Advertisement

Transition to decompensation and acute-on-chronic liver failure: Role of predisposing factors and precipitating events

  • Thierry Gustot
    Correspondence
    Corresponding author. Address: Liver Transplant Unit, Dept. of Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme, 808 route de Lennik 1070 Brussels, Belgium. Tel.: +3225553714; Fax:+3225554802.
    Affiliations
    Dept. Gastroenterology and Hepato-Pancreatology, C.U.B. Erasme Hospital, Brussels, Belgium

    Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium

    Inserm Unité 1149, Centre de Recherche sur l’inflammation (CRI), Paris, France

    UMR S_1149, Université Paris Diderot, Paris, France

    The EASL-CLIF Consortium, European Foundation-CLIF, Barcelona, Spain
    Search for articles by this author
  • Vanessa Stadlbauer
    Affiliations
    Department of Internal Medicine, Division of Gastroenterology and Hepatology, Medical University of Graz, Auenbruggerplatz 15, 8036, Graz, Austria

    Center of Biomarker Research in Medicine (CBmed), Graz, Austria
    Search for articles by this author
  • Author Footnotes
    † MICROB-PREDICT consortium (Horizon2020 grant agreement No 825694).
    Wim Laleman
    Footnotes
    † MICROB-PREDICT consortium (Horizon2020 grant agreement No 825694).
    Affiliations
    Department of Gastroenterology and Hepatology, Section of Liver and Biliopancreatic disorders, University Hospitals Leuven, KULeuven, Belgium
    Search for articles by this author
  • Carlo Alessandria
    Affiliations
    Division of Gastroenterology and Hepatology, Città della Salute e della Scienza Hospital, University of Turin, Turin, Italy
    Search for articles by this author
  • Mark Thursz
    Affiliations
    Division of Digestive Diseases, Imperial College, London, UK
    Search for articles by this author
  • Author Footnotes
    † MICROB-PREDICT consortium (Horizon2020 grant agreement No 825694).

      Summary

      The transition from compensated to decompensated cirrhosis results from a complex interplay of predisposing and precipitating factors and represents an inflection point in the probability of a patient surviving. With the progression of cirrhosis, patients accumulate multiple disorders (e.g. altered liver architecture, portal hypertension, local and systemic inflammation, bacterial translocation, gut dysbiosis, kidney vasoconstriction) that predispose them to decompensation. On the background of these factors, precipitating events (e.g. bacterial infection, alcoholic hepatitis, variceal haemorrhage, drug-induced liver injury, flare of liver disease) lead to acute decompensation (ascites, hepatic encephalopathy, variceal bleeding, jaundice) and/or organ failures, which characterise acute-on-chronic liver failure. In this review paper, we will discuss the current hypotheses and latest evidences regarding predisposing and precipitating factors associated with the transition to decompensated liver disease.

      Keywords

      Decompensation: a critical step in the natural history of cirrhosis

      Compensated cirrhosis is an asymptomatic condition characterised histologically based on the extent and morphology of fibrous scar tissue in the liver. Decompensated cirrhosis is a symptomatic disease state, arising from cirrhosis, characterised clinically by the development of ascites, encephalopathy and/or gastrointestinal bleeding due to portal hypertension. Decompensated cirrhosis is a more advanced disease state which develops after a variable duration of compensated cirrhosis and represents a turning point in terms of a patient’s quality of life, probability of hospitalisation, and mortality risk. The onset of decompensation may be insidious, resulting from slowly declining hepatic synthetic function and rising portal pressure. However, a significant proportion of hospital admissions occur in patients with acute onset of symptoms developing over a matter of hours or days. This acute decompensation (AD) may occur in patients with no previous evidence of impaired hepatic reserve and is associated with pathophysiological events which lead to the rapid deterioration in liver function. These precipitating events, which include infections, exacerbations of the underlying liver disease, alcoholic hepatitis, drug-induced liver injury, will be discussed later. The relative frequency of precipitating event types varies geographically. In Europe, the most frequent precipitating event of AD is bacterial infection, followed by active alcohol consumption (alcoholic hepatitis) and gastrointestinal haemorrhage.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      In China, HBV flares remain the main precipitating event, while active alcohol consumption (~50%) has overtaken hepatitis B and hepatitis E as the main precipitating factor of decompensation in India.
      • Shi Y.
      • Yang Y.
      • Hu Y.
      • Wu W.
      • Yang Q.
      • Zheng M.
      • et al.
      Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
      ,
      • Choudhury A.
      • Jindal A.
      • Maiwall R.
      • Sharma M.K.
      • Sharma B.C.
      • Pamecha V.
      • et al.
      Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.
      The transition from compensated to decompensated cirrhosis is accompanied by a profound change in mortality risk in the short, medium, and long term (see Table 1).
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      The short-term prognosis associated with AD is poor, particularly when accompanied by failure of other organs, categorised as acute-on-chronic-liver-failure (ACLF), with 28-day mortality rates ranging from 15%–80%, depending on the severity and number of organ failures.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      Quality of life measures in patients with compensated cirrhosis are not dissimilar to age- and gender-matched controls but decompensation is associated with a profound deterioration in quality of life.
      • Labenz C.
      • Toenges G.
      • Schattenberg J.M.
      • Nagel M.
      • Huber Y.
      • JU Marquardt
      • et al.
      Health-related quality of life in patients with compensated and decompensated liver cirrhosis.
      Furthermore, the need for hospital visits, admissions and healthcare costs increase substantially in patients following an episode of AD.
      • Desai A.P.
      • Mohan P.
      • Nokes B.
      • Sheth D.
      • Knapp S.
      • Boustani M.
      • et al.
      Increasing economic burden in hospitalized patients with cirrhosis: analysis of a national database.
      Table 1Estimation of prognosis based on the stage and the type of decompensation in cirrhosis.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • D’Amico G.
      • Garcia-Tsao G.
      • Pagliaro L.
      Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
      • 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.
      • Jepsen P.
      • Ott P.
      • Andersen P.K.
      • Sørensen H.T.
      • Vilstrup H.
      Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
      StageSpecificitiesTime pointMortality rates
      Compensated cirrhosisWithout varices
      If patients remained in this clinical status.
      1-year1%
      With varices
      If patients remained in this clinical status.
      1-year3.4%
      Acute decompensated cirrhosisVariceal bleeding1-year20%
      Ascites1-year30%
      Ascites + variceal bleeding1-year50%
      Hepatic encephalopathy1-year64%
      Bacterial infection1-year63%
      ACLF-1 (renal failure
      Renal failure was defined by creatinine levels ≥2 mg/dl.
      or 1 organ failure + renal or cerebral dysfunction
      Renal dysfunction was defined by creatinine levels of 1.5–1.9 mg/dl and cerebral dysfunction by grade I or II hepatic encephalopathy.
      )
      90-day40%
      ACLF-2 (2 organ failures)90-day52%
      ACLF-3 (3 organ failures or more)90-day80%
      ACLF, acute-on-chronic liver failure.
      If patients remained in this clinical status.
      # Renal failure was defined by creatinine levels ≥2 mg/dl.
      & Renal dysfunction was defined by creatinine levels of 1.5–1.9 mg/dl and cerebral dysfunction by grade I or II hepatic encephalopathy.
      The transition from the compensated to the decompensated state is a complex phenomenon resulting from the interaction between predisposing factors, which characterise the patient and their liver disease, and the occurrence of precipitating events (Fig. 1). Improving our understanding of the mechanisms responsible for this transition will be essential in the search for new preventive strategies. In this review paper, we will discuss the current hypotheses and latest evidence regarding predisposing and precipitating factors associated with the transition to decompensated liver disease.
      Figure thumbnail gr1
      Fig. 1Current hypothesis about transition to decompensation and acute-on-chronic liver failure. APAP, acetaminophen; DIKI, drug-induced kidney injury; DILI, drug-induced liver injury; PPI, proton pump inhibitor; TIPS, transjugular intrahepatic portosystemic shunt.

      Predisposing factors

      Evidence for clinically recognised factors

      Liver architecture and injuries

      It has been suggested that the degree of architectural distortion of the liver – in particular the thickness of fibrous septa and the size of regeneration nodules, which correlate with portal hypertension – is a predictor of liver-related events.
      • Kim S.U.
      • Oh H.J.
      • Wanless I.R.
      • Lee S.
      • Han K.-H.
      • Park Y.N.
      The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis.
      In addition, it has been shown that collagen proportionate area, used to quantify fibrosis in cirrhosis, is a predictor of clinical decompensation.
      • Hall A.
      • Germani G.
      • Isgrò G.
      • Burroughs A.K.
      • Dhillon A.P.
      Fibrosis distribution in explanted cirrhotic livers.
      The aetiology of cirrhosis also seems to influence its natural history, but studies remain scarce. One prospective study suggested that non-alcoholic fatty liver disease-related cirrhosis is associated with fewer episodes of decompensation than HCV-related cirrhosis in the pre-direct-acting antiviral (DAA) era.
      • Sanyal A.J.
      • Banas C.
      • Sargeant C.
      • Luketic V.A.
      • Sterling R.K.
      • Stravitz R.T.
      • et al.
      Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.
      Secondly, there is accumulating evidence that continuous liver injuries triggered by aetiological factors induce decompensation. This is mainly demonstrated by the fact that the control of aetiological factors by treatments or lifestyle interventions in patients with cirrhosis prevents future decompensation. For example, achieving a sustained virological response to DAAs significantly reduces episodes of decompensation in patients with compensated HCV-related cirrhosis.
      • Mendizabal M.
      • Piñero F.
      • Ridruejo E.
      • Herz Wolff F.
      • Anders M.
      • Reggiardo V.
      • et al.
      Disease progression in patients with hepatitis C virus infection treated with direct-acting antiviral agents.
      This has also been suggested for patients with HBV treated with nucleos(t)ide analogues
      • Lok A.S.F.
      • McMahon B.J.
      • Brown R.S.
      • Wong J.B.
      • Ahmed A.T.
      • Farah W.
      • et al.
      Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis.
      and patients with primary biliary cholangitis treated with ursodesoxycholic acid.
      • Rudic J.S.
      • Poropat G.
      • Krstic M.N.
      • Bjelakovic G.
      • Gluud C.
      Ursodeoxycholic acid for primary biliary cirrhosis.
      Moreover, in a retrospective study, behavioural and/or pharmacological treatment for alcohol use disorder was associated with a significant decrease in decompensation.
      • Rogal S.
      • Youk A.
      • Zhang H.
      • Gellad W.F.
      • Fine M.J.
      • Good C.B.
      • et al.
      Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis.

      Clinically significant portal hypertension

      The development of portal hypertension is central to decompensation of cirrhosis. It has been observed that the incidence of clinical decompensation begins to increase when the hepatic venous pressure gradient (HVPG) exceeds 10 mmHg, the threshold defining clinically significant portal hypertension (CSPH).
      • Ripoll C.
      • Groszmann R.
      • Garcia-Tsao G.
      • Grace N.
      • Burroughs A.
      • Planas R.
      • et al.
      Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
      Variceal haemorrhage generally occurs when HVPG exceeds 12 mmHg.
      • D’Amico G.
      • Garcia-Pagan J.C.
      • Luca A.
      • Bosch J.
      Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.
      Moreover, a recent large randomised controlled trial suggested that long-term administration of β-blockers prevents decompensation, not only by reducing the occurrence of variceal haemorrhage but also the development of ascites.
      • Villanueva C.
      • Albillos A.
      • Genescà J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • et al.
      β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.

      Kidney alterations: renal vasoconstriction, deranged autoregulation

      In advanced cirrhosis, renal sodium and fluid retention occur before the development of ascites.
      • Bernardi M.
      • Trevisani F.
      • Santini C.
      • De Palma R.
      • Gasbarrini G.
      Aldosterone related blood volume expansion in cirrhosis before and during the early phase of ascites formation.
      • Bolondi L.
      • Piscaglia F.
      • Gatta A.
      • Salerno F.
      • Bernardi M.
      • Ascione A.
      • et al.
      Effect of potassium canrenoate, an anti-aldosterone agent, on incidence of ascites and variceal progression in cirrhosis.
      • Bernardi M.
      • Li Bassi S.
      • Arienti V.
      • De Collibus C.
      • Scialpi C.
      • Boriani L.
      • et al.
      Systemic and regional hemodynamics in pre-ascitic cirrhosis: effects of posture.
      These changes are pathophysiologically linked to the compensatory homeostatic activation of the renin-angiotensin-aldosterone system, the sympathetic nervous system and, in later stages, the non-osmotic hypersecretion of arginine vasopressin. Neurohormonal activation aims to counterbalance the reduction in effective arterial blood volume secondary to portal hypertension-related vasodilation and, as cirrhosis progresses, to decreased cardiac output and systemic inflammatory response.
      • Ginès P.
      • Solà E.
      • Angeli P.
      • Wong F.
      • Nadim M.K.
      • Kamath P.S.
      Hepatorenal syndrome.
      In the kidney, enhanced neurohormonal activity affects renal function, with sodium and solute-free water retention and, eventually, vasoconstriction, leading to ascites, oedema, and renal failure.
      • Schrier R.W.
      • Arroyo V.
      • Bernardi M.
      • Epstein M.
      • Henriksen J.H.
      • Rodés J.
      Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
      • Arroyo V.
      • Ginès P.
      • Gerbes A.L.
      • Dudley F.J.
      • Gentilini P.
      • Laffi G.
      • et al.
      Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.
      • Ginès P.
      • Schrier R.W.
      Renal failure in cirrhosis.
      In this context, the increased activity of the sympathetic nervous system has been associated with the progressive impairment of renal autoregulation. While in healthy individuals renal autoregulation maintains constant renal blood flow independently of fluctuations in systemic arterial pressure,
      • Carlström M.
      • Wilcox C.S.
      • Arendshorst W.J.
      Renal autoregulation in health and disease.
      patients with cirrhosis are characterised by a progressive shift downward and rightward on the renal autoregulation curve.
      • Stadlbauer V.
      • Stadlbauer V.P.
      • Wright G.A.K.
      • Banaji M.
      • Mukhopadhya A.
      • Mookerjee R.P.
      • et al.
      Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.
      As a consequence, they have fragile kidney function and are prone to developing kidney failure.
      • Mindikoglu A.L.
      • Dowling T.C.
      • Wong-You-Cheong J.J.
      • Christenson R.H.
      • Magder L.S.
      • Hutson W.R.
      • et al.
      A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.
      In fact, for the same value of renal perfusion pressure, the corresponding renal blood flow is progressively reduced from compensated to decompensated patients, being the lowest in patients with more severe liver disease and hepatorenal syndrome.
      • Ginès P.
      • Solà E.
      • Angeli P.
      • Wong F.
      • Nadim M.K.
      • Kamath P.S.
      Hepatorenal syndrome.
      ,
      • Stadlbauer V.
      • Stadlbauer V.P.
      • Wright G.A.K.
      • Banaji M.
      • Mukhopadhya A.
      • Mookerjee R.P.
      • et al.
      Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.
      The transition from compensated to decompensated cirrhosis represents a turning point in terms of quality of life, probability of hospitalisation, and mortality risk.

      Extrahepatic comorbidities

      Patients with a combination of compensated cirrhosis and type 2 diabetes (T2D) have an increased risk of episodes of decompensation.
      • Liu T.-L.
      • Trogdon J.
      • Weinberger M.
      • Fried B.
      • Barritt A.S.
      Diabetes is associated with clinical decompensation events in patients with cirrhosis.
      The mechanisms responsible for this susceptibility are currently incompletely understood. T2D is a well-known risk factor for bacterial infection and some studies have suggested that diabetes confers an additional risk of infection in patients with compensated cirrhosis.
      • Nahon P.
      • Lescat M.
      • Layese R.
      • Bourcier V.
      • Talmat N.
      • Allam S.
      • et al.
      Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort).
      In contrast, in decompensated cirrhosis, diabetes does not increase the risk of infection.
      • Bossen L.
      • Dam G.A.
      • Vilstrup H.
      • Watson H.
      • Jepsen P.
      Diabetes does not increase infection risk or mortality following an infection in patients with cirrhosis and ascites.
      Patients with decompensated cirrhosis are particularly vulnerable to developing sarcopenia due to impaired oral intake and increased gluconeogenesis from skeletal muscle protein. Frailty and sarcopenia are currently considered to be independent predictors of mortality in decompensated cirrhosis, but it remains unknown whether they are predisposing factors in the transition to decompensated cirrhosis.
      • Lai J.C.
      • Feng S.
      • Terrault N.A.
      • Lizaola B.
      • Hayssen H.
      • Covinsky K.
      Frailty predicts waitlist mortality in liver transplant candidates.

      Current directions for research on predisposing factors

      Gut dysbiosis

      As the anatomical and functional relationship between the intestine and the liver, the gut-liver axis has been proposed to play a major role in the development of complications of cirrhosis and is discussed in detail in another chapter of this supplement. Typically, in patients with cirrhosis, the microbiome can be characterised by decreased microbial diversity, a loss of beneficial commensals, and an increase in potential pathogens.
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      Cirrhosis affects both the number of different species (alpha diversity) and the composition of species (beta diversity). The results for alpha diversity are not consistent in the literature, a factor that may be explained by differences in analytical techniques.
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      • Bajaj J.S.
      • Idilman R.
      • Mabudian L.
      • Hood M.
      • Fagan A.
      • Turan D.
      • et al.
      Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort.
      • Horvath A.
      • Rainer F.
      • Bashir M.
      • Leber B.
      • Schmerboeck B.
      • Klymiuk I.
      • et al.
      Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis.
      The alteration in microbial diversity reduces the resilience of the microbiome, making it susceptible to perturbations. The dysbiotic microbiome can find a new steady state and the dysbiosis itself may promote disease progression.
      • Sommer F.
      • Moltzau Anderson J.
      • Bharti R.
      • Raes J.
      • Rosenstiel P.
      The resilience of the intestinal microbiota influences health and disease.
      This raises the question of whether changes in the composition of the microbiome are the cause or the consequence of the disease, and whether they are involved in the progression of compensated to decompensated cirrhosis. There is no clear-cut answer to this question. When trying to differentiate cause from consequence, factors that contribute to dysbiosis need to be studied. Medications, aetiology, disease severity, nutritional status, and inflammation impact on the composition of the gut microbiome in cirrhosis and seem to overlap, at least partially.
      • Stadlbauer V.
      • Komarova I.
      • Klymiuk I.
      • Durdevic M.
      • Reisinger A.
      • Blesl A.
      • et al.
      Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis.
      This transition is characterised by the occurrence of ascites, variceal bleeding and/or hepatic encephalopathy or organ failures (in the case of ACLF).
      Drug intake is another driver of dysbiosis in cirrhosis: proton pump inhibitor use has been associated with reduced colonization resistance in patients with cirrhosis and healthy volunteers.
      • Freedberg D.E.
      • Toussaint N.C.
      • Chen S.P.
      • Ratner A.J.
      • Whittier S.
      • Wang T.C.
      • et al.
      Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial.
      ,
      • Horvath A.
      • Rainer F.
      • Bashir M.
      • Leber B.
      • Schmerboeck B.
      • Klymiuk I.
      • et al.
      Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis.
      Also “oralization”, defined as the increased abundance of bacterial species that are typical inhabitants of the oral cavity is a common feature found in cirrhosis and also in non-cirrhotic individuals who take proton pump inhibitors.
      • Freedberg D.E.
      • Toussaint N.C.
      • Chen S.P.
      • Ratner A.J.
      • Whittier S.
      • Wang T.C.
      • et al.
      Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial.
      ,
      • Bajaj J.S.
      • Acharya C.
      • Fagan A.
      • White M.B.
      • Gavis E.
      • Heuman D.M.
      • et al.
      Proton pump inhibitor initiation and withdrawal affects gut microbiota and readmission risk in cirrhosis.
      • Imhann F.
      • Bonder M.J.
      • Vich Vila A.
      • Fu J.
      • Mujagic Z.
      • Vork L.
      • et al.
      Proton pump inhibitors affect the gut microbiome.
      • Wellhöner F.
      • Döscher N.
      • Tergast T.L.
      • Vital M.
      • Plumeier I.
      • Kahl S.
      • et al.
      The impact of proton pump inhibitors on the intestinal microbiota in chronic hepatitis C patients.
      • Yamamoto K.
      • Ishigami M.
      • Honda T.
      • Takeyama T.
      • Ito T.
      • Ishizu Y.
      • et al.
      Influence of proton pump inhibitors on microbiota in chronic liver disease patients.
      • O’Leary J.G.
      • Reddy K.R.
      • Wong F.
      • Kamath P.S.
      • Patton H.M.
      • Biggins S.W.
      • et al.
      Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis.
      The combination of gastric acid loss and alcohol aggravates dysbiosis and leads to additional liver damage.
      • Llorente C.
      • Jepsen P.
      • Inamine T.
      • Wang L.
      • Bluemel S.
      • Wang H.J.
      • et al.
      Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus.
      Increasing severity of liver disease is associated with oralization,
      • Qin N.
      • Yang F.
      • Li A.
      • Prifti E.
      • Chen Y.
      • Shao L.
      • et al.
      Alterations of the human gut microbiome in liver cirrhosis.
      ,
      • Stadlbauer V.
      • Komarova I.
      • Klymiuk I.
      • Durdevic M.
      • Reisinger A.
      • Blesl A.
      • et al.
      Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis.
      ,
      • Bajaj J.S.
      • Acharya C.
      • Fagan A.
      • White M.B.
      • Gavis E.
      • Heuman D.M.
      • et al.
      Proton pump inhibitor initiation and withdrawal affects gut microbiota and readmission risk in cirrhosis.
      ,
      • Bajaj J.S.
      • Heuman D.M.
      • Hylemon P.B.
      • Sanyal A.J.
      • White M.B.
      • Monteith P.
      • et al.
      Altered profile of human gut microbiome is associated with cirrhosis and its complications.
      and diet and nutritional status affect microbial composition in patients with cirrhosis.
      • Bajaj J.S.
      • Idilman R.
      • Mabudian L.
      • Hood M.
      • Fagan A.
      • Turan D.
      • et al.
      Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort.
      ,
      • Stadlbauer V.
      • Komarova I.
      • Klymiuk I.
      • Durdevic M.
      • Reisinger A.
      • Blesl A.
      • et al.
      Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis.
      Intestinal dysbiosis has been hypothesised to impair the intestinal barrier and cause bacterial translocation (or translocation of bacterial products, called pathogen-associated molecular patterns [PAMPs]) contributing to intestinal and systemic inflammation.
      • Schnabl B.
      • Brenner D.A.
      Interactions between the intestinal microbiome and liver diseases.
      Decompensated cirrhosis is also associated with altered expression of tight junction proteins in the duodenum.
      • Assimakopoulos S.F.
      • Tsamandas A.C.
      • Tsiaoussis G.I.
      • Karatza E.
      • Triantos C.
      • Vagianos C.E.
      • et al.
      Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.
      From a clinical point of view, this concept is supported by studies showing an association between dysbiosis, markers of intestinal permeability, inflammation, bacterial translocation, and complications of cirrhosis.
      • Horvath A.
      • Rainer F.
      • Bashir M.
      • Leber B.
      • Schmerboeck B.
      • Klymiuk I.
      • et al.
      Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis.
      ,
      • Agiasotelli D.
      • Alexopoulou A.
      • Vasilieva L.
      • Hadziyannis E.
      • Goukos D.
      • Daikos G.L.
      • et al.
      High serum lipopolysaccharide binding protein is associated with increased mortality in patients with decompensated cirrhosis.
      • Bajaj J.S.
      • Thacker L.R.
      • Fagan A.
      • White M.B.
      • Gavis E.A.
      • Hylemon P.B.
      • et al.
      Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis.
      • Campillo B.
      • Pernet P.
      • Bories P.N.
      • Richardet J.P.
      • Devanlay M.
      • Aussel C.
      Intestinal permeability in liver cirrhosis: relationship with severe septic complications.
      • Rainer F.
      • Horvath A.
      • Sandahl T.D.
      • Leber B.
      • Schmerboeck B.
      • Blesl A.
      • et al.
      Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation.
      In contrast to gastrointestinal bacteria, very little is known about the role of the gastrointestinal mycobiome and nothing is known about the virome. In the near future, we must explore the link between mycobiome and virome alterations and decompensation. The impact of these alterations on AD and ACLF is currently being explored in the Horizon 2020 project MICROB-PREDICT (https://microb-predict.eu/).

      Cirrhosis-associated immune dysfunction

      Cirrhosis is associated with a multifaceted state of immune dysfunction, cirrhosis-associated immune dysfunction (CAID), which involves both immunodeficiency and persistent proinflammatory immune cell activation. CAID affects the innate and the adaptive arms of the immune system as well as cellular and acellular mechanisms.
      • Liaskou E.
      • Hirschfield G.M.
      Cirrhosis-associated immune dysfunction: novel insights in impaired adaptive immunity.
      ,
      • Wilde B.
      • Katsounas A.
      Immune dysfunction and albumin-related immunity in liver cirrhosis.
      The causes of CAID are also multifactorial, with well described mechanisms including: increased translocation of bacterial products due to impaired intestinal permeability, leading to activation of pattern recognition receptors and inadequate immune activation; a dysfunctional local immune surveillance system in the liver and reduced synthesis of proteins in the liver (such as antimicrobial substances, pattern recognition receptors); and impaired albumin function.
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      Systemic inflammation is a consequence of this immune stimulation and contributes to haemodynamic disturbances and portal hypertension, accelerating the development of decompensation and organ failures. Indeed, several studies have corroborated a positive correlation between progressive CSPH, increasing (systemic) inflammation, and evolving decompensation culminating in ACLF.
      • Kumar A.
      • Das K.
      • Sharma P.
      • Mehta V.
      • Sharma B.C.
      • Sarin S.K.
      Hemodynamic studies in acute-on-chronic liver failure.
      • Praktiknjo M.
      • Monteiro S.
      • Grandt J.
      • Kimer N.
      • Madsen J.L.
      • Werge M.P.
      • et al.
      Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure.
      • Mookerjee R.P.
      • Sen S.
      • Davies N.A.
      • Hodges S.J.
      • Williams R.
      • Jalan R.
      Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.
      • Bellot P.
      • García-Pagán J.C.
      • Francés R.
      • Abraldes J.G.
      • Navasa M.
      • Pérez-Mateo M.
      • et al.
      Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis.
      • Juanola O.
      • Ferrusquía-Acosta J.
      • García-Villalba R.
      • Zapater P.
      • Magaz M.
      • Marín A.
      • et al.
      Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis.
      As such, CSPH, together with systemic inflammation, is considered fundamental in the progression to ACLF. Recently, this was further corroborated by the PREDICT study, which subdivided AD into 3 subtypes (stable or unstable decompensated cirrhosis and pre-ACLF) defined by the absence of hospital readmission, the presence of readmission, or development of ACLF, respectively, during a follow-up of 3 months.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      In this study, the main driver of ACLF development seemed to be a worsening of systemic inflammation, while the unstable course of patients with unstable decompensated cirrhosis without ACLF seemed to be driven by severe portal hypertension. The tight interaction of CSPH and inflammation has been suggested as a predisposing factor in ACLF development. First, portal hypertension-induced venous congestion and splanchnic neoangiogenesis induce microcirculatory dysfunction leading to increased intestinal permeability (and thus bacterial translocation).
      • Reiberger T.
      • Ferlitsch A.
      • Payer B.A.
      • Mandorfer M.
      • Heinisch B.B.
      • Hayden H.
      • et al.
      Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
      • Verbeke L.
      • Farre R.
      • Verbinnen B.
      • Covens K.
      • Vanuytsel T.
      • Verhaegen J.
      • et al.
      The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.
      • D’Amico M.
      • Mejías M.
      • García-Pras E.
      • Abraldes J.G.
      • García-Pagán J.C.
      • Fernández M.
      • et al.
      Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats.
      Secondly, inflammation self-perpetuates and further enhances the dynamic component of increased intrahepatic vascular resistance, triggering or further escalating extrahepatic organ failure and thus shaping the host response to injury.
      • Ruiz-del-Arbol L.
      • Urman J.
      • Fernández J.
      • González M.
      • Navasa M.
      • Monescillo A.
      • et al.
      Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
      Thirdly, as portal hypertension progresses, impaired cardiac function (so-called cirrhotic cardiomyopathy) and hyperdynamic or hypodynamic circulation increasingly take effect, which not only compromises basal effective circulating volume but also predisposes to an incompetent cardio-haemodynamic compensatory system in response to potential additional deleterious precipitants, expediting end-organ dysfunction.
      • Ruiz-del-Arbol L.
      • Monescillo A.
      • Arocena C.
      • Valer P.
      • Ginès P.
      • Moreira V.
      • et al.
      Circulatory function and hepatorenal syndrome in cirrhosis.
      ,
      • Kazory A.
      • Ronco C.
      Hepatorenal syndrome or hepatocardiorenal syndrome: revisiting basic concepts in view of emerging data.
      Fourthly, clinical manifestations of portal hypertension are aggravated by its progression and, therefore, impact on end-organ function (e.g. the brain in cases of hepatic encephalopathy, the kidney in cases of refractory ascites) or indirectly promote infectious complications (e.g. (aspiration) pneumonia, spontaneous bacterial peritonitis).
      • Cordoba J.
      • Ventura-Cots M.
      • Simón-Talero M.
      • Amorós À.
      • Pavesi M.
      • Vilstrup H.
      • et al.
      Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
      ,
      • Simón-Talero M.
      • Roccarina D.
      • Martínez J.
      • Lampichler K.
      • Baiges A.
      • Low G.
      • et al.
      Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis.
      In parallel to this systemic inflammation, cirrhosis is associated with several alterations in the innate and adaptive components of the immune system leading to immunodeficiency, reviewed in detail elsewhere.
      • Albillos A.
      • Lario M.
      • Álvarez-Mon M.
      Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
      This state is characterised by an impaired response to microbial challenge and vaccination, and an increased probability of bacterial translocation leading to a high risk of bacterial infection, a well-known precipitant of AD.
      • Aggeletopoulou I.
      • Davoulou P.
      • Konstantakis C.
      • Thomopoulos K.
      • Triantos C.
      Response to hepatitis B vaccination in patients with liver cirrhosis.
      The majority of these abnormalities are described in already decompensated cirrhosis and they worsen in parallel with the severity of liver failure.
      • Vergis N.
      • Khamri W.
      • Beale K.
      • Sadiq F.
      • Aletrari M.O.
      • Moore C.
      • et al.
      Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.
      ,
      • Bernsmeier C.
      • Pop O.T.
      • Singanayagam A.
      • Triantafyllou E.
      • Patel V.C.
      • Weston C.J.
      • et al.
      Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK.
      Some studies have suggested that some alterations, in particular for neutrophils, are already present in compensated cirrhosis.
      • Tritto G.
      • Bechlis Z.
      • Stadlbauer V.
      • Davies N.
      • Francés R.
      • Shah N.
      • et al.
      Evidence of neutrophil functional defect despite inflammation in stable cirrhosis.
      ,
      • Potts J.R.
      • Farahi N.
      • Heard S.
      • Chilvers E.R.
      • Verma S.
      • Peters A.M.
      Circulating granulocyte lifespan in compensated alcohol-related cirrhosis: a pilot study.
      Numerous factors that predispose patients to acute decompensation have been described and/or suspected (e.g. degree of liver architecture disturbances, portal hypertension, renal vasoconstriction, bacterial translocation, gut dysbiosis, genetic polymorphisms).

      Course of cirrhosis: decrease of tolerance to organ damage

      In contrast to what might be expected, the CANONIC study revealed that patients with previous AD developed a less severe form of ACLF, lower levels of inflammatory mediators, and lower rates of 30-day mortality than patients without previous AD.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      A potential explanation for this apparent discrepancy was attributed to a differential decrease in tolerance which reflects the intrinsic capacity of host organs to endure the effects of a deleterious inflammatory response. Previous episodes of AD might, therefore, prime and stretch the mechanisms of tolerance, giving patients an advantage compared to those with no history of decompensation who seem unprepared for the inflammatory tsunami that culminates in ACLF.
      Shi et al. confirmed this specific finding from CANONIC by documenting that previous decompensation had no impact on the immediate short-term mortality of patients with ACLF.
      • Shi Y.
      • Zheng M.-H.
      • Yang Y.
      • Wei W.
      • Yang Q.
      • Hu A.
      • et al.
      Increased delayed mortality in patients with acute-on-chronic liver failure who have prior decompensation.
      Additionally, they demonstrated that patients with ACLF and a previous AD were distinct from those without as they were older and had less hepatic injury but suffered relatively more non-hepatic precipitating insults and displayed increased delayed mortality.
      Recently, Trebicka et al. anatomised the role of previous AD by demonstrating that compensated and recompensated patients have different pathways of inflammasome activation and systemic inflammation.
      • Monteiro S.
      • Grandt J.
      • Uschner F.E.
      • Kimer N.
      • Madsen J.L.
      • Schierwagen R.
      • et al.
      Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
      As such, they highlight the fact that patients who primarily exhibit a high degree of immune incompetence and develop AD nonetheless might suffer an increased risk of ACLF development. This premise is supported by a higher rate of detectable interleukin-1β, indicative of exaggerated inflammation, among recompensated patients. Moreover, these findings were paralleled by animal studies where the increased intrahepatic Il1b gene expression signature pinpoints hepatic inflammation as the primary origin of this elevated inflammatory condition after recompensation. Therefore, previous AD can shape response patterns and impact outcomes in a given patient.

      Albumin alterations

      Altered albumin structure and function is well described in cirrhosis. Oxidation of albumin, especially irreversibly oxidised albumin, increases with disease progression in cirrhosis, is predictive for survival in cirrhosis, and may play a role in systemic inflammation.
      • Alcaraz-Quiles J.
      • Casulleras M.
      • Oettl K.
      • Titos E.
      • Flores-Costa R.
      • Duran-Güell M.
      • et al.
      Oxidized albumin triggers a cytokine storm in leukocytes through P38 mitogen-activated protein kinase: role in systemic inflammation in decompensated cirrhosis.
      ,
      • Oettl K.
      • Birner-Gruenberger R.
      • Spindelboeck W.
      • Stueger H.P.
      • Dorn L.
      • Stadlbauer V.
      • et al.
      Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.
      Higher levels of ischaemia-modified albumin are associated with bacterial infections and higher mortality.
      • Giannone F.A.
      • Domenicali M.
      • Baldassarre M.
      • Bartoletti M.
      • Naldi M.
      • Laggetta M.
      • et al.
      Ischaemia-modified albumin: a marker of bacterial infection in hospitalized patients with cirrhosis.
      ,
      • 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.
      Further detailed analysis has revealed that certain post-transcriptional structural changes of albumin are associated with clinical complications of cirrhosis.
      • Domenicali M.
      • Baldassarre M.
      • Giannone F.A.
      • Naldi M.
      • Mastroroberto M.
      • Biselli M.
      • et al.
      Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis.
      Structural changes of albumin impair its binding and transport function as well as its antioxidant function. Structurally altered albumin has also been hypothesised to induce the formation of anti-albumin antibodies because of the presence of neoepitopes, which may further aggravate immune dysfunction. However, the clinical relevance of this hypothesis is still unclear.
      • Wilde B.
      • Katsounas A.
      Immune dysfunction and albumin-related immunity in liver cirrhosis.
      These alterations could be a predisposing factor for AD, but prospective studies are needed to confirm this hypothesis.

      Genetic predisposition

      Potential predisposing genetic factors for decompensation of cirrhosis have been identified. Until now, genetic studies in cirrhosis have mainly been based on studying single or small groups of gene polymorphisms with a defined hypothesis. Genome wide association studies to assess the genetic predisposition to decompensation have not yet been reported. Polymorphisms of pattern recognition receptors, such as nucleotide-binding oligomerisation domain containing 2 (NOD2), Toll-like receptor (TLR) 2 and 4, or nuclear dot protein 52 kDa have been associated with an increased risk of bacterial infections in some studies, but this has not been confirmed by other studies.
      • Fan W.-C.
      • Liu C.-W.
      • Ou S.-M.
      • Huang C.-C.
      • Li T.-H.
      • Lee K.-C.
      • et al.
      TLR4/CD14 variants-related serologic and immunologic dys-regulations predict severe sepsis in febrile de-compensated cirrhotic patients.
      • Reichert M.C.
      • Ripoll C.
      • Casper M.
      • Greinert R.
      • Vandieken E.
      • Grünhage F.
      • et al.
      Common NOD2 risk variants as major susceptibility factors for bacterial infections in compensated cirrhosis.
      • Schaapman J.J.
      • Amoros À.
      • van der Reijden J.J.
      • Laleman W.
      • Zeuzem S.
      • Bañares R.
      • et al.
      Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection.
      • Bruns T.
      • Peter J.
      • Reuken P.A.
      • Grabe D.H.
      • Schuldes S.R.
      • Brenmoehl J.
      • et al.
      NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis.
      Sodium dismutase polymorphisms, another critical enzyme in immune defence and cell damage, were associated with decompensation and risk of bacterial infections.
      • Schwab S.
      • Lehmann J.
      • Lutz P.
      • Jansen C.
      • Appenrodt B.
      • Lammert F.
      • et al.
      Influence of genetic variations in the SOD1 gene on the development of ascites and spontaneous bacterial peritonitis in decompensated liver cirrhosis.
      In another study, the PNPLA3 G/G genotype was associated with a 2-fold increase in the risk of decompensation.
      • Mandorfer M.
      • Scheiner B.
      • Stättermayer A.F.
      • Schwabl P.
      • Paternostro R.
      • Bauer D.
      • et al.
      Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension.
      Although genetic predisposition may play a role in shaping an individual’s risk of decompensation, the clinical relevance, and the consequences regarding the need for genetic testing are not yet clear.

      Epigenetic predisposition

      The dynamic nature of chromatin structure and nuclear organisation regulates gene expression through epigenetic modifications: DNA methylation, histone modification, chromatin organisation and remodelling. These epigenetic mechanisms have been implicated in a wide variety of diseases and influence disease expression. One study has suggested that CD14+ monocytes observed in alcoholic hepatitis display altered transcriptional and epigenetic profiles characterised by downregulation of key innate immune and metabolic pathways alongside upregulation of important immunomodulatory factors responsible for immune exhaustion.
      • Weichselbaum L.
      • Azouz A.
      • Smolen K.K.
      • Das J.
      • Splittgerber M.
      • Lepida A.
      • et al.
      Epigenetic basis for monocyte dysfunction in patients with severe alcoholic hepatitis.
      Exploring the role of epigenetic alterations in the progression and decompensation of cirrhosis is a new area of research.
      Precipitating events for ACLF vary between Western countries (bacterial infection, alcohol intake) and Eastern countries (flare of HBV, superimposed HAV or HEV).

      Precipitating events

      Many precipitating factors have been described and can cause specific types of AD. Hypnotic drugs, constipation, dehydration, and dyselectrolytemia are recognised as precipitating factors of hepatic encephalopathy. Excessive dietary sodium intake, drug-induced renal sodium retention, portal vein thrombosis, invasion of the portal vein by hepatocellular carcinoma, and hypoalbuminemia can cause ascites. Jaundice is mainly precipitated by direct liver injury such as alcoholic hepatitis, drug-induced liver injury (DILI), autoimmune hepatitis flare or superimposed HAV or HEV. Recently, 2 large European prospective (CANONIC and PREDICT) studies characterised AD of cirrhosis and its associated factors (summarised in Table 2).
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      Bacterial infections and alcohol-related liver injury are the most frequent precipitating events in Europe.
      Table 2Precipitating events of AD and ACLF in Europe (adapted from
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      ).
      Precipitating eventsAD without ACLFACLF
      Bacterial infection22%-29%33%-50%
      Active alcoholism in the past 3 months (suspected alcoholic hepatitis)15%-26%24.5%-43.5%
      Gastrointestinal bleeding16%-17%13%-20%
      Neurotoxic drugs8%8%
      Paracentesis without albumin10%10%
      TIPS5%4%
      DILI1.5%2%
      Viral hepatitis or other viral infections1%1.5%
      Drug-induced kidney injury0.3%0.5%
      Surgery0.3%0%
      Decompensated cardiopulmonary disease0.4%1.5%
      Dehydration0.3%0.5%
      Large hematomas0.3%0%
      Acute pancreatitis0.1%0.5%
      Portomesenteric vein thrombosis0.2%0.5%
      Extrahepatic autoimmune disease0.2%0%
      Cerebrovascular accident0%0.5%
      Bowel occlusion0.1%0%
      Indeterminate precipitating event
      Indeterminate precipitating event denoted the absence of all previously described precipitating event.
      59%-62%29%-44%
      More than one precipitating event5%-6%13.5%-25%
      ACLF, acute-on-chronic liver failure; AD, acute decompensation; DILI, drug-induced liver injury; TIPS, transjugular intrahepatic portosystemic shunt.
      # Indeterminate precipitating event denoted the absence of all previously described precipitating event.

      Bacterial infections

      Bacterial infection is frequent and often severe in patients with cirrhosis and is a main driver of AD. Infection is present at admission or occurs during hospitalisation in 25% to 35% of patients with cirrhosis.
      • Jalan R.
      • Fernandez J.
      • Wiest R.
      • Schnabl B.
      • Moreau R.
      • Angeli P.
      • et al.
      Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.
      The susceptibility of patients with cirrhosis to bacterial infections is explained by several predisposing factors: bacterial translocation, dysbiosis, and CAID-related immunodeficiency, as previously described. Overall, bacterial infection is considered to be the most frequent precipitant of AD (causing 22% to 29% of cases of AD and 33%–50% of cases of ACLF), suggesting that infection is a trigger of severe forms of AD.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      The PREDICT study supports this hypothesis by demonstrating a close temporal relationship between the infectious episode and the occurrence of ACLF.
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      In another study including patients with severe alcoholic hepatitis, the occurrence of prior infection was the only independent variable predicting the onset of ACLF. In a large prospective study of 1,672 patients with compensated (Child-Pugh A) biopsy-proven HCV- or HBV-related cirrhosis without previous history of decompensation, the 5-year cumulative incidence of bacterial infections was 13% and these infections preceded and precipitated episodes of decompensation.
      • Nahon P.
      • Lescat M.
      • Layese R.
      • Bourcier V.
      • Talmat N.
      • Allam S.
      • et al.
      Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort).
      In this cohort of patients with compensated cirrhosis, the most frequent sites of infection were the urinary tract and lung followed by the abdomen and skin. Bacterial infection precipitates and/or aggravates AD by increasing the intensity of systemic inflammation and portal hypertension, potentially leading to organ dysfunction/failure and variceal haemorrhage.
      • Clària J.
      • Stauber R.E.
      • Coenraad M.J.
      • Moreau R.
      • Jalan R.
      • Pavesi M.
      • et al.
      Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
      ,
      • Steib C.J.
      • Schewe J.
      • Gerbes A.L.
      Infection as a trigger for portal hypertension.

      Active alcohol consumption

      Alcohol use disorders remain the most common cause of end-stage liver disease and liver-related mortality in Europe and North America. Alcohol causes cirrhosis after prolonged periods of excess consumption but, in addition, it causes an acute presentation characterised by jaundice and liver failure, frequently accompanied by features of decompensation, known as alcoholic hepatitis. The incidence of alcoholic hepatitis is increasing in Europe and North America, although precise estimates are rarely available due to diagnostic or coding inaccuracy.
      • Doshi S.D.
      • Stotts M.J.
      • Hubbard R.A.
      • Goldberg D.S.
      The changing burden of alcoholic hepatitis: rising incidence and associations with age, gender, race, and geography.
      ,
      • Sandahl T.D.
      • Jepsen P.
      • Thomsen K.L.
      • Vilstrup H.
      Incidence and mortality of alcoholic hepatitis in Denmark 1999-2008: a nationwide population based cohort study.
      Amongst patients with alcoholic hepatitis 80%–90% already have cirrhosis and all have advanced fibrosis. Nevertheless, it is clear that AD can also occur in patients with alcoholic hepatitis in the absence of advanced cirrhosis.
      • Spahr L.
      • Rubbia-Brandt L.
      • Genevay M.
      • Hadengue A.
      • Giostra E.
      Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis.
      ,
      • 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.
      Episodes of alcoholic hepatitis appear to occur in a context of more intense alcohol consumption.
      Evidence from animal models as well as human studies demonstrate that alcohol bingeing increases permeability of the gut epithelial barrier resulting in excess quantities of bacterial products reaching the portal circulation.
      • Sarin S.K.
      • Pande A.
      • Schnabl B.
      Microbiome as a therapeutic target in alcohol-related liver disease.
      Bacterial cell wall components and hypomethylated CpG DNA signal through TLRs in hepatic Kupffer cells and macrophages to induce inflammation.
      • Saha B.
      • Tornai D.
      • Kodys K.
      • Adejumo A.
      • Lowe P.
      • McClain C.
      • et al.
      Biomarkers of macrophage activation and immune danger signals predict clinical outcomes in alcoholic hepatitis.
      Around 25% of patients with alcoholic hepatitis have an infection at the time of presentation and, thus, more circulating bacterial products available to incite an inflammatory response. Inflammation within the hepatic sinusoids triggers activation of stellate cells which transform into myofibrotic cells. Myofibroblast activation exacerbates portal venous hypertension through deposition of collagen and contraction leading to increased sinusoidal resistance.
      ACLF is characterised by intense systemic inflammation leading to organ failures.
      Novel insight into the pathogenesis of alcoholic hepatitis was provided by Argemi’s study of epigenetics and gene expression in hepatocytes of patients with alcoholic hepatitis.
      • Argemi J.
      • Latasa M.U.
      • Atkinson S.R.
      • Blokhin I.O.
      • Massey V.
      • Gue J.P.
      • et al.
      Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.
      Epigenetic modification of the hepatocyte nuclear factor 4 alpha (HNF4A) locus in alcoholic hepatitis leads to expression of a foetal isoform of HNF4a (HNF4a-P2) in response to transforming growth factor-β, rather than the normal adult isoform (HNF4a-P1). The consequence of this switch is suppression of numerous hepatocyte functions, including bile salt transportation, albumin synthesis, gluconeogenesis, coagulation factor production, and cytochrome-P450 enzyme expression. These findings partially explain the substantial loss of liver function observed despite the adequate number of hepatocytes.

      Variceal haemorrhage

      Variceal haemorrhage is considered to be a precipitating factor of AD or ACLF in around 15% of cases.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      As discussed earlier, portal hypertension predisposes to ACLF directly through haemodynamic derangements exacerbated by escalating inflammation and indirectly through its complications. Paradoxically, variceal haemorrhage was not observed more frequently in patients with ACLF than in patients with AD.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      A likely explanation is the successful implementation of Baveno recommendations in daily clinical practice for primary and secondary prophylaxis of variceal haemorrhage.
      • de Franchis R.
      • VI Faculty Baveno
      Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
      • Hernández-Gea V.
      • Procopet B.
      • Giráldez Á.
      • Amitrano L.
      • Villanueva C.
      • Thabut D.
      • et al.
      Preemptive-TIPS improves outcome in high-risk variceal bleeding: an observational study.
      • García-Pagán J.C.
      • Caca K.
      • Bureau C.
      • Laleman W.
      • Appenrodt B.
      • Luca A.
      • et al.
      Early use of TIPS in patients with cirrhosis and variceal bleeding.
      Thus, optimised management, including both prevention and intervention, has improved outcomes for these patients and, therefore, reduced variceal bleeding’s contribution as a trigger of AD and/or ACLF development. Support for this premise is provided by the recent data from the International Variceal Bleeding Observational Study Group and Baveno Cooperation who, in a large multicentre international real-life study, identified ACLF at admission as an independent risk factor for rebleeding and mortality in patients with acute variceal haemorrhage.
      • Trebicka J.
      • Gu W.
      • Ibáñez-Samaniego L.
      • Hernández-Gea V.
      • Pitarch C.
      • Garcia E.
      • et al.
      Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.
      Moreover, preemptive transjugular intrahepatic portosystemic shunt (TIPS) was associated with improved survival in patients with ACLF and variceal bleeding, highlighting the fact that portal hypertension is indeed a pivotal and necessary predisposing factor in the pathophysiology of ACLF and that TIPS is not a frequent worsening or predisposing factor for ACLF.
      • Trebicka J.
      • Gu W.
      • Ibáñez-Samaniego L.
      • Hernández-Gea V.
      • Pitarch C.
      • Garcia E.
      • et al.
      Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.

      Drug-induced liver injury

      DILI can result from the administration of a variety of potentially hepatotoxic compounds, including prescription drugs, over-the-counter medications, and herbal and dietary supplements.
      European Association for the Study of the Liver
      Electronic address: [email protected], clinical practice guideline panel: chair:, panel members, EASL governing board representative: EASL clinical practice guidelines: drug-induced liver injury.
      Whether patients with pre-existing chronic liver diseases are at increased risk of DILI is still a matter of debate.
      • Teschke R.
      • Danan G.
      Drug-induced liver injury: is chronic liver disease a risk factor and a clinical issue?.
      However, frequent need for polypharmacy, drug-drug interactions, and potential impairment of drug metabolism are likely to increase the incidence of DILI in patients with cirrhosis. Furthermore, higher DILI-related mortality has been demonstrated in patients with pre-existing liver disease compared to those without (16% vs. 5.2%, respectively).
      • Chalasani N.
      • Bonkovsky H.L.
      • Fontana R.
      • Lee W.
      • Stolz A.
      • Talwalkar J.
      • et al.
      Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
      DILI can precipitate decompensation of a previously compensated cirrhosis, and ACLF can occur in the most severe cases as well, entailing a high mortality risk.
      European Association for the Study of the Liver
      Electronic address: [email protected], clinical practice guideline panel: chair:, panel members, EASL governing board representative: EASL clinical practice guidelines: drug-induced liver injury.
      ,
      • Hoofnagle J.H.
      Hepatic decompensation during direct-acting antiviral therapy of chronic hepatitis C.
      ,
      • Devarbhavi H.
      • Choudhury A.K.
      • Sharma M.K.
      • Maiwall R.
      • Al Mahtab M.
      • Rahman S.
      • et al.
      Drug-induced acute-on-chronic liver failure in asian patients.

      Flare of liver disease

      Autoimmune hepatitis (AIH) is an inflammatory process of the liver often characterised by a chronic, fluctuating, asymptomatic, although progressive, course. The clinical picture varies widely, from indolent disease with modest abnormalities of liver enzymes up to acute hepatic failure requiring urgent liver transplantation in patients without chronic histological alterations.
      • Mieli-Vergani G.
      • Vergani D.
      • Czaja A.J.
      • Manns M.P.
      • Krawitt E.L.
      • Vierling J.M.
      • et al.
      ,
      European Association for the Study of the Liver
      EASL clinical practice guidelines: autoimmune hepatitis.
      Cirrhosis is present in up to 40% of adults upon initial clinical presentation and AIH manifests as decompensated cirrhosis in 10% of patients, with a minority of these cases having features of ACLF.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: autoimmune hepatitis.
      • Ahn J.
      • Flamm S.L.
      • Anand L.
      • Choudhury A.
      • Bihari C.
      • Sharma B.C.
      • Kumar M.
      • Maiwall R.
      • et al.
      Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy.
      • Czaja A.J.
      • Davis G.L.
      • Ludwig J.
      • Baggenstoss A.H.
      • Taswell H.F.
      Autoimmune features as determinants of prognosis in steroid-treated chronic active hepatitis of uncertain etiology.
      • Feld J.J.
      • Dinh H.
      • Arenovich T.
      • Marcus V.A.
      • Wanless I.R.
      • Heathcote E.J.
      Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome.
      • Li Y.-N.
      • Ma H.
      • Zhou L.
      • Zhang J.
      • Guo L.-P.
      • Li S.-Q.
      • et al.
      Autoimmune hepatitis-related cirrhosis: clinical features and effectiveness of immunosuppressive treatment in Chinese patients.
      • Montano-Loza A.J.
      • Carpenter H.A.
      • Czaja A.J.
      Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease.
      • Roberts S.K.
      • Therneau T.M.
      • Czaja A.J.
      Prognosis of histological cirrhosis in type 1 autoimmune hepatitis.
      Acute flares of AIH occurring in patients with established liver damage can result in jaundice, complications of end-stage liver disease and, finally, liver failure. Therefore, early diagnosis and prompt initiation of adequate immunosuppressive therapy in patients with active disease are essential to avoid further disease progression and decompensation. Regression of fibrosis after successful treatment has been reported.
      European Association for the Study of the Liver
      EASL clinical practice guidelines: autoimmune hepatitis.
      ,
      • Feld J.J.
      • Dinh H.
      • Arenovich T.
      • Marcus V.A.
      • Wanless I.R.
      • Heathcote E.J.
      Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome.
      • Li Y.-N.
      • Ma H.
      • Zhou L.
      • Zhang J.
      • Guo L.-P.
      • Li S.-Q.
      • et al.
      Autoimmune hepatitis-related cirrhosis: clinical features and effectiveness of immunosuppressive treatment in Chinese patients.
      • Montano-Loza A.J.
      • Carpenter H.A.
      • Czaja A.J.
      Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease.
      However, immunosuppressive therapy may be contraindicated in patients with AIH and decompensated cirrhosis, as the risks of therapy may overcome those of the disease. In these patients, treatment should be carefully tailored to the individual patient’s characteristics.
      • Mieli-Vergani G.
      • Vergani D.
      • Czaja A.J.
      • Manns M.P.
      • Krawitt E.L.
      • Vierling J.M.
      • et al.
      ,
      European Association for the Study of the Liver
      EASL clinical practice guidelines: autoimmune hepatitis.
      In more than half of cases of acute decompensation and in almost half of cases of ACLF, the classical diagnostic work-up is not able to identify the precipitating event.
      Hepatitis B flares are a well-known factor for progression towards cirrhosis and repeated, severe flares can boost the transition to decompensation.
      • Chang M.-L.
      • Liaw Y.-F.
      Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management.
      In untreated (naïve) patients, HBV flares may occur either spontaneously or be favoured by immune restoration (e.g. start of active antiretroviral therapy in HIV-HBV coinfected patients or of anti-tuberculosis therapy) or they can be induced by immunosuppression, cancer chemotherapy or DAA therapy for HCV.
      • Chang M.-L.
      • Liaw Y.-F.
      Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management.
      ,
      European Association for the Study of the Liver
      Electronic address: [email protected], European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      Acute exacerbations of the disease can also occur in chronic hepatitis B patients during the course (emergence of drug resistance) or after discontinuation of nucleos(t)ide analogue therapy.
      • Chang M.-L.
      • Liaw Y.-F.
      Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management.
      HBV flares occurring in patients with cirrhosis entail a high risk (about 20%) of progression to decompensation, liver failure and even death, and always require immediate management with effective antiviral therapy.
      • Chang M.-L.
      • Liaw Y.-F.
      Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management.
      ,
      • Joo M.K.
      • Yeon J.E.
      • Kim J.H.
      • Jung Y.K.
      • Lee S.J.
      • Kim J.H.
      • et al.
      Chronic cirrhotic hepatitis B patients with a high incidence of hepatic decompensation after viral breakthrough with lamivudine-resistant mutants and during rescue treatment.
      Accordingly, current guidelines discourage discontinuation of antiviral treatment in patients with cirrhosis. When immunosuppression or chemotherapy are needed, screening for HBsAg, anti-HBs and anti-HBc status is mandatory and prophylactic or preemptive antiviral therapy should be started, according to the phase of HBV infection and the risk of HBV reactivation.
      European Association for the Study of the Liver
      Electronic address: [email protected], European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
      In Wilson’s disease the severity of hepatic involvement at diagnosis can vary widely, from asymptomatic biochemical abnormalities to chronic liver disease to, in about half of patients, established cirrhosis with or without overt decompensation.
      European Association for Study of Liver
      EASL clinical practice guidelines: Wilson’s disease.
      ,
      • Ferenci P.
      • Steindl-Munda P.
      • Vogel W.
      • Jessner W.
      • Gschwantler M.
      • Stauber R.
      • et al.
      Diagnostic value of quantitative hepatic copper determination in patients with Wilson’s Disease.
      Acute liver failure can also occur, either at first clinical presentation or during follow-up, particularly in case of non-adherence to chelation treatment, leading to a rapid and severe clinical deterioration, usually on the background of an already, often unknown, established cirrhosis.
      European Association for Study of Liver
      EASL clinical practice guidelines: Wilson’s disease.
      ,
      • Walshe J.M.
      • Dixon A.K.
      Dangers of non-compliance in Wilson’s disease.
      ,
      • Strand S.
      • Hofmann W.J.
      • Grambihler A.
      • Hug H.
      • Volkmann M.
      • Otto G.
      • et al.
      Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95 (APO-1/Fas) mediated apoptosis.
      Life-long treatment with copper chelating agents can achieve clinical and laboratory improvement, preventing further disease progression and decompensation.
      European Association for Study of Liver
      EASL clinical practice guidelines: Wilson’s disease.
      Therefore, transition to decompensation in Wilson’s disease can be the result of the natural progression of an unrecognised and/or untreated liver disease, and, in some cases, associated with ACLF. ACLF in Wilson’s disease is a life-threatening event, mainly affecting children or young adults and entailing extremely high mortality rates (70%–100%), with death often occurring in the first 2–4 weeks from presentation.
      • Devarbhavi H.
      • Reddy V.V.
      • Singh R.
      Wilson disease presenting with acute on chronic liver failure: a single-center experience of outcome and predictors of mortality in 68 patients.
      Therefore, urgent referral of these patients to a specialised intensive care unit and liver transplant centre is mandatory.
      European Association for Study of Liver
      EASL clinical practice guidelines: Wilson’s disease.
      ,
      European Association for the Study of the Liver
      Electronic address: [email protected], Clinical practice guidelines panel, Wendon, Panel members, Cordoba J, Dhawan A, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.

      Superimposed viral hepatitis

      Acute superinfection with hepatotropic viruses, such as hepatitis A and E, is well recognised as a precipitating event for decompensation of cirrhosis. Hepatitis A superinfection has been recognised for the past 25 years as a factor that aggravates the disease course,
      • Keeffe E.B.
      Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases?.
      leading to the recommendation by several guidelines to test and, in cases lacking serological evidence of previous infection, to vaccinate all patients with chronic liver diseases against hepatitis A. Hepatitis A testing is also advisable in patients with AD of cirrhosis who present with elevated transaminases and high bilirubin.
      • Reiss G.
      • Keeffe E.B.
      Review article: hepatitis vaccination in patients with chronic liver disease.
      Hepatitis E is especially relevant in highly endemic areas with a high prevalence of genotype 4, such as the Indian subcontinent, where HEV was reported to trigger decompensation in 8%–66% of patients in several cohort studies.
      • Imhann F.
      • Bonder M.J.
      • Vich Vila A.
      • Fu J.
      • Mujagic Z.
      • Vork L.
      • et al.
      Proton pump inhibitors affect the gut microbiome.
      In Europe and America, genotype 3 is responsible for autochthonous infections. Only limited data are available on the impact of hepatitis E on decompensation of cirrhosis in these areas,
      • Frias M.
      • López-López P.
      • Rivero A.
      • Rivero-Juarez A.
      Role of hepatitis E virus infection in acute-on-chronic liver failure.
      but hepatitis E testing in cases of decompensation seems to be advisable irrespective of travel history. A vaccine is not generally available and the safety and efficacy in cirrhosis needs to be explored.
      Other viral infections, such as cytomegalovirus or Epstein Barr virus infections, that may affect the liver, seem to be rare events but should also be considered when the initial search for precipitating events of decompensation in cirrhosis does not reveal a clear cause.
      • Rosi S.
      • Poretto V.
      • Cavallin M.
      • Angeli P.
      • Amodio P.
      • Sattin A.
      • et al.
      Hepatic decompensation in the absence of obvious precipitants: the potential role of cytomegalovirus infection/reactivation.
      ,
      • Koay L.-B.
      • Tsai S.-L.
      • Sun C.-S.
      • Wu K.-T.
      Chronic autoimmune hepatitis with Epstein-Barr virus superinfection: a case report and review of literature.
      SARS-CoV-2 infection, which can affect the liver by binding to angiotensin-converting enzyme 2 receptors, confers a high risk of AD, development of ACLF, and mortality in cirrhosis.
      • Ioannou G.N.
      • Liang P.S.
      • Locke E.
      • Green P.
      • Berry K.
      • O’Hare A.M.
      • et al.
      Cirrhosis and SARS-CoV-2 infection in US Veterans: risk of infection, hospitalization, ventilation and mortality.
      ,
      • Marjot T.
      • Moon A.M.
      • Cook J.A.
      • Abd-Elsalam S.
      • Aloman C.
      • Armstrong M.J.
      • et al.
      Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.

      Unknown factors

      No precipitating factor is identified in 60% of AD and 29%–44% of ACLF, depending on the study.
      • Moreau R.
      • Jalan R.
      • Gines P.
      • Pavesi M.
      • Angeli P.
      • Cordoba J.
      • et al.
      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      ,
      • Shi Y.
      • Yang Y.
      • Hu Y.
      • Wu W.
      • Yang Q.
      • Zheng M.
      • et al.
      Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
      ,
      • Trebicka J.
      • Fernandez J.
      • Papp M.
      • Caraceni P.
      • Laleman W.
      • Gambino C.
      • et al.
      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      Several explanations exist. First, there could be an undiagnosed precipitating event such as some specific bacterial infection, undeclared drug intake, or hidden alcohol intake. Sometimes the causal link between the precipitating factor and the decompensation episode is difficult to establish based on the interval between the 2 events, which can be extremely variable. That said, decompensation could also result from the progressive accumulation of predisposing factors (dysbiosis, translocation, inflammation, portal hypertension) leading to an acute destabilisation of the compensatory state of cirrhosis without an evident precipitating event.

      Conclusions

      The transition from compensated to decompensated cirrhosis is driven by a complex interplay between liver injuries, local inflammation, gut dysbiosis, increasing gut permeability, and subsequent bacterial translocation with progressive portal hypertension being a pivotal and essential axiom. Several events that precipitate decompensation have been described, but in almost half of the cases no factor is discovered. Further progression of this highly interacting chain of events forms the prelude to progressive systemic inflammation culminating in ACLF. The challenge of future investigations is to integrate multi-omic data into well-characterised prospective cohorts of patients to decipher the complex mechanisms underlying the transition from compensated to decompensated cirrhosis. This strategy is required to prevent decompensation and significantly improve the outcomes of patients with cirrhosis.

      Abbreviations

      ACLF, acute-on-chronic liver failure; AD, acute decompensation; CAID, cirrhosis-associated immune dysfunction; CSPH, clinically significant portal hypertension; DAA, direct-acting antiviral; DILI, drug-induced liver injury; HNF4A, hepatocyte nuclear factor 4 alpha; HVPG, hepatic venous pressure gradient; TIPS, Transjugular intrahepatic portosystemic shunt; TLR, Toll-like receptor.

      Financial support

      The authors received no financial support in relation to the production of the manuscript.

      Authors’ contributions

      All authors designed the manuscript. All authors wrote part of the manuscript. TG prepared the final version. All authors approved the final version of the manuscript to be published.

      Conflict of interest

      TG gives advice to Promethera Biosciences, Martin Pharmaceuticals, Goliver therapeutics, and Abbvie and has received grants from Gilead. VS has received speaker’s honoraria/travel expenses from Astellas, Institut Allergosan, Fresenius, MSD, Gilead and research support: Institut Allergosan, Fresenius, Winclove Probiotics. MT received a grant from Novartis. CA and WL have nothing to disclose.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Appendix A. Supplementary data

      The following is the supplementary data to this article:

      Transparency declaration

      This article is published as part of a supplement entitled New Concepts and Perspectives in Decompensated Cirrhosis. Publication of the supplement was supported financially by CSL Behring. The sponsor had no involvement in content development, the decision to submit the manuscript or in the acceptance of the manuscript for publication.

      References

        • Moreau R.
        • Jalan R.
        • Gines P.
        • Pavesi M.
        • Angeli P.
        • Cordoba J.
        • et al.
        Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
        Gastroenterology. 2013; 144 (1437.e1-9): 1426-1437https://doi.org/10.1053/j.gastro.2013.02.042
        • Shi Y.
        • Yang Y.
        • Hu Y.
        • Wu W.
        • Yang Q.
        • Zheng M.
        • et al.
        Acute-on-chronic liver failure precipitated by hepatic injury is distinct from that precipitated by extrahepatic insults.
        Hepatology. 2015; 62: 232-242https://doi.org/10.1002/hep.27795
        • Choudhury A.
        • Jindal A.
        • Maiwall R.
        • Sharma M.K.
        • Sharma B.C.
        • Pamecha V.
        • et al.
        Liver failure determines the outcome in patients of acute-on-chronic liver failure (ACLF): comparison of APASL ACLF research consortium (AARC) and CLIF-SOFA models.
        Hepatol Int. 2017; 11: 461-471https://doi.org/10.1007/s12072-017-9816-z
        • Trebicka J.
        • Fernandez J.
        • Papp M.
        • Caraceni P.
        • Laleman W.
        • Gambino C.
        • et al.
        The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
        J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.06.013
        • Labenz C.
        • Toenges G.
        • Schattenberg J.M.
        • Nagel M.
        • Huber Y.
        • JU Marquardt
        • et al.
        Health-related quality of life in patients with compensated and decompensated liver cirrhosis.
        Eur J Intern Med. 2019; 70: 54-59https://doi.org/10.1016/j.ejim.2019.09.004
        • Desai A.P.
        • Mohan P.
        • Nokes B.
        • Sheth D.
        • Knapp S.
        • Boustani M.
        • et al.
        Increasing economic burden in hospitalized patients with cirrhosis: analysis of a national database.
        Clin Transl Gastroenterol. 2019; 10e00062https://doi.org/10.14309/ctg.0000000000000062
        • Kim S.U.
        • Oh H.J.
        • Wanless I.R.
        • Lee S.
        • Han K.-H.
        • Park Y.N.
        The Laennec staging system for histological sub-classification of cirrhosis is useful for stratification of prognosis in patients with liver cirrhosis.
        J Hepatol. 2012; 57: 556-563https://doi.org/10.1016/j.jhep.2012.04.029
        • Hall A.
        • Germani G.
        • Isgrò G.
        • Burroughs A.K.
        • Dhillon A.P.
        Fibrosis distribution in explanted cirrhotic livers.
        Histopathology. 2012; 60: 270-277https://doi.org/10.1111/j.1365-2559.2011.04094.x
        • Sanyal A.J.
        • Banas C.
        • Sargeant C.
        • Luketic V.A.
        • Sterling R.K.
        • Stravitz R.T.
        • et al.
        Similarities and differences in outcomes of cirrhosis due to nonalcoholic steatohepatitis and hepatitis C.
        Hepatol Baltim Md. 2006; 43: 682-689https://doi.org/10.1002/hep.21103
        • Mendizabal M.
        • Piñero F.
        • Ridruejo E.
        • Herz Wolff F.
        • Anders M.
        • Reggiardo V.
        • et al.
        Disease progression in patients with hepatitis C virus infection treated with direct-acting antiviral agents.
        Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2020; https://doi.org/10.1016/j.cgh.2020.02.044
        • Lok A.S.F.
        • McMahon B.J.
        • Brown R.S.
        • Wong J.B.
        • Ahmed A.T.
        • Farah W.
        • et al.
        Antiviral therapy for chronic hepatitis B viral infection in adults: a systematic review and meta-analysis.
        Hepatol Baltim Md. 2016; 63: 284-306https://doi.org/10.1002/hep.28280
        • Rudic J.S.
        • Poropat G.
        • Krstic M.N.
        • Bjelakovic G.
        • Gluud C.
        Ursodeoxycholic acid for primary biliary cirrhosis.
        Cochrane Database Syst Rev. 2012; 12: CD000551https://doi.org/10.1002/14651858.CD000551.pub3
        • Rogal S.
        • Youk A.
        • Zhang H.
        • Gellad W.F.
        • Fine M.J.
        • Good C.B.
        • et al.
        Impact of alcohol use disorder treatment on clinical outcomes among patients with cirrhosis.
        Hepatol Baltim Md. 2020; 71: 2080-2092https://doi.org/10.1002/hep.31042
        • Ripoll C.
        • Groszmann R.
        • Garcia-Tsao G.
        • Grace N.
        • Burroughs A.
        • Planas R.
        • et al.
        Hepatic venous pressure gradient predicts clinical decompensation in patients with compensated cirrhosis.
        Gastroenterology. 2007; 133: 481-488https://doi.org/10.1053/j.gastro.2007.05.024
        • D’Amico G.
        • Garcia-Pagan J.C.
        • Luca A.
        • Bosch J.
        Hepatic vein pressure gradient reduction and prevention of variceal bleeding in cirrhosis: a systematic review.
        Gastroenterology. 2006; 131: 1611-1624https://doi.org/10.1053/j.gastro.2006.09.013
        • Villanueva C.
        • Albillos A.
        • Genescà J.
        • Garcia-Pagan J.C.
        • Calleja J.L.
        • Aracil C.
        • et al.
        β blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
        Lancet Lond Engl. 2019; 393: 1597-1608https://doi.org/10.1016/S0140-6736(18)31875-0
        • Bernardi M.
        • Trevisani F.
        • Santini C.
        • De Palma R.
        • Gasbarrini G.
        Aldosterone related blood volume expansion in cirrhosis before and during the early phase of ascites formation.
        Gut. 1983; 24: 761-766https://doi.org/10.1136/gut.24.8.761
        • Bolondi L.
        • Piscaglia F.
        • Gatta A.
        • Salerno F.
        • Bernardi M.
        • Ascione A.
        • et al.
        Effect of potassium canrenoate, an anti-aldosterone agent, on incidence of ascites and variceal progression in cirrhosis.
        Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2006; 4: 1395-1402https://doi.org/10.1016/j.cgh.2006.06.005
        • Bernardi M.
        • Li Bassi S.
        • Arienti V.
        • De Collibus C.
        • Scialpi C.
        • Boriani L.
        • et al.
        Systemic and regional hemodynamics in pre-ascitic cirrhosis: effects of posture.
        J Hepatol. 2003; 39: 502-508https://doi.org/10.1016/s0168-8278(03)00324-6
        • Ginès P.
        • Solà E.
        • Angeli P.
        • Wong F.
        • Nadim M.K.
        • Kamath P.S.
        Hepatorenal syndrome.
        Nat Rev Dis Primer. 2018; 4: 23https://doi.org/10.1038/s41572-018-0022-7
        • Schrier R.W.
        • Arroyo V.
        • Bernardi M.
        • Epstein M.
        • Henriksen J.H.
        • Rodés J.
        Peripheral arterial vasodilation hypothesis: a proposal for the initiation of renal sodium and water retention in cirrhosis.
        Hepatol Baltim Md. 1988; 8: 1151-1157https://doi.org/10.1002/hep.1840080532
        • Arroyo V.
        • Ginès P.
        • Gerbes A.L.
        • Dudley F.J.
        • Gentilini P.
        • Laffi G.
        • et al.
        Definition and diagnostic criteria of refractory ascites and hepatorenal syndrome in cirrhosis. International Ascites Club.
        Hepatol Baltim Md. 1996; 23: 164-176https://doi.org/10.1002/hep.510230122
        • Ginès P.
        • Schrier R.W.
        Renal failure in cirrhosis.
        N Engl J Med. 2009; 361: 1279-1290https://doi.org/10.1056/NEJMra0809139
        • Carlström M.
        • Wilcox C.S.
        • Arendshorst W.J.
        Renal autoregulation in health and disease.
        Physiol Rev. 2015; 95: 405-511https://doi.org/10.1152/physrev.00042.2012
        • Stadlbauer V.
        • Stadlbauer V.P.
        • Wright G.A.K.
        • Banaji M.
        • Mukhopadhya A.
        • Mookerjee R.P.
        • et al.
        Relationship between activation of the sympathetic nervous system and renal blood flow autoregulation in cirrhosis.
        Gastroenterology. 2008; 134: 111-119https://doi.org/10.1053/j.gastro.2007.10.055
        • Mindikoglu A.L.
        • Dowling T.C.
        • Wong-You-Cheong J.J.
        • Christenson R.H.
        • Magder L.S.
        • Hutson W.R.
        • et al.
        A pilot study to evaluate renal hemodynamics in cirrhosis by simultaneous glomerular filtration rate, renal plasma flow, renal resistive indices and biomarkers measurements.
        Am J Nephrol. 2014; 39: 543-552https://doi.org/10.1159/000363584
        • Liu T.-L.
        • Trogdon J.
        • Weinberger M.
        • Fried B.
        • Barritt A.S.
        Diabetes is associated with clinical decompensation events in patients with cirrhosis.
        Dig Dis Sci. 2016; 61: 3335-3345https://doi.org/10.1007/s10620-016-4261-8
        • Nahon P.
        • Lescat M.
        • Layese R.
        • Bourcier V.
        • Talmat N.
        • Allam S.
        • et al.
        Bacterial infection in compensated viral cirrhosis impairs 5-year survival (ANRS CO12 CirVir prospective cohort).
        Gut. 2015; https://doi.org/10.1136/gutjnl-2015-310275
        • Bossen L.
        • Dam G.A.
        • Vilstrup H.
        • Watson H.
        • Jepsen P.
        Diabetes does not increase infection risk or mortality following an infection in patients with cirrhosis and ascites.
        JHEP Rep Innov Hepatol. 2019; 1: 265-269https://doi.org/10.1016/j.jhepr.2019.07.008
        • Lai J.C.
        • Feng S.
        • Terrault N.A.
        • Lizaola B.
        • Hayssen H.
        • Covinsky K.
        Frailty predicts waitlist mortality in liver transplant candidates.
        Am J Transpl Off J Am Soc Transpl Am Soc Transpl Surg. 2014; 14: 1870-1879https://doi.org/10.1111/ajt.12762
        • Qin N.
        • Yang F.
        • Li A.
        • Prifti E.
        • Chen Y.
        • Shao L.
        • et al.
        Alterations of the human gut microbiome in liver cirrhosis.
        Nature. 2014; https://doi.org/10.1038/nature13568
        • Bajaj J.S.
        • Idilman R.
        • Mabudian L.
        • Hood M.
        • Fagan A.
        • Turan D.
        • et al.
        Diet affects gut microbiota and modulates hospitalization risk differentially in an international cirrhosis cohort.
        Hepatol Baltim Md. 2018; https://doi.org/10.1002/hep.29791
        • Horvath A.
        • Rainer F.
        • Bashir M.
        • Leber B.
        • Schmerboeck B.
        • Klymiuk I.
        • et al.
        Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis.
        Sci Rep. 2019; https://doi.org/10.1038/s41598-019-48352-5
        • Sommer F.
        • Moltzau Anderson J.
        • Bharti R.
        • Raes J.
        • Rosenstiel P.
        The resilience of the intestinal microbiota influences health and disease.
        Nat Rev Microbiol. 2017; https://doi.org/10.1038/nrmicro.2017.58
        • Stadlbauer V.
        • Komarova I.
        • Klymiuk I.
        • Durdevic M.
        • Reisinger A.
        • Blesl A.
        • et al.
        Disease severity and proton pump inhibitor use impact strongest on faecal microbiome composition in liver cirrhosis.
        Liver Int Off J Int Assoc Study Liver. 2020; https://doi.org/10.1111/liv.14382
        • Freedberg D.E.
        • Toussaint N.C.
        • Chen S.P.
        • Ratner A.J.
        • Whittier S.
        • Wang T.C.
        • et al.
        Proton pump inhibitors alter specific taxa in the human gastrointestinal microbiome: a crossover trial.
        Gastroenterology. 2015; 149 (e9): 883-885https://doi.org/10.1053/j.gastro.2015.06.043
        • Horvath A.
        • Rainer F.
        • Bashir M.
        • Leber B.
        • Schmerboeck B.
        • Klymiuk I.
        • et al.
        Biomarkers for oralization during long-term proton pump inhibitor therapy predict survival in cirrhosis.
        Sci Rep. 2019; 9: 12000https://doi.org/10.1038/s41598-019-48352-5
        • Bajaj J.S.
        • Acharya C.
        • Fagan A.
        • White M.B.
        • Gavis E.
        • Heuman D.M.
        • et al.
        Proton pump inhibitor initiation and withdrawal affects gut microbiota and readmission risk in cirrhosis.
        Am J Gastroenterol. 2018; 113: 1177-1186https://doi.org/10.1038/s41395-018-0085-9
        • Imhann F.
        • Bonder M.J.
        • Vich Vila A.
        • Fu J.
        • Mujagic Z.
        • Vork L.
        • et al.
        Proton pump inhibitors affect the gut microbiome.
        Gut. 2016; 65: 740-748https://doi.org/10.1136/gutjnl-2015-310376
        • Wellhöner F.
        • Döscher N.
        • Tergast T.L.
        • Vital M.
        • Plumeier I.
        • Kahl S.
        • et al.
        The impact of proton pump inhibitors on the intestinal microbiota in chronic hepatitis C patients.
        Scand J Gastroenterol. 2019; 54: 1033-1041https://doi.org/10.1080/00365521.2019.1647280
        • Yamamoto K.
        • Ishigami M.
        • Honda T.
        • Takeyama T.
        • Ito T.
        • Ishizu Y.
        • et al.
        Influence of proton pump inhibitors on microbiota in chronic liver disease patients.
        Hepatol Int. 2019; 13: 234-244https://doi.org/10.1007/s12072-019-09932-9
        • O’Leary J.G.
        • Reddy K.R.
        • Wong F.
        • Kamath P.S.
        • Patton H.M.
        • Biggins S.W.
        • et al.
        Long-term use of antibiotics and proton pump inhibitors predict development of infections in patients with cirrhosis.
        Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2015; 13 (e1-2): 753-759https://doi.org/10.1016/j.cgh.2014.07.060
        • Llorente C.
        • Jepsen P.
        • Inamine T.
        • Wang L.
        • Bluemel S.
        • Wang H.J.
        • et al.
        Gastric acid suppression promotes alcoholic liver disease by inducing overgrowth of intestinal Enterococcus.
        Nat Commun. 2017; 8: 837https://doi.org/10.1038/s41467-017-00796-x
        • Bajaj J.S.
        • Heuman D.M.
        • Hylemon P.B.
        • Sanyal A.J.
        • White M.B.
        • Monteith P.
        • et al.
        Altered profile of human gut microbiome is associated with cirrhosis and its complications.
        J Hepatol. 2014; 60: 940-947https://doi.org/10.1016/j.jhep.2013.12.019
        • Schnabl B.
        • Brenner D.A.
        Interactions between the intestinal microbiome and liver diseases.
        Gastroenterology. 2014; 146: 1513-1524https://doi.org/10.1053/j.gastro.2014.01.020
        • Assimakopoulos S.F.
        • Tsamandas A.C.
        • Tsiaoussis G.I.
        • Karatza E.
        • Triantos C.
        • Vagianos C.E.
        • et al.
        Altered intestinal tight junctions’ expression in patients with liver cirrhosis: a pathogenetic mechanism of intestinal hyperpermeability.
        Eur J Clin Invest. 2012; 42: 439-446https://doi.org/10.1111/j.1365-2362.2011.02609.x
        • Agiasotelli D.
        • Alexopoulou A.
        • Vasilieva L.
        • Hadziyannis E.
        • Goukos D.
        • Daikos G.L.
        • et al.
        High serum lipopolysaccharide binding protein is associated with increased mortality in patients with decompensated cirrhosis.
        Liver Int Off J Int Assoc Study Liver. 2017; 37: 576-582https://doi.org/10.1111/liv.13264
        • Bajaj J.S.
        • Thacker L.R.
        • Fagan A.
        • White M.B.
        • Gavis E.A.
        • Hylemon P.B.
        • et al.
        Gut microbial RNA and DNA analysis predicts hospitalizations in cirrhosis.
        JCI Insight. 2018; 3https://doi.org/10.1172/jci.insight.98019
        • Campillo B.
        • Pernet P.
        • Bories P.N.
        • Richardet J.P.
        • Devanlay M.
        • Aussel C.
        Intestinal permeability in liver cirrhosis: relationship with severe septic complications.
        Eur J Gastroenterol Hepatol. 1999; 11: 755-759https://doi.org/10.1097/00042737-199907000-00013
        • Rainer F.
        • Horvath A.
        • Sandahl T.D.
        • Leber B.
        • Schmerboeck B.
        • Blesl A.
        • et al.
        Soluble CD163 and soluble mannose receptor predict survival and decompensation in patients with liver cirrhosis, and correlate with gut permeability and bacterial translocation.
        Aliment Pharmacol Ther. 2018; 47: 657-664https://doi.org/10.1111/apt.14474
        • Liaskou E.
        • Hirschfield G.M.
        Cirrhosis-associated immune dysfunction: novel insights in impaired adaptive immunity.
        EBioMedicine. 2019; 50: 3-4https://doi.org/10.1016/j.ebiom.2019.10.056
        • Wilde B.
        • Katsounas A.
        Immune dysfunction and albumin-related immunity in liver cirrhosis.
        Mediators Inflamm. 2019; 2019: 7537649https://doi.org/10.1155/2019/7537649
        • Albillos A.
        • Lario M.
        • Álvarez-Mon M.
        Cirrhosis-associated immune dysfunction: distinctive features and clinical relevance.
        J Hepatol. 2014; 61: 1385-1396https://doi.org/10.1016/j.jhep.2014.08.010
        • Kumar A.
        • Das K.
        • Sharma P.
        • Mehta V.
        • Sharma B.C.
        • Sarin S.K.
        Hemodynamic studies in acute-on-chronic liver failure.
        Dig Dis Sci. 2009; 54: 869-878https://doi.org/10.1007/s10620-008-0421-9
        • Praktiknjo M.
        • Monteiro S.
        • Grandt J.
        • Kimer N.
        • Madsen J.L.
        • Werge M.P.
        • et al.
        Cardiodynamic state is associated with systemic inflammation and fatal acute-on-chronic liver failure.
        Liver Int Off J Int Assoc Study Liver. 2020; 40: 1457-1466https://doi.org/10.1111/liv.14433
        • Mookerjee R.P.
        • Sen S.
        • Davies N.A.
        • Hodges S.J.
        • Williams R.
        • Jalan R.
        Tumour necrosis factor alpha is an important mediator of portal and systemic haemodynamic derangements in alcoholic hepatitis.
        Gut. 2003; 52: 1182-1187
        • Bellot P.
        • García-Pagán J.C.
        • Francés R.
        • Abraldes J.G.
        • Navasa M.
        • Pérez-Mateo M.
        • et al.
        Bacterial DNA translocation is associated with systemic circulatory abnormalities and intrahepatic endothelial dysfunction in patients with cirrhosis.
        Hepatol Baltim Md. 2010; 52: 2044-2052https://doi.org/10.1002/hep.23918
        • Juanola O.
        • Ferrusquía-Acosta J.
        • García-Villalba R.
        • Zapater P.
        • Magaz M.
        • Marín A.
        • et al.
        Circulating levels of butyrate are inversely related to portal hypertension, endotoxemia, and systemic inflammation in patients with cirrhosis.
        FASEB J Off Publ Fed Am Soc Exp Biol. 2019; 33: 11595-11605https://doi.org/10.1096/fj.201901327R
        • Reiberger T.
        • Ferlitsch A.
        • Payer B.A.
        • Mandorfer M.
        • Heinisch B.B.
        • Hayden H.
        • et al.
        Non-selective betablocker therapy decreases intestinal permeability and serum levels of LBP and IL-6 in patients with cirrhosis.
        J Hepatol. 2013; 58: 911-921https://doi.org/10.1016/j.jhep.2012.12.011
        • Verbeke L.
        • Farre R.
        • Verbinnen B.
        • Covens K.
        • Vanuytsel T.
        • Verhaegen J.
        • et al.
        The FXR agonist obeticholic acid prevents gut barrier dysfunction and bacterial translocation in cholestatic rats.
        Am J Pathol. 2015; 185: 409-419https://doi.org/10.1016/j.ajpath.2014.10.009
        • D’Amico M.
        • Mejías M.
        • García-Pras E.
        • Abraldes J.G.
        • García-Pagán J.C.
        • Fernández M.
        • et al.
        Effects of the combined administration of propranolol plus sorafenib on portal hypertension in cirrhotic rats.
        Am J Physiol Gastrointest Liver Physiol. 2012; 302: G1191-G1198https://doi.org/10.1152/ajpgi.00252.2011
        • Ruiz-del-Arbol L.
        • Urman J.
        • Fernández J.
        • González M.
        • Navasa M.
        • Monescillo A.
        • et al.
        Systemic, renal, and hepatic hemodynamic derangement in cirrhotic patients with spontaneous bacterial peritonitis.
        Hepatol Baltim Md. 2003; 38: 1210-1218https://doi.org/10.1053/jhep.2003.50447
        • Ruiz-del-Arbol L.
        • Monescillo A.
        • Arocena C.
        • Valer P.
        • Ginès P.
        • Moreira V.
        • et al.
        Circulatory function and hepatorenal syndrome in cirrhosis.
        Hepatol Baltim Md. 2005; 42: 439-447https://doi.org/10.1002/hep.20766
        • Kazory A.
        • Ronco C.
        Hepatorenal syndrome or hepatocardiorenal syndrome: revisiting basic concepts in view of emerging data.
        Cardiorenal Med. 2019; 9: 1-7https://doi.org/10.1159/000492791
        • Cordoba J.
        • Ventura-Cots M.
        • Simón-Talero M.
        • Amorós À.
        • Pavesi M.
        • Vilstrup H.
        • et al.
        Characteristics, risk factors, and mortality of cirrhotic patients hospitalized for hepatic encephalopathy with and without acute-on-chronic liver failure (ACLF).
        J Hepatol. 2014; 60: 275-281https://doi.org/10.1016/j.jhep.2013.10.004
        • Simón-Talero M.
        • Roccarina D.
        • Martínez J.
        • Lampichler K.
        • Baiges A.
        • Low G.
        • et al.
        Association between portosystemic shunts and increased complications and mortality in patients with cirrhosis.
        Gastroenterology. 2018; 154 (e4): 1694-1705https://doi.org/10.1053/j.gastro.2018.01.028
        • Aggeletopoulou I.
        • Davoulou P.
        • Konstantakis C.
        • Thomopoulos K.
        • Triantos C.
        Response to hepatitis B vaccination in patients with liver cirrhosis.
        Rev Med Virol. 2017; 27https://doi.org/10.1002/rmv.1942
        • Vergis N.
        • Khamri W.
        • Beale K.
        • Sadiq F.
        • Aletrari M.O.
        • Moore C.
        • et al.
        Defective monocyte oxidative burst predicts infection in alcoholic hepatitis and is associated with reduced expression of NADPH oxidase.
        Gut. 2016; https://doi.org/10.1136/gutjnl-2015-310378
        • Bernsmeier C.
        • Pop O.T.
        • Singanayagam A.
        • Triantafyllou E.
        • Patel V.C.
        • Weston C.J.
        • et al.
        Patients with acute-on-chronic liver failure have increased numbers of regulatory immune cells expressing the receptor tyrosine kinase MERTK.
        Gastroenterology. 2015; 148 (e14): 603-615https://doi.org/10.1053/j.gastro.2014.11.045
        • Tritto G.
        • Bechlis Z.
        • Stadlbauer V.
        • Davies N.
        • Francés R.
        • Shah N.
        • et al.
        Evidence of neutrophil functional defect despite inflammation in stable cirrhosis.
        J Hepatol. 2011; 55: 574-581https://doi.org/10.1016/j.jhep.2010.11.034
        • Potts J.R.
        • Farahi N.
        • Heard S.
        • Chilvers E.R.
        • Verma S.
        • Peters A.M.
        Circulating granulocyte lifespan in compensated alcohol-related cirrhosis: a pilot study.
        Physiol Rep. 2016; 4https://doi.org/10.14814/phy2.12836
        • Shi Y.
        • Zheng M.-H.
        • Yang Y.
        • Wei W.
        • Yang Q.
        • Hu A.
        • et al.
        Increased delayed mortality in patients with acute-on-chronic liver failure who have prior decompensation.
        J Gastroenterol Hepatol. 2015; 30: 712-718https://doi.org/10.1111/jgh.12787
        • Monteiro S.
        • Grandt J.
        • Uschner F.E.
        • Kimer N.
        • Madsen J.L.
        • Schierwagen R.
        • et al.
        Differential inflammasome activation predisposes to acute-on-chronic liver failure in human and experimental cirrhosis with and without previous decompensation.
        Gut. 2020; https://doi.org/10.1136/gutjnl-2019-320170
        • Alcaraz-Quiles J.
        • Casulleras M.
        • Oettl K.
        • Titos E.
        • Flores-Costa R.
        • Duran-Güell M.
        • et al.
        Oxidized albumin triggers a cytokine storm in leukocytes through P38 mitogen-activated protein kinase: role in systemic inflammation in decompensated cirrhosis.
        Hepatol Baltim Md. 2018; 68: 1937-1952https://doi.org/10.1002/hep.30135
        • Oettl K.
        • Birner-Gruenberger R.
        • Spindelboeck W.
        • Stueger H.P.
        • Dorn L.
        • Stadlbauer V.
        • et al.
        Oxidative albumin damage in chronic liver failure: relation to albumin binding capacity, liver dysfunction and survival.
        J Hepatol. 2013; 59: 978-983https://doi.org/10.1016/j.jhep.2013.06.013
        • Giannone F.A.
        • Domenicali M.
        • Baldassarre M.
        • Bartoletti M.
        • Naldi M.
        • Laggetta M.
        • et al.
        Ischaemia-modified albumin: a marker of bacterial infection in hospitalized patients with cirrhosis.
        Liver Int Off J Int Assoc Study Liver. 2015; 35: 2425-2432https://doi.org/10.1111/liv.12860
        • 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.
        Hepatol Baltim Md. 2009; 50: 555-564https://doi.org/10.1002/hep.22913
        • Domenicali M.
        • Baldassarre M.
        • Giannone F.A.
        • Naldi M.
        • Mastroroberto M.
        • Biselli M.
        • et al.
        Posttranscriptional changes of serum albumin: clinical and prognostic significance in hospitalized patients with cirrhosis.
        Hepatol Baltim Md. 2014; 60: 1851-1860https://doi.org/10.1002/hep.27322
        • Fan W.-C.
        • Liu C.-W.
        • Ou S.-M.
        • Huang C.-C.
        • Li T.-H.
        • Lee K.-C.
        • et al.
        TLR4/CD14 variants-related serologic and immunologic dys-regulations predict severe sepsis in febrile de-compensated cirrhotic patients.
        PLoS One. 2016; 11e0166458https://doi.org/10.1371/journal.pone.0166458
        • Reichert M.C.
        • Ripoll C.
        • Casper M.
        • Greinert R.
        • Vandieken E.
        • Grünhage F.
        • et al.
        Common NOD2 risk variants as major susceptibility factors for bacterial infections in compensated cirrhosis.
        Clin Transl Gastroenterol. 2019; 10e00002https://doi.org/10.14309/ctg.0000000000000002
        • Schaapman J.J.
        • Amoros À.
        • van der Reijden J.J.
        • Laleman W.
        • Zeuzem S.
        • Bañares R.
        • et al.
        Genetic variants of innate immunity receptors are associated with mortality in cirrhotic patients with bacterial infection.
        Liver Int Off J Int Assoc Study Liver. 2020; 40: 646-653https://doi.org/10.1111/liv.14392
        • Bruns T.
        • Peter J.
        • Reuken P.A.
        • Grabe D.H.
        • Schuldes S.R.
        • Brenmoehl J.
        • et al.
        NOD2 gene variants are a risk factor for culture-positive spontaneous bacterial peritonitis and monomicrobial bacterascites in cirrhosis.
        Liver Int Off J Int Assoc Study Liver. 2012; 32: 223-230https://doi.org/10.1111/j.1478-3231.2011.02561.x
        • Schwab S.
        • Lehmann J.
        • Lutz P.
        • Jansen C.
        • Appenrodt B.
        • Lammert F.
        • et al.
        Influence of genetic variations in the SOD1 gene on the development of ascites and spontaneous bacterial peritonitis in decompensated liver cirrhosis.
        Eur J Gastroenterol Hepatol. 2017; 29: 800-804https://doi.org/10.1097/MEG.0000000000000878
        • Mandorfer M.
        • Scheiner B.
        • Stättermayer A.F.
        • Schwabl P.
        • Paternostro R.
        • Bauer D.
        • et al.
        Impact of patatin-like phospholipase domain containing 3 rs738409 G/G genotype on hepatic decompensation and mortality in patients with portal hypertension.
        Aliment Pharmacol Ther. 2018; 48: 451-459https://doi.org/10.1111/apt.14856
        • Weichselbaum L.
        • Azouz A.
        • Smolen K.K.
        • Das J.
        • Splittgerber M.
        • Lepida A.
        • et al.
        Epigenetic basis for monocyte dysfunction in patients with severe alcoholic hepatitis.
        J Hepatol. 2020; 73: 303-314https://doi.org/10.1016/j.jhep.2020.02.017
        • Trebicka J.
        • Fernandez J.
        • Papp M.
        • Caraceni P.
        • Laleman W.
        • Gambino C.
        • et al.
        PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
        J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.11.019
        • Jalan R.
        • Fernandez J.
        • Wiest R.
        • Schnabl B.
        • Moreau R.
        • Angeli P.
        • et al.
        Bacterial infections in cirrhosis: a position statement based on the EASL Special Conference 2013.
        J Hepatol. 2014; 60: 1310-1324https://doi.org/10.1016/j.jhep.2014.01.024
        • Clària J.
        • Stauber R.E.
        • Coenraad M.J.
        • Moreau R.
        • Jalan R.
        • Pavesi M.
        • et al.
        Systemic inflammation in decompensated cirrhosis: characterization and role in acute-on-chronic liver failure.
        Hepatology. 2016; 64: 1249-1264https://doi.org/10.1002/hep.28740
        • Steib C.J.
        • Schewe J.
        • Gerbes A.L.
        Infection as a trigger for portal hypertension.
        Dig Dis Basel Switz. 2015; 33: 570-576https://doi.org/10.1159/000375352
        • Doshi S.D.
        • Stotts M.J.
        • Hubbard R.A.
        • Goldberg D.S.
        The changing burden of alcoholic hepatitis: rising incidence and associations with age, gender, race, and geography.
        Dig Dis Sci. 2020; https://doi.org/10.1007/s10620-020-06346-8
        • Sandahl T.D.
        • Jepsen P.
        • Thomsen K.L.
        • Vilstrup H.
        Incidence and mortality of alcoholic hepatitis in Denmark 1999-2008: a nationwide population based cohort study.
        J Hepatol. 2011; 54: 760-764https://doi.org/10.1016/j.jhep.2010.07.016
        • Spahr L.
        • Rubbia-Brandt L.
        • Genevay M.
        • Hadengue A.
        • Giostra E.
        Early liver biopsy, intraparenchymal cholestasis, and prognosis in patients with alcoholic steatohepatitis.
        BMC Gastroenterol. 2011; 11: 115https://doi.org/10.1186/1471-230X-11-115
        • 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.
        J Hepatol. 2011; 55: 1103-1111https://doi.org/10.1016/j.jhep.2011.02.021
        • Sarin S.K.
        • Pande A.
        • Schnabl B.
        Microbiome as a therapeutic target in alcohol-related liver disease.
        J Hepatol. 2019; 70: 260-272https://doi.org/10.1016/j.jhep.2018.10.019
        • Saha B.
        • Tornai D.
        • Kodys K.
        • Adejumo A.
        • Lowe P.
        • McClain C.
        • et al.
        Biomarkers of macrophage activation and immune danger signals predict clinical outcomes in alcoholic hepatitis.
        Hepatol Baltim Md. 2019; 70: 1134-1149https://doi.org/10.1002/hep.30617
        • Argemi J.
        • Latasa M.U.
        • Atkinson S.R.
        • Blokhin I.O.
        • Massey V.
        • Gue J.P.
        • et al.
        Defective HNF4alpha-dependent gene expression as a driver of hepatocellular failure in alcoholic hepatitis.
        Nat Commun. 2019; 10: 3126https://doi.org/10.1038/s41467-019-11004-3
        • de Franchis R.
        • VI Faculty Baveno
        Expanding consensus in portal hypertension: report of the Baveno VI Consensus Workshop: stratifying risk and individualizing care for portal hypertension.
        J Hepatol. 2015; 63: 743-752https://doi.org/10.1016/j.jhep.2015.05.022
        • Hernández-Gea V.
        • Procopet B.
        • Giráldez Á.
        • Amitrano L.
        • Villanueva C.
        • Thabut D.
        • et al.
        Preemptive-TIPS improves outcome in high-risk variceal bleeding: an observational study.
        Hepatol Baltim Md. 2019; 69: 282-293https://doi.org/10.1002/hep.30182
        • García-Pagán J.C.
        • Caca K.
        • Bureau C.
        • Laleman W.
        • Appenrodt B.
        • Luca A.
        • et al.
        Early use of TIPS in patients with cirrhosis and variceal bleeding.
        N Engl J Med. 2010; 362: 2370-2379https://doi.org/10.1056/NEJMoa0910102
        • Trebicka J.
        • Gu W.
        • Ibáñez-Samaniego L.
        • Hernández-Gea V.
        • Pitarch C.
        • Garcia E.
        • et al.
        Rebleeding and mortality risk are increased by ACLF but reduced by pre-emptive TIPS.
        J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.04.024
        • European Association for the Study of the Liver
        Electronic address: [email protected], clinical practice guideline panel: chair:, panel members, EASL governing board representative: EASL clinical practice guidelines: drug-induced liver injury.
        J Hepatol. 2019; 70: 1222-1261https://doi.org/10.1016/j.jhep.2019.02.014
        • Teschke R.
        • Danan G.
        Drug-induced liver injury: is chronic liver disease a risk factor and a clinical issue?.
        Expert Opin Drug Metab Toxicol. 2017; 13: 425-438https://doi.org/10.1080/17425255.2017.1252749
        • Chalasani N.
        • Bonkovsky H.L.
        • Fontana R.
        • Lee W.
        • Stolz A.
        • Talwalkar J.
        • et al.
        Features and outcomes of 899 patients with drug-induced liver injury: the DILIN prospective study.
        Gastroenterology. 2015; 148 (e7): 1340-1352https://doi.org/10.1053/j.gastro.2015.03.006
        • Hoofnagle J.H.
        Hepatic decompensation during direct-acting antiviral therapy of chronic hepatitis C.
        J Hepatol. 2016; 64: 763-765https://doi.org/10.1016/j.jhep.2016.01.007
        • Devarbhavi H.
        • Choudhury A.K.
        • Sharma M.K.
        • Maiwall R.
        • Al Mahtab M.
        • Rahman S.
        • et al.
        Drug-induced acute-on-chronic liver failure in asian patients.
        Am J Gastroenterol. 2019; 114: 929-937https://doi.org/10.14309/ajg.0000000000000201
        • Mieli-Vergani G.
        • Vergani D.
        • Czaja A.J.
        • Manns M.P.
        • Krawitt E.L.
        • Vierling J.M.
        • et al.
        Autoimmune Hepatitis Nat Rev Dis Primer. 2018; 4: 18017https://doi.org/10.1038/nrdp.2018.17
        • European Association for the Study of the Liver
        EASL clinical practice guidelines: autoimmune hepatitis.
        J Hepatol. 2015; 63: 971-1004https://doi.org/10.1016/j.jhep.2015.06.030
        • Ahn J.
        • Flamm S.L.
        Autoimmune Hepatitis Curr Treat Options Gastroenterol. 2005; 8: 481-492https://doi.org/10.1007/s11938-005-0035-7
        • Anand L.
        • Choudhury A.
        • Bihari C.
        • Sharma B.C.
        • Kumar M.
        • Maiwall R.
        • et al.
        Flare of autoimmune hepatitis causing acute on chronic liver failure: diagnosis and response to corticosteroid therapy.
        Hepatol Baltim Md. 2019; 70: 587-596https://doi.org/10.1002/hep.30205
        • Czaja A.J.
        • Davis G.L.
        • Ludwig J.
        • Baggenstoss A.H.
        • Taswell H.F.
        Autoimmune features as determinants of prognosis in steroid-treated chronic active hepatitis of uncertain etiology.
        Gastroenterology. 1983; 85: 713-717
        • Feld J.J.
        • Dinh H.
        • Arenovich T.
        • Marcus V.A.
        • Wanless I.R.
        • Heathcote E.J.
        Autoimmune hepatitis: effect of symptoms and cirrhosis on natural history and outcome.
        Hepatol Baltim Md. 2005; 42: 53-62https://doi.org/10.1002/hep.20732
        • Li Y.-N.
        • Ma H.
        • Zhou L.
        • Zhang J.
        • Guo L.-P.
        • Li S.-Q.
        • et al.
        Autoimmune hepatitis-related cirrhosis: clinical features and effectiveness of immunosuppressive treatment in Chinese patients.
        Chin Med J (Engl). 2016; 129: 2434-2440https://doi.org/10.4103/0366-6999.191760
        • Montano-Loza A.J.
        • Carpenter H.A.
        • Czaja A.J.
        Features associated with treatment failure in type 1 autoimmune hepatitis and predictive value of the model of end-stage liver disease.
        Hepatol Baltim Md. 2007; 46: 1138-1145https://doi.org/10.1002/hep.21787
        • Roberts S.K.
        • Therneau T.M.
        • Czaja A.J.
        Prognosis of histological cirrhosis in type 1 autoimmune hepatitis.
        Gastroenterology. 1996; 110: 848-857https://doi.org/10.1053/gast.1996.v110.pm8608895
        • Chang M.-L.
        • Liaw Y.-F.
        Hepatitis B flares in chronic hepatitis B: pathogenesis, natural course, and management.
        J Hepatol. 2014; 61: 1407-1417https://doi.org/10.1016/j.jhep.2014.08.033
        • European Association for the Study of the Liver
        Electronic address: [email protected], European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection.
        J Hepatol. 2017; 67: 370-398https://doi.org/10.1016/j.jhep.2017.03.021
        • Joo M.K.
        • Yeon J.E.
        • Kim J.H.
        • Jung Y.K.
        • Lee S.J.
        • Kim J.H.
        • et al.
        Chronic cirrhotic hepatitis B patients with a high incidence of hepatic decompensation after viral breakthrough with lamivudine-resistant mutants and during rescue treatment.
        Scand J Gastroenterol. 2008; 43: 1514-1521https://doi.org/10.1080/00365520802273033
        • European Association for Study of Liver
        EASL clinical practice guidelines: Wilson’s disease.
        J Hepatol. 2012; 56: 671-685https://doi.org/10.1016/j.jhep.2011.11.007
        • Ferenci P.
        • Steindl-Munda P.
        • Vogel W.
        • Jessner W.
        • Gschwantler M.
        • Stauber R.
        • et al.
        Diagnostic value of quantitative hepatic copper determination in patients with Wilson’s Disease.
        Clin Gastroenterol Hepatol Off Clin Pract J Am Gastroenterol Assoc. 2005; 3: 811-818https://doi.org/10.1016/s1542-3565(05)00181-3
        • Walshe J.M.
        • Dixon A.K.
        Dangers of non-compliance in Wilson’s disease.
        Lancet Lond Engl. 1986; 1: 845-847https://doi.org/10.1016/s0140-6736(86)90949-9
        • Strand S.
        • Hofmann W.J.
        • Grambihler A.
        • Hug H.
        • Volkmann M.
        • Otto G.
        • et al.
        Hepatic failure and liver cell damage in acute Wilson’s disease involve CD95 (APO-1/Fas) mediated apoptosis.
        Nat Med. 1998; 4: 588-593https://doi.org/10.1038/nm0598-588
        • Devarbhavi H.
        • Reddy V.V.
        • Singh R.
        Wilson disease presenting with acute on chronic liver failure: a single-center experience of outcome and predictors of mortality in 68 patients.
        J Clin Exp Hepatol. 2019; 9: 569-573https://doi.org/10.1016/j.jceh.2019.02.006
        • European Association for the Study of the Liver
        Electronic address: [email protected], Clinical practice guidelines panel, Wendon, Panel members, Cordoba J, Dhawan A, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure.
        J Hepatol. 2017; 66: 1047-1081https://doi.org/10.1016/j.jhep.2016.12.003
        • Keeffe E.B.
        Is hepatitis A more severe in patients with chronic hepatitis B and other chronic liver diseases?.
        Am J Gastroenterol. 1995; 90: 201-205
        • Reiss G.
        • Keeffe E.B.
        Review article: hepatitis vaccination in patients with chronic liver disease.
        Aliment Pharmacol Ther. 2004; 19: 715-727https://doi.org/10.1111/j.1365-2036.2004.01906.x
        • Frias M.
        • López-López P.
        • Rivero A.
        • Rivero-Juarez A.
        Role of hepatitis E virus infection in acute-on-chronic liver failure.
        Biomed Res Int. 2018; 2018: 9098535https://doi.org/10.1155/2018/9098535
        • Rosi S.
        • Poretto V.
        • Cavallin M.
        • Angeli P.
        • Amodio P.
        • Sattin A.
        • et al.
        Hepatic decompensation in the absence of obvious precipitants: the potential role of cytomegalovirus infection/reactivation.
        BMJ Open Gastroenterol. 2015; 2e000050https://doi.org/10.1136/bmjgast-2015-000050
        • Koay L.-B.
        • Tsai S.-L.
        • Sun C.-S.
        • Wu K.-T.
        Chronic autoimmune hepatitis with Epstein-Barr virus superinfection: a case report and review of literature.
        Hepatogastroenterology. 2008; 55: 1781-1784
        • Ioannou G.N.
        • Liang P.S.
        • Locke E.
        • Green P.
        • Berry K.
        • O’Hare A.M.
        • et al.
        Cirrhosis and SARS-CoV-2 infection in US Veterans: risk of infection, hospitalization, ventilation and mortality.
        Hepatol Baltim Md. 2020; https://doi.org/10.1002/hep.31649
        • Marjot T.
        • Moon A.M.
        • Cook J.A.
        • Abd-Elsalam S.
        • Aloman C.
        • Armstrong M.J.
        • et al.
        Outcomes following SARS-CoV-2 infection in patients with chronic liver disease: an international registry study.
        J Hepatol. 2020; https://doi.org/10.1016/j.jhep.2020.09.024
        • D’Amico G.
        • Garcia-Tsao G.
        • Pagliaro L.
        Natural history and prognostic indicators of survival in cirrhosis: a systematic review of 118 studies.
        J Hepatol. 2006; 44: 217-231https://doi.org/10.1016/j.jhep.2005.10.013
        • 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.
        Gastroenterology. 2010; 139 (1256.e1-5): 1246-1256https://doi.org/10.1053/j.gastro.2010.06.019
        • Jepsen P.
        • Ott P.
        • Andersen P.K.
        • Sørensen H.T.
        • Vilstrup H.
        Clinical course of alcoholic liver cirrhosis: a Danish population-based cohort study.
        Hepatol Baltim Md. 2010; 51: 1675-1682https://doi.org/10.1002/hep.23500