ICU Management & Practice, Volume 16 - Issue 3, 2016

Evolving Concepts in Acute-on-Chronic Liver Failure

Evolving Concepts in Acute-on-Chronic Liver Failure
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Most patients with liver cirrhosis ‏remain in a compensated stage for ‏more than 10 years, regardless of ‏the aetiology of the liver disease. The progression ‏to decompensated cirrhosis is defined by ‏the occurrence of a major complication such ‏as ascites, variceal bleeding and/or hepatic ‏encephalopathy. From here on most patients ‏will not die because of a progressive, irreversible ‏decrease in liver function, but because ‏of a relatively sudden event that precipitates ‏an acute deterioration in their clinical condition, ‏a syndrome termed acute-on-chronic ‏liver failure (ACLF). For many intensive care ‏specialists, ACLF stands for a critically ill patient ‏who is suffering from an intra- or extrahepatic ‏acute insult with serious repercussions ‏on both an existing chronic liver disease and ‏on other organ functions. It also means that, ‏as compared to the average intensive care unit ‏(ICU) patient, the patient has an unusually high ‏risk of death.


Concepts about cirrhosis have evolved ‏significantly in recent years, and major ‏advances have been made in defining the ‏natural history of ACLF (for general reviews ‏see Arroyo et al. 2016; Bernal et al. 2015; Sarin ‏and Choudhury 2016). The syndrome is highly ‏challenging for intensivists and poses difficult ‏questions related to the recognition of precipitating ‏factors, pathogenesis of extrahepatic ‏organ failures, accurate prognosis, medical ‏management, evaluation for urgent liver ‏transplantation and finally the identification ‏of those situations that may render intensive ‏care futile. The present appraisal will focus on ‏recent insights and their potential repercussions ‏on the way intensivists should understand and ‏manage patients with ACLF.

Definition and Natural History of Acute-on-Chronic Liver Failure


There is no uncontested universal definition for ‏ACLF and the two most widely used definitions ‏depend on the origin of the hepatologists— ‏West versus East (Arroyo et al 2015; Sarin et al. ‏2014). For the purpose of this text we will use ‏the definition of the European Association for ‏the Study of the Liver – Chronic Liver Failure ‏(EASL-CLIF) Consortium, because extrahepatic ‏organ failure(s) and short-term mortality are ‏central to the definition and therefore more ‏closely mimic circumstances in the ICU. This ‏definition is based on a prospective, multicentre, ‏observational study (CANONIC study) ‏of 1343 patients who were hospitalised for ‏acute decompensation of cirrhosis (Moreau ‏et al 2013). ACLF is thus defined as a specific ‏syndrome comprising acute decompensation ‏of cirrhosis (development of ascites, variceal ‏bleeding, hepatic encephalopathy and/or ‏bacterial infections), organ failure and high ‏short-term mortality (by definition 28-day ‏mortality rate ≥15%) (Arroyo et al 2015). ‏ ‏

Based on the chronic liver failure (CLIF) Acute-on-Chronic Liver Failure in Cirrhosis ‏(CANONIC) study a new grading system for ‏severity of ACLF (grade 0 to 4) has been introduced ‏built on a modified Sequential Organ ‏Failure Assessment (SOFA) score (Tables 1 and ‏2). This new grading system is proving useful ‏to diagnose the condition, to study the natural ‏history of ACLF, to stratify patients in interventional ‏trials and for prognostication (Gustot ‏et al 2015; Silva et al. 2015; Shi et al. 2016).


In the CANONIC study the prevalence of ‏ACLF in patients presenting to the hospital with ‏acute decompensation of cirrhosis was 31%. ‏Twenty-three percent had ACLF at the time of ‏admission and another 11% developed ACLF ‏during hospitalisation. Twenty-four percent ‏of the patients required care in the ICU with ‏one in three not fulfilling criteria for ACLF at ‏the time of admission to the ICU. A similar ‏prevalence ranging from 24 to 34% has been ‏reported in other large studies from China, ‏North America and Scandinavia (Li et al 2016; ‏Bajaj et al. 2014a; Sargenti et al. 2015). Almost ‏half of the patients with ACLF did not have ‏a prior history of acute decompensation, or ‏had developed the first decompensating event ‏within the three months prior to the diagnosis ‏of ACLF. This observation is relevant to ‏the extent that ACLF is not necessarily the final ‏event in a progressive course of decompensating ‏liver disease, but may occur at any point ‏in time after diagnosis of cirrhotic liver disease.


The clinical course of the condition is very ‏dynamic. One study observed resolution of ‏ACLF in 42.5% of patients across all grades of ‏ACLF, 53.5% in ACLF-1, 34.6% in ACLF-2 and ‏16% in ACLF-3 (Table 1) (Gustot et al. 2015). ‏In the CANONIC study the overall 28-day and ‏90-day mortality rates for patients with ACLF, ‏who did not undergo liver transplantation, ‏were 32.8% and 51.2%. Similar rates have been reported in other studies (Li et al. 2016). ‏These mortality rates are clearly different from ‏those in patients with acute decompensation ‏of liver cirrhosis but not fulfilling criteria for ‏ACLF (1.9% and 9.3%, respectively). The most ‏frequent cause of death in patients with ACLF ‏was multiple organ failure without septic or ‏hypovolaemic shock (40%), followed by septic ‏shock in approximately 25% of cases. The aetiology ‏of cirrhosis does not seem to be determinant ‏of outcome, but patients with gastrointestinal ‏haemorrhage as a precipitating factor do ‏better than patients who were not bleeding at ‏admission (McPhail et al. 2014).


It is often assumed that acute decompensation ‏of liver function is triggered by a clinically ‏identifiable, precipitating event. The trigger may ‏have a hepatic origin, such as drug-induced liver ‏injury, viral or ischaemic hepatitis, liver surgery ‏or undue alcohol consumption. It can also have ‏an extrahepatic origin such as acute bacterial ‏infection, major surgery or paracentesis. Interestingly, ‏in the CANONIC study, in 43.6% of the ‏patients with ACLF, no precipitating event could ‏be identified (Moreau et al. 2013). This observation ‏underscores the fact that in the majority ‏of patients we are not yet able to diagnose ‏the pathogenetic mechanism leading to acute ‏decompensation. Acute bacterial infection was ‏the most frequent precipitating event in 33% of ‏the patients (Moreau et al. 2013). ‏


See Also: Liver Intensive Care

Prevalence and Pathogenesis of Organ Dysfunctions Associated With ACLF


Organ dysfunction or failure is highly prevalent ‏in ACLF. Hepatic, renal, cerebral, coagulation ‏and circulatory dysfunctions are well known, ‏but important derangements in the function ‏of the heart, immune system, adrenal glands ‏and muscle have been also well documented. ‏In ACLF patients in the CANONIC study kidney ‏failure (56%) was the most frequent organ ‏failure followed by liver failure (44%), coagulation ‏(28%), cerebral (24%), circulation ‏(17%) and lung failure with 9%. The number ‏of failing organs correlates with increasing ‏white cell count and C-reactive protein (CRP) ‏levels (Jalan and Williams 2002).


Two pathogenetic mechanisms seem to be ‏important drivers of both intra- and extrahepatic ‏organ dysfunction: systemic inflammation ‏and dysbiosis of the microbiome (Bernardi ‏M. et al. 2015). Systemic inflammation may ‏be induced by bacterial pathogen-associated ‏molecular patterns (PAMPs) or by virulence ‏factors produced by bacteria. Patients with ‏cirrhosis have increased permeability of the ‏gut related to portal hypertension, inflammation- ‏mediated damage to the gut barrier and ‏altered gut flora. The result is increased translocation ‏of particularly Gram-negative bacteria, ‏PAMPs or virulence factors from the intestinal ‏lumen to the systemic circulation. The prevalence ‏of translocation of enteric organisms to ‏mesenteric lymph nodes in cirrhotic patients is ‏significantly increased according to the Child- ‏Pugh classification: 3.4% in Child A, 8.1% in ‏Child B and 30.8% in Child C patients (Cirera ‏et al. 2001). Systemic inflammation may also ‏be induced by ongoing necrosis of hepatocytes ‏or damage to the extracellular matrix caused ‏by alcohol, viral disease or any other aetiopathogenetic ‏mechanisms of cirrhosis. In this ‏case the molecules inducing inflammation are ‏called damage-associated molecular patterns ‏(DAMPs). How inflammation contributes to ‏organ dysfunction in ACLF has not yet been ‏fully elucidated. Besides the well-described ‏severe immune dysfunction associated with ‏cirrhosis with increased susceptibility to infection, ‏the following concepts are likely to be ‏important (Verbeke et al. 2011):

  1. The effects caused by immunopathology, a ‏term that describes the potential negative ‏impact of an excessive immune response ‏(Iwasaki and Medzhitov 2015). Either ‏PAMPs or DAMPs can cause immunopathology ‏that in turn may cause organ ‏dysfunction. In this case defence mechanisms ‏directed at controlling infection or ‏immunopathology are insufficient. This is ‏the likely mechanism in ACLF precipitated ‏by acute bacterial infection or severe alcoholic ‏hepatitis.
  2. Failed tolerance, a concept that describes ‏the incapacity to develop tolerance mechanisms ‏to persistent infection–mediated ‏inflammation (Medzhitov et al 2012). In ‏this case persistent ‘low-grade’ systemic ‏exposure to PAMPs or DAMPs may be the ‏reason for ongoing ‘sterile’ inflammation ‏for which no tolerance can be developed. ‏This concept provides an array of potential ‏new therapeutic targets aimed at increasing ‏tolerance.


Recent evidence points to gut dysbiosis as a ‏second important pathogenetic driver of organ ‏dysfunction in ACLF (Bajaj et al. 2014b; Chen ‏et al. 2015; Rai et al. 2014). Several factors ‏contribute to altered microbiota in cirrhosis, ‏including increased intestinal permeability, ‏abnormal small intestinal motility, impaired ‏antimicrobial defence, small intestinal bacterial ‏overgrowth, decreased bile acid production and ‏compromised enterohepatic circulation (Rai ‏et al. 2014). In stable cirrhosis there is a clear ‏change in diversity and composition of gut ‏microbiota with progressive dysbiosis in the ‏setting of decompensation. Similar changes have been reported in ACLF. In a recent trial ‏a relative abundance of Pasteurellacae was an ‏independent predictor for mortality and, ‏interestingly, the use of antibiotics had only ‏moderate impact on the gut flora (Chen et al. ‏2015). Robust correlations were also observed ‏between specific bacterial families and inflammatory ‏cytokines such as interleukin-6 and ‏TNF-alpha. A clear mechanistic link between ‏pathogenic colonic mucosal microbiota and ‏poor cognition has been demonstrated for ‏hepatic encephalopathy (Rai et al. 2014; Bajaj ‏et al. 2012). Remarkably, treatment with lactulose ‏in patients with hepatic encephalopathy ‏did not change faecal flora composition. It ‏remains unclear how gut dysbiosis contributes ‏to organ dysfunction. Current findings ‏suggest that relative gut overgrowth of one type ‏of bacteria or metabolites of certain bacteria ‏species can contribute to inflammation and ‏thereby to organ dysfunction.

Potential New Therapeutic Approaches


In specific situations early treatment of precipitating ‏events such as alcoholic hepatitis with ‏steroids or reactivation of hepatitis B with ‏antivirals can reduce mortality. However, ‏and for the most part, medical management ‏of organ failure in ACLF remains supportive. ‏Randomised trials with extracorporeal liver ‏support systems aimed at blood purification ‏did not result in survival benefits (Banares et ‏al. 2013; Kribben et al. 2012).


A recent observational study reported ‏improved clinical outcome with plasma ‏exchange in hepatitis B-related ACLF (Chen ‏2016). High hopes are placed in regenerative ‏therapy of cirrhosis including the use of growth ‏factors, the combination of G-CSF and erythropoietin, ‏hepatocyte and stem cell transplantation ‏(King et al. 2015; Kedarisetty et al. 2015, ‏Shiota and Itaba 2016; Duan et al. 2013; Garg ‏et al. 2012; Zekri et al. 2015). Granulocytecolony ‏stimulating factor (G-CSF) therapy in ‏ACLF reduced organ dysfunction and improved ‏survival (Chavez-Tapia et al. 2015). It is unclear ‏if the positive results obtained in randomised ‏trials with administration of G-SCF in ACLF ‏patients will be applicable in more severe forms ‏of ACLF in the ICU (Duan et al. 2013; Garg et ‏al. 2012).


Prognosis, Futility and Eligibility for Liver Transplantation


Many intensivists take a reserved attitude ‏towards the admission of ACLF patients because ‏of the dim prognosis of the syndrome. However, ‏several new facts have emerged in recent years ‏that defend a change in attitude and justify a ‏full evaluation for transplant for every patient ‏with ACLF admitted to the ICU. First, new data ‏show that liver fibrosis and even cirrhosis are ‏potentially reversible if the underlying cause is ‏removed, with significant improvement in longterm ‏survival (Ramachandran 2015). Second, ‏the outcome of ACLF in the ICU has improved ‏considerably. In expert ICUs survival of patients ‏with cirrhosis and organ failure improved from ‏40% in the year 2000 to 63% in the year 2010 ‏(McPhail et al. 2014). Similarly, ICU mortality ‏of cirrhotic patients with septic shock has ‏decreased from 74% in 1998 to 65.5% in ‏2010 (Galbois et al. 2014). Third, the course ‏of the disease is very dynamic with resolution ‏or improvement of ACLF in 4.2% of patients. ‏Eighty-one precent reach their final ACLF grade ‏at one week after admission, and it is now clear ‏that for most patients prognostication will be ‏considerably more accurate if done towards the ‏end of the first week of ICU stay (Gustot et al. ‏2015). Fourth, prognostication for these patients ‏has improved. New scoring systems, such as ‏the Chronic Liver Failure Consortium Acuteon- ‏Chronic Liver Failure score (CLIF-C ACLF) ‏score that incorporates a modified SOFA-score ‏(CLIF-Organ Failure [OF] score), age and white ‏blood cell count can be calculated on a daily ‏base in order to monitor evolution/resolution ‏of ACLF and provide a significantly better estimate ‏of risk for mortality than the model for ‏end-stage liver disease (MELD) or Child-Pugh ‏score (Jalan et al. 2014).


Considering the above, indiscriminate refusal of ICU admission ‏of ACLF patients is not acceptable any more, since no specific ‏group of patients can be identified at the time of diagnosis for ‏which medical ICU treatment may be considered futile. However, ‏intensivists also need to acknowledge that patients with four or ‏more organ failures or a CLIF-C ACLF score > 64 after one week of ‏ICU care have 28-day mortality rates in the range of 90 to 100%. ‏If ineligible for transplantation withdrawal of care is a reasonable ‏option for these patients.


Liver transplantation in ACLF is controversial and fraught with ‏uncertainties regarding case selection and timing (Pamecha et al. ‏2015; Reddy et al. 2015). Only 15-25 % of patients are actually ‏transplanted (Gustot et al. 2015, Finkenstedt et al. 2013). Recent ‏series have reported encouraging results with 1- and 5-year survival ‏of 80-90% (Finkenstedt et al. 2013; Chan et al. 2009). Even patients ‏with ACLF-3 may expect a 1-year survival probability of 78% ‏(Gustot et al. 2015) ‏.



Major progress has been made in defining the natural history and ‏prognosis of ACLF. Regenerative therapies and liver transplantation ‏in selected cases hold promise for the future.


Conflict of Interest


Philippe Meersseman and Alexander Wilmer declare that they have ‏no conflict of interest.




ACLF acute-on-chronic liver failure

CANONIC CLIF Acute-on-Chronic Liver Failure in Cirrhosis

CLIF chronic liver failure

CLIF-C Chronic Liver Failure Consortium

CRP c-reactive protein

DAMP damage-associated molecular patterns

G-CSF Granulocyte-colony stimulating factor

ICU intensive care unit

MELD model for end-stage liver disease

OF organ failure

PAMP pathogen-associated molecular patterns

SOFA sequential organ failure assessment

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