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Towards a new definition of decompensated cirrhosis

      Summary

      There is a universal agreement that the occurrence of clinical complications, such as ascites, hepatic encephalopathy, gastrointestinal bleeding, and jaundice mark the transition from the compensated to the decompensated stage of cirrhosis. Decompensation is associated with a substantial worsening of patient prognosis and is therefore considered the most important stratification variable for the risk of death. However, this classification is an oversimplification, as it does not discriminate between the prognostic subgroups that characterise the course of decompensation, which depends on the type and number of decompensating events. A deeper insight into the clinical course of decompensated cirrhosis is provided by observational studies characterising acute decompensation (AD), which occurs mostly in patients who have already experienced decompensating events. Decompensation presents as AD in a portion of patients while in many others it presents as a slow development of ascites or mild grade 1 or 2 hepatic encephalopathy, or jaundice, not requiring hospitalisation. Thus, we propose that decompensation of cirrhosis occurs through 2 distinct pathways: a non-acute and an acute (which includes acute-on-chronic liver failure) pathway. Moreover, while non-acute decompensation is the most frequent pathway of the first decompensation, AD mostly represents further decompensation.

      Keywords

      Linked Article

      • Corrigendum to ‘Towards a new definition of decompensated cirrhosis’ [J Hepatol 76 (2022) 202–207]
        Journal of HepatologyVol. 76Issue 3
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          It has come to our attention that there is an error in the Introduction of our manuscript. The sentence (starting bottom line, left column of the first PDF page), ‘However, the combination of ascites, bleeding, hepatic encephalopathy and jaundice, associated or not with other signs, was included in the definition in 80% of studies.’ should read, ‘However, any combination of ascites, bleeding, hepatic encephalopathy and jaundice, associated or not with other signs, was included in the definition in 80% of studies.’ We ask our readers to note this important distinction and we apologise for any inconvenience caused.
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      Introduction

      Defining the evolutionary stages and their prognosis in chronic diseases is of paramount clinical importance, as it constitutes the foundation guiding management strategies. For decades it has been understood that the natural history of cirrhosis is marked by a prognostic watershed, represented by the development of complications related to portal hypertension and impaired liver function, such as gastrointestinal bleeding, hepatic encephalopathy, jaundice and ascites formation.
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      This led to the concept that the course of the disease can be divided into 2 distinct clinical states: the usually asymptomatic compensated stage, characterised by preserved quality of life and a median survival exceeding 12 years, and the decompensated stage, marked by the occurrence of complications, with median survival dropping to 2–4 years.
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      However, although there is an almost unanimous consensus on the prognostic weight of decompensation, a corresponding consensus on its definition is still lacking. In a systematic review of predictors of decompensation including 91 studies, the definition of decompensation was based on 6 different combinations of development of ascites, gastrointestinal bleeding, hepatic encephalopathy, jaundice, hepatocellular carcinoma, increase in Child-Pugh score, prolongation of prothrombin time, development of oesophago-gastric varices, and need for diuretics.
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      Prediction of decompensation in patients with compensated cirrhosis: does etiology matter?.
      However, the combination of ascites, bleeding, hepatic encephalopathy and jaundice, associated or not with other signs, was included in the definition in 80% of studies. These findings clearly indicate the need for a consensus definition of decompensation. Therefore, herein, we refer to decompensated cirrhosis as the presence or history of any one of ascites, bleeding, hepatic encephalopathy, or jaundice.
      Although classifying cirrhosis as compensated and decompensated is clinically sound, it oversimplifies the clinical course of the disease, which encompasses many different prognostic subgroups. In fact, it has been shown that the outcome of decompensation depends on the type and number of decompensating events. Ascites is by far the most frequent first decompensating event, presenting alone in 36% of patients and in combination with other complications in 37%.
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      Therefore, it marks transition to decompensation in 73% of patients and is widely considered the hallmark of decompensation. Moreover, ascites is associated with worse outcomes than variceal bleeding alone, while the combination of both bleeding and ascites is associated with the worst outcomes.
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      In accordance with these findings, an inception cohort study showed that the 5-year mortality risk is 20% for patients decompensating with bleeding alone, 30% with any non-bleeding event, mostly ascites, and 88% with any combination of ≥2 events.
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      In a comprehensive risk stratification of the whole course of cirrhosis, these conditions have been designated as states 3, 4 and 5, with states 1 and 2 pertaining to compensated cirrhosis: absence of varices defining state 1 and presence of varices state 2, with a 5-year risk of death of 1.5% and 10%, respectively.
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      One proposal to increase granularity in the risk stratification of decompensated cirrhosis is to include patients with very advanced disease in a further decompensation state. This was first suggested after 2 meta-analyses showed that infections and renal failure occurring in decompensated cirrhosis are associated with 1-year mortality of 63%.
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      It is now clear that bacterial infections and systemic inflammation play a key role throughout the course of cirrhosis by precipitating or aggravating decompensation and organ dysfunction beyond the liver, with circulatory and renal dysfunction being a major manifestation.
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      The American Association for the Study of Liver Disease guidance for portal hypertension proposed that this disease state should include recurrent variceal haemorrhage, refractory ascites, hyponatremia, hepatorenal syndrome, recurrent hepatic encephalopathy and jaundice.
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      Such disease progression is characterised by severe clinical deterioration, very high levels of inflammatory markers,
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      and very high mortality in the order of 60% to 80% at 1 year.
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      The CANONIC and PREDICT studies

      Deeper insights into the clinical course of decompensated cirrhosis have been provided by 2 recent large observational studies looking at acute decompensation (AD). The first, the CANONIC study,
      • Moreau R.
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      Acute-on-chronic liver failure is a distinct syndrome that develops in patients with acute decompensation of cirrhosis.
      aimed to establish diagnostic criteria for acute-on-chronic liver failure (ACLF), introduced the concept of AD as a distinct clinical presentation of decompensation of cirrhosis defined by the acute development of ≥1 major complication(s): first or recurrent grade 2 or 3 ascites within less than 2 weeks, first or recurrent acute hepatic encephalopathy in patients with previously normal consciousness, acute gastrointestinal bleeding, and any type of acute bacterial infection. Therefore, the concept of AD is essentially based on the rapidity of onset of the complications on which the definition of decompensation is based. This rapidity of presentation has been observed in hospitalised patients, with 73% having experienced previous decompensating events (CANONIC). Additionally, the CANONIC study introduced bacterial infection as a defining event of AD. Although bacterial infections were not traditionally considered as a marker of decompensation, they were considered as such and included in the definition of AD because of their high prevalence and association to bacterial translocation and impaired leukocyte functions in cirrhosis.
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      Moreover, the prognosis of patients with cirrhosis worsens once a bacterial infection has occurred irrespective of its resolution.
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      Infections in patients with cirrhosis increase mortality four-fold and should be used in determining prognosis.
      ,
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      Even though the need for hospitalisation was not included among the diagnostic criteria of AD, only patients admitted to hospital were included in the CANONIC study. This may represent a source of selection bias, as the criteria used to decide whether to admit a patient are subjective and can vary among different centres. Moreover, the proportion and outcome of patients presenting features of AD who are not admitted to hospital remain undefined.
      A further important step forward in the risk stratification of decompensation proposed by the CANONIC study was the definition of ACLF based on the development of organ failures: liver, kidney, brain, circulation, coagulation, and lung. The number of organ failures subclassifies ACLF into grades 1, 2 or 3 according to whether it is associated with 1, 2 or ≥3 organ failures. Patients with ACLF had a worse short-term outcome than those with AD: 28-day mortality ranged from 5% in patients with AD without ACLF to 22–77% in those with ACLF at admission, depending on the grade of ACLF. This range was further expanded from 6% in AD without ACLF to 92% in ACLF grade 3, considering the final diagnosis made a week after hospital admission.
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      Several investigations confirmed AD as a distinct entity with respect to either compensated, or stable decompensated cirrhosis, or ACLF in terms of extent of systemic inflammation, assessed by determining either indirect parameters such as white blood cell count and C reactive protein or circulating levels of pro-inflammatory cytokines, post-transcriptional abnormalities of serum albumin, severity of cirrhosis assessed by commonly used prognostic scores such as Child-Pugh and model for end-stage liver disease (MELD) scores,
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      and presence of extrahepatic organ dysfunction and failure.
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      Addressing profiles of systemic inflammation across the different clinical phenotypes of acutely decompensated cirrhosis.
      Indeed, AD clearly stands in between compensated or stable decompensated cirrhosis and ACLF. Furthermore, the 3-month mortality of patients with AD without ACLF can be more accurately predicted by a specific prognostic score, the CLIF Consortium acute decompensation score (CLIF-C ADs)
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      based on age, serum sodium, white-cell count, creatinine, and international normalised ratio, and differs from the traditional Child-Pugh, MELD and MELD-Na
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      scores, which were developed in the setting of compensated and stable decompensated cirrhosis, long before the definition of AD.
      The second study, PREDICT, looked at the clinical events occurring over a 3-month period from AD and 3- and 12-month mortality risk.
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      The PREDICT study uncovers three clinical courses of acutely decompensated cirrhosis that have distinct pathophysiology.
      Like the CANONIC study, it included hospitalised patients with 80% having had a previous decompensating event. Three different courses were identified, irrespective of the aetiology of cirrhosis: i) pre-ACLF, developing ACLF during follow-up; ii) unstable decompensated cirrhosis, followed by at least a re-hospitalisation without developing ACLF; iii) stable decompensated cirrhosis, neither developing ACLF nor requiring hospital re-admission. These patient groups were clearly stratified in terms of 3- and 12-month mortality (0% to 9.5% in the stable decompensated cirrhosis group vs. 21% to 35.6% in the unstable decompensated cirrhosis group vs. 53.7% to 67.4% in the pre-ACLF group, respectively). Indirect markers of systemic inflammation, such as white blood cell count and, mainly, serum C reactive protein levels, increased progressively from the stable decompensated cirrhosis to the pre-ACLF group. Furthermore, while these markers tended to fade over time in unstable and stable decompensated cirrhosis, they kept increasing during the index hospitalisation in the pre-ACLF group. Based on these and previous findings, it has recently been proposed that systemic inflammation plays a major role in the development of AD, its recurrence, and evolution to ACLF, which is the extreme manifestation of this pathophysiological mechanism.
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      Future directions: acute vs. non-acute decompensation

      The picture of AD emerging from the CANONIC and PREDICT studies led to major advances in our understanding of the clinical course of decompensated cirrhosis. Moreover, an analysis of the PREDICT study database revealed how precipitating factors influence AD phenotypes and their outcome.
      • Trebicka J.
      • Fernandez J.
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      • Laleman W.
      • Gambino C.
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      PREDICT identifies precipitating events associated with the clinical course of acutely decompensated cirrhosis.
      Indeed, precipitating events were more often identifiable in the AD-ACLF cohort (71% of patients) than in the AD without ACLF cohort (38%), and the number of precipitants, rather than their nature, was significantly associated with the risk of 3-month mortality, although alcoholic hepatitis, bacterial infections or both were the most frequently identified precipitating factors. Still, more refinements are needed. It would be desirable for the definition of AD to be based on objective clinical criteria, including the severity of liver and other organ dysfunctions. A second relevant issue relates to the real impact of AD in the clinical course of cirrhosis. Although we know from the CANONIC and PREDICT studies that about a quarter of patients presenting with AD have no history of previous decompensation, its incidence in compensated and decompensated patients is still unsettled. The incidence of ACLF in this clinical context has only been assessed in 1 study including 466 outpatients with or without previous decompensation:
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      Incidence, predictors and outcomes of acute-on-chronic liver failure in outpatients with cirrhosis.
      118 developed ACLF after a mean of 45 ± 41 months of follow-up. One-year incidence was 57/305 (18.7%) among decompensated and 4/161 (2.5%) among compensated patients. Unfortunately, this study did not assess the incidence of AD. Finally, the concept (and current definition) of AD does not apply to patients who develop decompensation in a progressive way, as in the case of the many patients who present with slow and progressive ascites formation or mild grade 1 or 2 hepatic encephalopathy or jaundice.
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      Outcomes and mortality of grade 1 ascites and recurrent ascites in patients with cirrhosis.
      Unpublished data from a multicentre European database including 1,858 consecutive patients with cirrhosis showed that first decompensation occurs with only 1 decompensating event in 58% of patients and with any combination of ≥2 events in 42% of patients.
      • D’Amico G.
      • Villanueva C.
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      • Dollinger M.M.
      • Planas R.
      • Sola R.
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      Clinical stages of cirrhosis a multicenter study of 1858 patients.
      Corresponding findings from an inception cohort study of the clinical course of cirrhosis were 73% and 27%, respectively, confirming that the first decompensation occurs with only 1 decompensating event in approximately two-thirds of patients,
      • D’Amico G.
      • Pasta L.
      • Morabito A.
      • D’Amico M.
      • Caltagirone M.
      • Malizia G.
      • et al.
      Competing risks and prognostic stages in cirrhosis: a 25-year inception cohort study of 494 patients.
      while AD was characterised by ≥2 decompensating events in most patients, both in the CANONIC and PREDICT studies. Inception cohort studies where the inception point is the first diagnosis of cirrhosis will clarify the real impact of AD relative to non-acute decompensation (NAD) and the different outcomes of first or subsequent episodes of AD. Thus, summing up the presently available knowledge on the clinical course of cirrhosis, 2 distinct modalities of transition to decompensation may be recognised (Fig. 1):
      • AD: first or recurrent grade 2 or 3 ascites within less than 2 weeks, first or recurrent acute hepatic encephalopathy in patients with previous normal consciousness, acute gastrointestinal bleeding, and any type of acute bacterial infection.
        • 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.
      • NAD: slow ascites formation, mild grade 1 or 2 hepatic encephalopathy, or progressive jaundice in non-cholestatic cirrhosis.
      Figure thumbnail gr1
      Fig. 1New definition of decompensation.
      We propose that decompensation of cirrhosis may be characterised by an acute onset (AD) or by a progressive, non-acute onset (NAD). AD is defined as any first or recurrent grade 2 or 3 ascites within less than 2 weeks, first or recurrent acute hepatic encephalopathy in patients with previous normal consciousness, acute gastrointestinal bleeding, and any type of acute bacterial infection. NAD is defined as slow ascites formation, hepatic encephalopathy grade 1–2 or higher if manageable in an out-patient setting, or progressive jaundice in non-cholestatic cirrhosis. AD presents as: ACLF in approximately 16% of cases; pre-ACLF in 17%; UDC in 22%, characterised by persistent albeit unstable inflammatory status resulting in further AD events within 1 year; SDC, 48% with stable decrease of systemic inflammation and no further AD for at least 1 year. NAD presents with the progressive development of any single event (58–72%) or any combination (28–42%) of ascites, encephalopathy or jaundice (in non-cholestatic cirrhosis). Over time, SDC might become undistinguishable from NAD if inflammation subsides. AD progresses to death or OLT either directly (ACLF or UDC phenotypes), or through further AD events. NAD progresses either to AD through further decompensation or directly to death or OLT through progressive liver function deterioration without the occurrence of AD with or without further decompensation. ∗ACLF: 16%, pre-ACLF: 17%, UDC: 22%, SDC: 48%; overall 80% with previous decompensating events; #patients free of previous decompensating events: 1 decompensating event 58-72%, ≥2 decompensating events 28-42%. ACLF, acute-on-chronic liver failure; AD, acute decompensation; NAD, non-acute decompensation; OLT, orthotopic liver transplantation; SDC, stable decompensated cirrhosis; UDC, unstable decompensated cirrhosis.
      It is therefore clear that AD and NAD have different places in the clinical course of cirrhosis with AD representing mostly further decompensation and NAD mostly the first decompensating event (Box 1).
      NAD and AD along the clinical course of cirrhosis.
      ACLF, acute-on-chronic liver failure; AD, acute decompensation; NAD, non-acute decompensation.
      Although jaundice has frequently been included in the definition of NAD,
      • D’Amico G.
      • Perricone G.
      Prediction of decompensation in patients with compensated cirrhosis: does etiology matter?.
      this is not straightforward because of its relevance in cholestatic vs. non-cholestatic chronic liver disease. In fact, while solid data exist on the development of NAD marked by ascites or grade 1 or 2 hepatic encephalopathy, scarce data are available on the relevance of jaundice as a marker of decompensation.
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      Of note, jaundice was either not even considered in the definition of clinical decompensation
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      Nevertheless, the role of jaundice as a marker of first NAD should be defined as it is still widely included in the definition of decompensation in the majority of published studies.
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      Other well-known clinical complications of cirrhosis such as hepatocellular carcinoma, malnutrition, sarcopenia and frailty have relevant negative prognostic implications in patients with cirrhosis.
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      have never been considered as markers of decompensation. In our opinion this is justified because these complications may occur at any time along the course of the liver disease without a well-known relationship with the main pathways of decompensation, AD and NAD. Also, it is now clear that the degree of portal hypertension as indicated by the presence of oesophageal varices, is the most important indicator of the risk of decompensation and increasing severity of cirrhosis.
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      Yet, even in patients without oesophageal varices, clinically significant portal hypertension indicated by a hepatic vein pressure gradient (HVPG) ≥10 mmHg is significantly associated with the risk of decompensation and disease progression
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      B-blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      However, since both HVPG and oesophageal varices may be present independently of overt clinical decompensation they should be considered as predictors of disease progression rather than indicators of decompensation per se.
      Although death or liver transplantation were the only 2 recognised final outcomes of decompensated cirrhosis, re-compensation has recently appeared on the scene. This is based on the not infrequent disappearance of any decompensation sign following effective aetiological treatments. Re-compensation is conceivably associated with reduction of fibrosis and portal hypertension, as shown after successful aetiological treatment in compensated cirrhosis.
      • Villanueva C.
      • Albillos A.
      • Genesca J.
      • Garcia-Pagan J.C.
      • Calleja J.L.
      • Aracil C.
      • et al.
      B-blockers to prevent decompensation of cirrhosis in patients with clinically significant portal hypertension (PREDESCI): a randomised, double-blind, placebo-controlled, multicentre trial.
      • Marcellin P.
      • Gane E.
      • Buti M.
      • Afdhal N.
      • Sievert W.
      • Jacobson I.M.
      • et al.
      Regression of cirrhosis during treatment with tenofovir disoproxil fumarate for chronic hepatitis B: a 5-year open-label follow-up study.
      • Di Marco V.
      • Calvaruso V.
      • Ferraro D.
      • Bavetta M.G.
      • Cabibbo G.
      • Conte E.
      • et al.
      Effects of eradicating hepatitis C virus infection in patients with cirrhosis differ with stage of portal hypertension.
      However, the stability of re-compensation is far from certain. Indeed, the risk of de novo/additional clinical decompensation in patients with HCV-related cirrhosis is still about 7% 2 years after sustained virological response, being associated with baseline HVPG ≥16 mmHg and a history of ascites.
      • Lens S.
      • Baiges A.
      • Alvarado E.
      • LLop E.
      • Martinez J.
      • Fortea J.I.
      • et al.
      Clinical outcome and hemodynamic changes following HCV eradication with oral antiviral therapy in patients with clinically significant portal hypertension.
      However, to assess the real impact of re-compensation and its stability, a consensus definition is needed. In our opinion, this would likely require a symptom-free time-period from previous decompensation and the ability to maintain this state without any standard of care treatment other than the aetiological one. Criteria to withdraw standard of care other than aetiological treatment is a crucial issue in defining re-compensation because it may harm patients not yet fully re-compensated. Identification of such criteria will require expert consensus and prospective validation studies. It is conceivable that non-invasive markers of portal hypertension and liver fibrosis, as well as liver function measures, would be part of such criteria. While re-compensation might be expected after aetiologic cure resulting in a progressive reduction of fibrosis and portal hypertension, and even reversion of cirrhosis,
      • Shim J.H.
      • Lee H.C.
      • Kang Kim K.M.
      • Lim Y.S.
      • Chung Y.H.
      • et al.
      Efficacy of entecavir in treatment-naïve patients with hepatitis B virus-related decompensated cirrhosis.
      • Gentile I.
      • Scotto R.
      • Coppola C.
      • Staiano L.
      • Amoruso D.C.
      • De Simone T.
      • et al.
      Treatment with direct-acting antivirals improves the clinical outcome in patients with HCV-related decompensated cirrhosis: results from an Italian real-life cohort (Liver Network Activity-LINA cohort).
      • Capone R.R.
      • Buhac I.
      • Kohberger R.C.
      • Balint J.A.
      Resistant ascites in alcoholic liver cirrhosis: course and prognosis.
      this is not expected to happen with ongoing exposure to the aetiological agent, even with disease-modifying treatments such as long-term use of human albumin, beta-blockers, and/or statins.
      • Caraceni P.
      • Riggio O.
      • Angeli P.
      • Alessandria C.
      • Neri S.
      • Foschi F.G.
      Long-term albumin administration in decompensated cirrhosis (ANSWER): an open-label randomized trial.
      ,
      • Bernardi M.
      • Caraceni P.
      Novel perspectives in the management of decompensated cirrhosis.
      The sole or main target of these agents is to reduce the risk of further decompensation, thereby prolonging survival and increasing quality of life. Therefore, accurate predictors of the risk of further decompensation are needed to define re-compensation. For now, patients recovering from decompensation should still be carefully monitored because of the risk of new/further decompensation.

      Abbreviations

      ACLF, acute-on-chronic liver failure; AD, acute decompensation; HVPG, hepatic vein pressure gradient; MELD, model for end-stage liver disease; NAD, non-acute decompensation.

      Financial support

      The authors received no financial support to produce this manuscript.

      Authors’ contributions

      All 3 authors contributed equally to the production of this manuscript.

      Conflict of interest

      P.A.: 2016-2020 Biovie Advisory Board; 2018-2020 CSL Behring Speaker Invitation and Advisory Board; 2018-2020 Grifols Speaker invitation and Advisory Board; 2018-2020 Ferring Advisory Board. The other authors report no conflicts of interest.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following is the supplementary data to this article:

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