes P.C.
      Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage.
      ,
      • Donovan J.P.
      • Schafer D.F.
      • Shaw Jr., B.W.
      • Sorrell M.F.
      Cerebral edema and increased intracranial pressure in chronic liver disease.
      ]. Local and systemic changes have been implicated in the pathophysiology of the development of this neurological syndrome. From the pathophysiological perspective, like the situation in acute liver failure, brain swelling is an important feature of ACLF also [
      • Crippin J.S.
      • Gross Jr., J.B.
      • Lindor K.D.
      Increased intracranial pressure and hepatic encephalopathy in chronic liver disease.
      ,
      • Jalan R.
      • Dabos K.
      • Redhead D.N.
      • Lee A.
      • Hayes P.C.
      Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage.
      ,
      • Donovan J.P.
      • Schafer D.F.
      • Shaw Jr., B.W.
      • Sorrell M.F.
      Cerebral edema and increased intracranial pressure in chronic liver disease.
      ,
      • Wright G.
      • Davies N.A.
      • Shawcross D.L.
      • Hodges S.J.
      • Zwingmann C.
      • Brooks H.F.
      • et al.
      Endotoxemia produces coma and brain swelling in bile duct ligated rats.
      ]. As the syndrome occurs on the background of existing cirrhosis and chronic portacaval shunting, a degree of brain atrophy protects from this brain swelling, resulting in an increase in intracranial pressure. There are, however, several reports of significant increases in intracranial pressure in patients with ACLF [
      • Crippin J.S.
      • Gross Jr., J.B.
      • Lindor K.D.
      Increased intracranial pressure and hepatic encephalopathy in chronic liver disease.
      ,
      • Jalan R.
      • Dabos K.
      • Redhead D.N.
      • Lee A.
      • Hayes P.C.
      Elevation of intracranial pressure following transjugular intrahepatic portosystemic stent-shunt for variceal haemorrhage.
      ,
      • Donovan J.P.
      • Schafer D.F.
      • Shaw Jr., B.W.
      • Sorrell M.F.
      Cerebral edema and increased intracranial pressure in chronic liver disease.
      ]. Studies using MRI have shown that this increase in brain swelling can be reversed with liver transplantation supporting the notion that, like acute liver failure, the brain manifestation of ACLF is a reversible disorder [
      • García Martínez R.
      • Rovira A.
      • Alonso J.
      • Aymerich F.X.
      • Huerga E.
      • Jacas C.
      • et al.
      A long-term study of changes in the volume of brain ventricles and white matter lesions after successful liver transplantation.
      ]. Ammonia is thought to play a key role in the development of HE but no direct relationship between the severity of hyperammonemia and HE could be demonstrated [
      • Shawcross D.L.
      • Sharifi Y.
      • Canavan J.B.
      • Yeoman A.D.
      • Abeles R.D.
      • Taylor N.J.
      • et al.
      Infection and systemic inflammation, not ammonia, are associated with grade 3/4 hepatic encephalopathy, but not mortality in cirrhosis.
      ]. On the background of this hyperammonemia, an added hepatic insult and/or superimposed inflammation leads to the development of brain edema suggesting a synergy between ammonia and inflammation. The synergy between ammonia and inflammation has been demonstrated in animal models of cirrhosis where acute brain swelling was observed following administration of endotoxin mimicking the clinical situation seen in ACLF [
      • Wright G.
      • Davies N.A.
      • Shawcross D.L.
      • Hodges S.J.
      • Zwingmann C.
      • Brooks H.F.
      • et al.
      Endotoxemia produces coma and brain swelling in bile duct ligated rats.
      ]. The mechanism is likely to be related to generation of cytokines in the brain, increased iNOS expression, oxidative stress and formation of nitrated protein adducts [
      • Wright G.
      • Davies N.A.
      • Shawcross D.L.
      • Hodges S.J.
      • Zwingmann C.
      • Brooks H.F.
      • et al.
      Endotoxemia produces coma and brain swelling in bile duct ligated rats.
      ,
      • Pedersen H.R.
      • Ring-Larsen H.
      • Olsen N.V.
      • Larsen F.S.
      Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital.
      ]. Studies in animal models have suggested that ammonia may prime the brain to the deleterious effects of superimposed inflammation by induction of microglial cells, which have a huge repertoire for cytokine production; and a reduction in ammonia in cirrhotic models prevents the effect of superimposed inflammation [
      • Wright G.
      • Davies N.A.
      • Shawcross D.L.
      • Hodges S.J.
      • Zwingmann C.
      • Brooks H.F.
      • et al.
      Endotoxemia produces coma and brain swelling in bile duct ligated rats.
      ,
      • Pedersen H.R.
      • Ring-Larsen H.
      • Olsen N.V.
      • Larsen F.S.
      Hyperammonemia acts synergistically with lipopolysaccharide in inducing changes in cerebral hemodynamics in rats anaesthetised with pentobarbital.
      ,
      • Rodrigo R.
      • Cauli O.
      • Gomez-Pinedo U.
      • Agusti A.
      • Hernandez-Rabaza V.
      • Garcia-Verdugo J.M.
      • et al.
      Hyperammonemia induces neuroinflammation that contributes to cognitive impairment in rats with hepatic encephalopathy.
      ,
      • Wright G.
      • Vairappan B.
      • Stadlbauer V.
      • Mookerjee R.P.
      • Davies N.A.
      • Jalan R.
      Reduction in hyperammonaemia by ornithine phenylacetate prevents lipopolysaccharide-induced brain edema and coma in cirrhotic rats.
      ]. Conversely, reduction in bacterial translocation using a non-absorbable antibiotic, rifaximin was shown to prevent the occurrence of HE, suggesting that reducing inflammation may be protective as well [
      • Bass N.M.
      • Mullen K.D.
      • Sanyal A.
      • Poordad F.
      • Neff G.
      • Leevy C.B.
      • et al.
      Rifaximin treatment in hepatic encephalopathy.
      ]. Cerebral blood flow is known to be progressively reduced in cirrhosis but in ACLF may be paradoxically increased as seen in patients with acute liver failure. In a recent study, the acute effect of insertion of a transjugular intrahepatic shunt, which is known to induce endotoxemia, was studied in patients with cirrhosis. The study demonstrated that TIPSS-induced endotoxemia led to an increase in the rate of production of nitric oxide, which was associated with endothelial dysfunction and increased cerebral blood flow supporting the hypothesis that multiple hits and brain swelling is a feature of ACLF [
      • Jalan R.
      • Olde Damink S.W.
      • Ter Steege J.C.
      • Redhead D.N.
      • Lee A.
      • Hayes P.C.
      • et al.
      Acute endotoxemia following transjugular intrahepatic stent-shunt insertion is associated with systemic and cerebral vasodilatation with increased whole body nitric oxide production in critically ill cirrhotic patients.
      ] (Fig. 5). However, the insertion of TIPSS in relatively well cirrhotics without hepatic encephalopathy undergoing TIPSS was not associated with a change in cerebral blood flow, stressing the pathophysiologically distinct nature of ACLF from otherwise stable cirrhosis [
      • Iversen P.
      • Keiding S.
      • Mouridsen K.
      • Ott P.
      • Vilstrup H.
      Transjugular intrahepatic portosystemic shunt does not alter cerebral blood flow.
      ].
      Figure thumbnail gr5
      Fig. 5Pathophysiological mechanisms of brain dysfunction in acute-on chronic liver failure. This figure describes the possible mechanisms underlying the pathogenesis of hepatic encephalopathy in acute-on chronic liver failure. It is likely that similar mechanisms are operative in other organs, where susceptibility to an inflammatory insult is provided by organ characteristics that are a feature of that particular organ in cirrhosis.

      Cardiac and systemic hemodynamics

      In patients with decompensated cirrhosis, a hyperdynamic circulation is the key hemodynamic feature. The increased cardiac output observed in this situation is mainly due to a vasodilated splanchnic bed but paradoxically, the blood flow in other organ, such as kidneys, brain and peripheral organs, is decreased [
      • Helmy A.
      • Jalan R.
      • Newby D.E.
      • Hayes P.C.
      • Webb D.J.
      Role of angiotensin II in regulation of basal and sympathetically stimulated vascular tone in early and advanced cirrhosis.
      ]. Additionally, patients with cirrhosis may have an underlying cirrhotic cardiomyopathy, which may make them susceptible to cardiovascular collapse during an acute inflammatory insult, but data supporting that hypothesis does not exist [
      • Liu H.
      • Lee S.S.
      Acute-on-chronic liver failure: the heart and systemic hemodynamics.
      ]. The hallmark of ACLF is cardiovascular collapse akin to the patients with acute liver failure and severe sepsis, often requiring large doses of inotropes. Unlike decompensated cirrhosis, where the cardiac output remains elevated, in ACLF, despite splanchnic vasodilation, the cardiac output can be reduced and both systolic and diastolic functions are affected. This cardiovascular abnormality is associated with increased risk of death, particularly in those patients who present with renal dysfunction [
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Ginès P.
      • Moreira V.
      • et al.
      Circulatory function and hepatorenal syndrome in cirrhosis.
      ]. In another study, where the definition of ACLF was based upon the APASL criteria, no differences in cardiac output were observed, highlighting the fact that the designation is crucial in defining which patients are being described. The mechanisms underlying the cardiac dysfunction in ACLF are likely similar to those in severe sepsis, such as cardiovascular-active factors like TNF and nitric oxide which are increased, and cortisol which is decreased [
      • Fernández J.
      • Escorsell A.
      • Zabalza M.
      • Felipe V.
      • Navasa M.
      • Mas A.
      • et al.
      Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival.
      ]. The former can further dilate the vasculature and the latter decreases the sensitivity to vasoconstrictors. However, no study has yet demonstrated the benefit of vasodilators/vasoconstrictors in the management of ACLF. It is important to monitor the cardiac situation using appropriate methods to guide fluid replacement and inotrope support. The choice of inotropes is also unclear but vasopressin analogue in this situation should be used cautiously as it may further reduce cardiac perfusion and an already compromised hepatic blood flow [
      • Møller S.
      • Hansen E.F.
      • Becker U.
      • Brinch K.
      • Henriksen J.H.
      • Bendtsen F.
      Central and systemic haemodynamic effects of terlipressin in portal hypertensive patients.
      ].

      Coagulation

      Routine diagnostic tests of coagulation are usually abnormal in patients with cirrhosis due to multiple defects. An increased bleeding tendency has been attributed to the degree of abnormalities in these tests, but this has not been formally proven [
      • Lisman T.
      • Leebeek F.W.
      • de Groot P.G.
      Haemostatic abnormalities in patients with liver disease.
      ]. Thrombin generation is normal in stable cirrhotics with a rebalancing of pro- and anti-coagulant factors (providing there are sufficient platelets >50,000 × 109/L). Since hypercoagulation may exist [
      • Tripodi A.
      • Primignani M.
      • Chantarangkul V.
      • Dell’Era A.
      • Clerici M.
      • de Franchis R.
      • et al.
      An imbalance of pro- vs. anti-coagulation factors in plasma from patients with cirrhosis.
      ], bleeding abnormalities are far less frequent than it would be expected [
      • Senzolo M.
      • Coppell J.
      • Cholongitas E.
      • Riddell A.
      • Triantos C.K.
      • Perry D.
      • et al.
      The effects of glycosaminoglycans on coagulation: a thromboelastographic study.
      ]. In cirrhosis with sepsis, endogenous low-molecular weight heparinoids are detected, and disappear with resolution of infection [
      • Montalto P.
      • Vlachogiannakos J.
      • Cox D.J.
      • Pastacaldi S.
      • Patch D.
      • Burroughs A.K.
      Bacterial infection in cirrhosis impairs coagulation by a heparin effect: a prospective study.
      ]. Antibiotics are known to reduce early variceal rebleeding rates [
      • Jun C.H.
      • Park C.H.
      • Lee W.S.
      • Joo Y.E.
      • Kim H.S.
      • Choi S.K.
      • et al.
      Antibiotic prophylaxis using third generation cephalosporins can reduce the risk of early rebleeding in the first acute gastroesophageal variceal hemorrhage: a prospective randomized study.
      ]. The use of prophylactic blood products to correct abnormalities to prevent bleeding is empirical and often guided by local protocols; virtually none of these are evidence-based [
      • Segal J.B.
      • Dzik W.H.
      Paucity of studies to support that abnormal coagulation test results predict bleeding in the setting of invasive procedures: an evidence-based review.
      ]. Moreover, normalization of abnormal coagulation parameters is difficult to achieve, and creates volume excess, increasing the risk of transfusion-related acute lung injury and other transfusion reactions. Even recombinant factor VIIa, which corrects prothrombin time, does not reduce blood loss during variceal bleeding [
      • Bosch J.
      • Thabut D.
      • Albillos A.
      • Carbonell N.
      • Spicak J.
      • Massard J.
      • et al.
      International Study Group on rFVIIa in UGI hemorrhage. recombinant factor VIIa for variceal bleeding in patients with advanced cirrhosis: a randomized, controlled trial.
      ]. Conversely, antifibrinolytic agents do reduce blood loss during liver transplantation, but have not been evaluated prophylactically during other procedures or for bleeding. Apart from increased fibrinolysis, which is seen in ACLF, defective platelet function is the other major abnormality [
      • Lisman T.
      • Porte R.J.
      Platelet function in patients with cirrhosis.
      ]. The thrombopoietin analog eltrombopag may be thrombogenic at least in stable cirrhosis (there has been a suspended trial in this area), probably because of the interaction with the very high levels of vWF in cirrhosis. The use of fresh frozen plasma is limited by the volume of transfusions; safer prothrombin complex concentrates which have 20 times the concentration of factors than FFP are now available [
      • Mannucci P.M.
      • Franchi F.
      • Dioguardi N.
      Correction of abnormal coagulation in chronic liver disease by combined use of fresh-frozen plasma and prothrombin complex concentrates.
      ]. Currently, prophylactic transfusions of any coagulation products are difficult to justify and it is likely that more comprehensive, global tests of coagulation are needed to guide the correction of coagulation on an individual basis [
      • Stravitz R.T.
      • Lisman T.
      • Luketic V.A.
      • Sterling R.K.
      • Puri P.
      • Fuchs M.
      • et al.
      Minimal effects of acute liver injury/acute liver failure on hemostasis as assessed by thromboelastography.
      ].

      Hepato-adrenal axis

      Adrenal insufficiency is reported in 51–68% of patients with cirrhosis and severe sepsis, particularly in patients with high Child-Pugh and MELD scores and hemodynamic instability. Adrenal insufficiency is associated with increased mortality compared to patients without adrenal insufficiency [
      • Tsai M.H.
      • Peng Y.S.
      • Chen Y.C.
      • Liu N.J.
      • Ho Y.P.
      • Fang J.T.
      • et al.
      Adrenal insufficiency in patients with cirrhosis, severe sepsis and septic shock.
      ]. Administration of hydrocortisone to patients with septic shock and adrenal insufficiency was shown to improve the circulatory function but routine use of hydrocortisone during sepsis has not been confirmed to improve the outcome [
      • Fernandez J.
      • Escorsell A.
      • Zabalza M.
      • Felipe V.
      • Navasa M.
      • Mas A.
      • et al.
      Adrenal insufficiency in patients with cirrhosis and septic shock: effect of treatment with hydrocortisone on survival.
      ]. Interpretation of response to synacthen test in cirrhosis and ACLF is difficult due to methodological constraints, so no conclusions can be made.

      Intensive care management, organ support and transplantation

      Intensive care management of patients with ACLF has been recently reviewed and a full description is beyond the scope of this review. The essential principles are those of multiple organ support to allow the treatment of the precipitating event and the recovery of the liver. The two specific aspects of treatment relevant to this group of patients are discussed below [
      • Olson J.C.
      • Wendon J.A.
      • Kramer D.J.
      • Vicente A.
      • Jalan R.
      • Garcia-Tsao G.
      • et al.
      Intensive care of the patient with cirrhosis.
      ].
      Liver support devices are intended to provide detoxification functions to patients with ACLF until liver transplantation, recovery or futility. The overall efficacy of liver support devices have failed to reach a level sufficient to gain approval for widespread use [
      • Stadlbauer V.
      • Davies N.A.
      • Sen S.
      • Jalan R.
      Artificial liver support systems in the management of complications of cirrhosis.
      ]. Liver support devices are of two main types; artificial livers-acellular devices such as albumin dialysis and plasma-exchange/diafiltration, and bio-artificial livers, which incorporate cells from human, animal, or transformed sources. An unpublished study using the ELAD device which incorporates liver cancer cells, C3A cells, into the device, was shown in a preliminary study to be useful in patients with ACLF, mainly induced by HBV reactivation in a small randomised controlled study [
      • Zhong-Ping Duan J.Z.
      • Xin S.
      • Ju Chen M.
      • He D.
      • Brotherthon J.
      • Maxwell K.
      • et al.
      Interim results of randomized controlled trial of ELAD in acute on chronic liver disease.
      ]. A pivotal clinical trial in USA and Europe has been stopped. None of the bioartificial liver devices as far as we know, are in clinical trials for ACLF patients at present.
      The best studied artificial liver support devices are the molecular adsorbents recirculating system (MARS) and Prometheus devices, which are based upon the principles of albumin dialysis [
      • Stange J.
      • Mitzner S.
      • Ramlow W.
      • Gliesche T.
      • Hickstein H.
      • Schmidt R.
      A new procedure for the removal of protein bound drugs and toxins”.
      ]. These devices are based on the concept that albumin is a complex molecule with a plethora of physiological functions besides providing oncotic properties [
      • Jalan R.
      • Schnurr K.
      • Mookerjee R.P.
      • Sen S.
      • Cheshire L.
      • Hodges S.
      • et al.
      Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.
      ]. Studies have demonstrated that during hepatic failure, the circulating albumin undergoes structural and functional modifications that negatively affect its biological activity [
      • Jalan R.
      • Schnurr K.
      • Mookerjee R.P.
      • Sen S.
      • Cheshire L.
      • Hodges S.
      • et al.
      Alterations in the functional capacity of albumin in patients with decompensated cirrhosis is associated with increased mortality.
      ]. These devices are designed to provide additional detoxification functions. Several studies have confirmed that the use of these devices can remove inflammatory molecules, reduce NO and improve systemic and hepatic hemodynamics, severe hepatic encephalopathy leading to large clinical trials [
      • Sen S.
      • Davies N.A.
      • Mookerjee R.P.
      • Cheshire L.M.
      • Hodges S.J.
      • Williams R.
      • et al.
      Pathophysiological effects of albumin dialysis in acute-on-chronic liver failure: a randomized controlled study.
      ]. The randomised controlled trial of the Prometheus device in patients with ACLF has been recently published [

      Kribben A, Gerken G, Haag S, Herget-Rosenthal S, Treichel U, Betz C, et al. Effects of fractionated plasma separation and adsorption on survival in patients with acute-on-chronic liver failure. Gastroenterology 2012 (in press).

      ]. The data show that the approach is safe and well tolerated, although there is no overall significant survival benefit at 28 days. Subgroup analysis suggested that patients with a MELD score of >30 and those with hepatorenal syndrome may have some benefit. MARS was tested in a similar cohort, the RELIEF trial, which has been reported in a preliminary communication and again failed to show any survival benefit [
      • Banares R.
      • Nevens F.
      • Larsen F.
      • et al.
      Extracorporeal liver support with the molecular adsorbent recirculating system (MARS) in patients with acute-on-chronic liver failure (AOCLF) the RELIEF trial.
      ]. A better definition of ACLF would allow the study of a more homogenous cohort, but it is likely that modifications to the current devices will be necessary to improve their efficacy and capacity.
      Liver transplantation in patients with ACLF has not been systematically analysed but a recent retrospective study was performed in 332 patients of whom 157 patients had ACLF and 175 patients had no ACLF pre-transplant [
      • Bahirwani R.
      • Shaked O.
      • Bewtra M.
      • Forde K.
      • Reddy K.R.
      Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes.
      ]. Thirty-four patients received a liver-kidney transplant, of whom 10 (29.4%) had ACLF. The definition was based on a rapid increase in MELD by >5 points. The results showed that the group with ACLF had a 26% mortality compared with a mortality of 17% in the non-ACLF group. The difference was statistically different in univariate analysis, but when only single organ transplants were analysed, the results were not statistically different. On multivariate analysis, ACLF was not an independent predictor of post-transplant mortality, arguing strongly that this is a good indication for transplantation [
      • Bahirwani R.
      • Shaked O.
      • Bewtra M.
      • Forde K.
      • Reddy K.R.
      Acute-on-chronic liver failure before liver transplantation: impact on posttransplant outcomes.
      ]. The timing of transplantation is crucial as patients with ACLF may provide a window of opportunity. Therefore, living-donor transplantation is an attractive option, the experience of which has been reported extensively from South-East Asia, mainly in patients with ACLF resulting from re-activation of hepatitis B virus infection. The data from Hong Kong suggests that although the patients with ACLF and HRS had stormier post-operative course, living donor transplantation could be performed safely and overall there were no significant differences in survival with 5-year survivals of about 80% [
      • Chen Z.
      • Wen T.
      • Zeng Y.
      • Wang L.
      • Lu J.J.
      • Gong S.
      • et al.
      A single institution experience with living donor liver transplantation for acute-on-chronic hepatitis B liver failure.
      ]. Similar observations have been made regarding the safety and feasibility of living donor transplantation from the Chinese groups [

      Chok KS, Fung JY, Chan SC, Cheung TT, Sharr WW, Chan AC, et al. Outcomes of living-donor liver transplantation in patients with preoperative type-1 hepatorenal syndrome and acute hepatic decompensation. Liver Transpl 2012 (in press).

      ]. Currently, in most countries there is no priority for ACLF patients who have significantly higher short-term mortality. A better understanding of the natural history and prognostic criteria will allow ACLF to be incorporated as a possible new indication for high urgency allocation.

      Conflict of interest

      The authors declared that they do not have anything to disclose regarding funding or conflict of interest with respect to this manuscript.

      Acknowledgements

      A lot of the manuscript is based around the discussions during a meeting that took place at Atlanta, 2010; ‘Intensive Care of the Patient with Acute-on Chronic Liver Failure: Summary of an American Association for the Study of Liver Diseases and European Association for the Study of the Liver Single Topic Conference.’

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