Review

Acute-on chronic liver failure

Rajiv Jalan1,⇑, Pere Gines2, Jody C Olson3, Rajeshwar P Mookerjee1, Richard Moreau4,
Guadalupe Garcia-Tsao5, Vicente Arroyo2, Patrick S Kamath3
1
Liver Failure Group, UCL Institute for Liver and Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street, London,
United Kingdom; 2Liver Unit, Hospital Clínic, University of Barcelona, Barcelona, Catalunya, Spain, Institut d’Investigacions Biomèdiques
August-Pi-Sunyer (IDIBAPS), Centro de Investigación Biomédica en Red de Enfermedades Hepáticas yDigestivas (CIBEREHED), Spain; 3Division of
Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States; 4INSERM, U773, Centre de Recherche
Biomédicale Bichat-Beaujon CRB3, Paris and Clichy, France; 5Section of Digestive Diseases, Yale University School of Medicine,
New Haven, CT, United States

Summary manifesting as jaundice and coagulopathy, complicated within

Acute-on-chronic liver failure (ACLF) is an increasingly recogni-
sed entity encompassing an acute deterioration of liver function
in patients with cirrhosis, which is usually associated with a
precipitating event and results in the failure of one or more
organs and high short term mortality. Prospective data to define
this is lacking but there is a large body of circumstantial evidence
suggesting that this condition is a distinct clinical entity. From
the pathophysiologic perspective, altered host response to injury
and infection play important roles in its development. This
review focuses upon the current understanding of this syndrome
from the clinical, prognostic and pathophysiologic perspectives
and indicates potential biomarkers and therapeutic targets for
intervention.
Ó 2012 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.
4 weeks by ascites and/or encephalopathy in a patient with previously
diagnosed or undiagnosed chronic liver disease’; and a second at a
EASL-AASLD single topic symposium [3]; ‘Acute deterioration of
pre-existing, chronic liver disease, usually related to a precipitating
event and associated with increased mortality at 3 months due to
multi-system organ failure’. These definitions are too imprecise to
allow homogeneous diagnostic criteria and clinical studies are cur-
rently underway to reach an evidence-based definition. The latter
definition implies that organ failure is a central component of this
syndrome and leads to the hypothesis that the organs may behave
differently to chronic decompensated liver disease. This review
focuses upon the current understanding of this syndrome from
the clinical, prognostic and pathophysiologic perspectives and
indicates potential biomarkers and therapeutic targets for inter-
vention. It is the second definition that will be used in the descrip-
tion that follows unless otherwise stated.

Introduction Epidemiology

Acute-on-chronic liver failure (ACLF) is an increasingly recognised
entity encompassing an acute deterioration of liver function in
patients with cirrhosis, either secondary to superimposed liver
injury or due to extrahepatic precipitating factors such as infection
culminating in the end-organ dysfunction (Fig. 1). Occasionally, no
specific precipitating event can be found. Although the exact path-
ophysiology of the development of ACLF remains to be elucidated,
unregulated inflammation is thought to be a major contributing
factor. A characteristic feature of ACLF is its rapid progression,
the requirement for multiple organ supports and a high incidence
of short and medium term mortality of 50–90% [1]. The condition
remains undefined but two consensus working definitions for this
syndrome exist. The first was put forward by the Asia–Pacific
association for the study of liver disease [2]; ‘Acute hepatic insult
Data regarding the epidemiology of ACLF is rare. At the recently
held EASL-AASLD Single Topic Symposium on the management
of critically ill cirrhotic patients in the ICU (Atlanta, 2010), data
were presented from the nationwide in-patient sample in the
US for the year 2006. Using the parameters of the need for
mechanical ventilation and/or invasive cardiovascular monitor-
ing, 26,300 patients were identified. In-hospital mortality was
found to be 53% and the mean length of hospitalization was about
14 days. The total charges associated with the ICU admissions
alone were 3 billion US dollars with a suggestion that the ICU
mortality in cirrhotic patients has remained unchanged [3]. It is
likely that a significant proportion of these patients had ACLF
but is difficult to confirm until evidence-based definition of ACLF
is derived.

Keywords: Acute-on chronic liver failure; Hepatorenal syndrome; Hepatic ence-

phalopathy; Immune failure; Liver support; Liver transplantation. Clinical and prognostic factors (P)
Received 3 April 2012; received in revised form 19 June 2012; accepted 19 June 2012
⇑ Corresponding author. Address: Liver Failure Group, UCL Institute for Liver and
Data on the natural history of patients with cirrhosis progressing
Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street,
London NW3 2PF, United Kingdom. Tel.: +44 2074332795. to multiorgan failure and its outcome are limited. In a study
E-mail address: r.jalan@ucl.ac.uk (R. Jalan). reported in a preliminary form, the group at UCL hypothesized

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 JOURNAL OF HEPATOLOGY
Acute insult Table 1. SOFA scoring system.
100
Organ Measurement Score
PaO2 to FIO2 ratio ≥400 mmHg 0
Liver function (%)

300 to 399 mmHg 1

Threshold for organ failure 200 to 299 mmHg 2
100 to 199 mmHg 3
?Too late!
<100 mmHg 4
Chronic decompensation
of cirrhosis Platelet count ≥150,000 per µl 0
0
Months 100,000 to 149,999 per µl 1
50,000 to 99,999 per µl 2
Fig. 1. Acute-on chronic liver failure: diagrammatic representation of the 20,000 to 49,999 per µl 3
clinical concept. This figure describes the clinical concept of ACLF to distinguish
it from chronic decompensated cirrhosis. The red line describes the course of a <20,000 per µl 4
patient with chronic decompensation of cirrhosis that during evolution of their Serum bilirubin <1.2 mg/dl 0
liver disease will at some point develop organ dysfunction. This is usually in
association with advanced liver disease where the only option for treatment is 1.2 to 1.9 mg/dl 1
liver transplantation and the chances of reversibility of liver disease are very 2.0 to 5.9 mg/dl 2
limited. This is in contradistinction to the patient with acute-on chronic liver
failure (depicted by the blue line) who may often have a good liver reserve and 6.0 to 11.9 mg/dl 3
can deteriorate acutely over a short period, usually in association with a ≥12.0 mg/dl 4
precipitating illness that results in organ failure and high risk of death. The
patient may also have advanced liver disease but be stable and deteriorate Hypotension MAP ≥70 mmHg 0
acutely following a precipitating event, and progress to organ failure. By contrast, MAP <70 mmHg, 1
this patient has a potential for reversibility and recovery to the state the patient no pressor agents used
was in, prior to the acute event.
Dobutamine, any dose 2
Dopamine 5 µg/kg/min 2
that in patients with cirrhosis who present with acute deteriora- Dopamine >5 to 15 µg/kg/min 3
tion of cirrhosis due to a precipitating factor and progress to Dopamine >15 µg/kg/min 4
develop a single organ dysfunction have significantly different Epinephrine ≤0.1 µg/kg/min 3
outcome to those that do not develop a single organ dysfunction
Epinephrine >0.1 µg/kg/min 4
[4]. In a prospective study to explore this hypothesis, a group of
patients with liver cirrhosis that were admitted to a single unit Norepinephrine ≤0.1 µg/kg/min 3
over a 5.5-year period and managed according pre-defined man- Norepinephrine >0.1 µg/kg/min 4
agement guidelines were analyzed. Organ failure was defined as Glasgow coma score 15 0
the need for support of any organ. The patients were followed-up 13-14 1
clinically and biochemically until death or transplantation.
10-12 2
Among the approximately 500 patients studied, about one third
developed a single organ failure, of which 53% died during the 6-9 3
first hospital admission, also indicating that the occurrence of a 3-5 4
single organ dysfunction was reversible in nearly 50% of cases. Serum creatinine or Serum creatinine <1.2 mg/dl 0
The study also showed that both the severity of inflammation urine output Serum creatinine 1.2 to 1.9 mg/dl 1
and the occurrence of new infection were associated with a
Serum creatinine 2.0 to 3.4 mg/dl 2
higher risk of death [5].
The prognostic factors determining the outcome of patients Serum creatinine 3.5 to 4.9 mg/dl 3
with cirrhosis and multiorgan failure are currently under evalua- Urine output 200 to 499 ml/day 3
tion, but it seems that the scoring systems addressing the sever- Serum creatinine >5.0 mg/dl 4
ity of liver disease, such as Child-Pugh score [6] or Model of End
Urine output <200 ml/day 4
Stage Liver Disease (MELD) [7] perform less well than the scoring
MAP, mean arterial pressure.
systems addressing organ dysfunction such as the Sequential
Organ Failure Assessment (SOFA) (Table 1) [8] or the Acute Phys-
iology, Age and Chronic Health Evaluation (APACHE) [9] scores.
The available data describing the outcome of patients with cir-
rhosis who develop organ failure and are admitted to the ICU
are summarized in Table 2 and 3 [10–44]. Critical examination liver disease measured using conventional clinical and biochem-
of the data indicates two fundamentally important conclusions. ical testing (Child-Pugh score) that is important, but the degree of
First, the data suggest that the occurrence of an organ failure in end-organ failure that determines outcome. In these complex
patients with cirrhosis with a defined severity of liver disease patients, a concept similar to the PIRO concept in sepsis (predis-
indicates a poor prognosis with very wide survival figures, which position, infection/inflammation, response, organ failure) [45] might
is possibly related to criteria for ICU admission. This notion is be useful in describing pathophysiology and clinical categories
supported by the second conclusion that it is not the severity of (Fig. 2).

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

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

Pathophysiological basis
Precipitating event (I)
ACLF usually results following a precipitating event on the back-
ground of established cirrhosis. The ‘event’ may directly exagger-
ate liver injury such as alcoholic hepatitis, drug-induced liver
injury, superimposed viral hepatitis, portal vein thrombosis and
ischemic hepatitis or liver decompensation may be consequent
upon extra-hepatic insults such as trauma, surgery, variceal
bleeding or infection. In a proportion of patients, there may be
no identifiable precipitating event. The best studied precipitating
events are surgery and superimposed viral hepatitis in relation to
the development of ACLF. The most important predictors of
post-operative mortality were severity of liver disease as
determined by the MELD score, age, and the American Society
of Anesthesiologists (ASA) score [46]. Patients with a low MELD
score who die immediately following surgery often had cerebral
edema [47].
When HAV infection occurs in the setting of cirrhosis, there is
a substantial risk of ACLF and death [48]. Hepatitis E virus (HEV)
is an important cause of ACLF in Southern and Central Asia, China,
Africa, and the Indian subcontinent and leads to rapid hepatic
decompensation and death. In a prospective study of 107 patients
with cirrhosis of varying severity, mortality was much higher in
patients with superimposed HEV infection vs. non-infected cir-
rhotics. Mortality rate between HEV infected vs. non-infected cir-
rhotics at 4 weeks was 43% vs. 22% (p = 0.001) respectively and
70% vs. 30% (p = 0.001) at one year [49]. Patients who acquire
acute HBV infection in the setting of chronic liver disease are

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

Reference Number of Patient APACHE II APACHE III SOFA OFS Child-Pugh

patients selection (AUROC) (AUROC) (AUROC) (AUROC) score (AUROC)
Zauner et al., 1996 198 Cirrhosis on ICU 0.75 0.8 - - -
Zimmerman et al., 1996 117 Cirrhosis on ICU, Accurate for
MV risk stratification
Singh et al., 1998 54 Cirrhosis on ICU Predicts Does not
mortality predict mortality
Kress et al., 2000 138 Cirrhosis on ICU Predicts
mortality
Afessa et al., 2000 111 Cirrhosis on ICU, 0.78 0.76
bleeding
Wehler et al., 2001 143 Cirrhosis on ICU 0.79 0.94 0.74
Ho et al., 2003 135 Cirrhosis on ICU 0.833 0.75
Tsai et al., 2003 111 Cirrhosis on ICU 0.901 0.748
Chen et al., 2003 76 Cirrhosis on ICU, 0.887 0.900 0.706
bleeding
Tsai et al., 2004 160 Cirrhosis on ICU 0.892 0.906 0.712
Chen et al., 2004 67 Cirrhosis on ICU, 0.878 0.873
renal failure
Rabe et al., 2004 76 Cirrhosis on ICU, 0.66 0.87
MV
Gildea et al., 2004 420 Cirrhosis on ICU Predicts
mortality
Cholongitas et al., 2006 312 Cirrhosis on ICU 0.78 0.83 0.72
Chen et al., 2006 102 Cirrhosis on ICU 0.91 0.91
Jenq et al., 2007 134 Cirrhosis and 0.92
renal failure on ICU
Cholangitas et al., 2008 128 Cirrhosis on ICU 0.78 0.88 0.85 0.78
after 48 h
Fang et al., 2008 111 Cirrhosis on ICU
with renal failure
Juneja et al., 2009 104 Cirrhosis on ICU 0.90 0.93
Cholangitas et al., 2009 412 Cirrhosis on ICU 0.84
Thomson et al., 2010 137 Cirrhosis on ICU
Filloux et al., 2010 86 Cirrhosis on ICU
Juneja et al., 2011 73 Cirrhosis on ICU 0.77 0.94 0.83
requiring mechanical
ventilation
Levesque et al., 2012 377 Cirrhosis on ICU 0.92 0.79
Cavallazzi et al., 441 Cirrhosis on ICU
2012
ICU, intensive care unit; MV, mechanical ventilation.

more likely to suffer decompensation, which is common in carri-
ers who receive immunosuppressive therapy [50,51]. In a study
from India, patients with reactivation of HBV and ACLF were
shown to have improved survival if they were treated with ten-
ofovir compared with no therapy [52]. Although the ethics of this
study can be questioned, it illustrates that early intervention may
prevent occurrence of multiorgan failure by aggressively target-
ing the precipitating event. This principle is also illustrated by
the demonstration that survival of patients with variceal bleeding
can be improved by the prompt use of antibiotics, which reduces
the risk of infection [53]. Rapid control of the bleeding episode
with the insertion of a transjugular intrahepatic stent shunt in
patients with advanced liver disease or those with active
bleeding saves lives [54,55]. It is likely that the common end
point that leads from the precipitating event to the development
of ACLF is an altered host response to injury, resulting in an
inappropriate inflammatory response and immune dysfunction
increasing the susceptibility to infection [56].
Inflammation and infection (R)
The role of a systemic inflammatory response (SIRS), which is a
collection of simple and relatively crude clinical and hematolog-
ical measure using heart and respiratory rate, white cell count,
and temperature, in determining the outcome of patients with
liver failure was first fully described in the acute liver failure,

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

Predisposition Severity of cirrhosis • Aetiology Early identification

• Pugh score Risk stratification
• MELD Preventative strategies
• [Biomarkers] [Novel interventions]

Injury Precipitating event • Hepatic Rapid intervention to treat event

• Extra-hepatic Bundles of care
• [Therapies] [Novel interventions]

• Inflammation Vigilance, monitoring

Response Inflammation • Immune failure Goal directed approaches
• [Biomarkers] [Biomarkers and novel interventions]

Organ Organ failure • SOFA Intensive care, organ support

• APACHE Liver transplantation
• [Biomarkers] [Liver support, stem cell therapies]

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

where the presence of SIRS was associated with more severe
encephalopathy, associated infection, renal failure, and poor
outcome [57–59]. Elevated levels of multiple pro- and anti-
inflammatory cytokines have been described in ACLF including
TNF-a, sTNF-aR1, sTNF-aR2, IL-2, IL-2R, IL-6, IL-8, IL-10, and
IFN-! [60,61]. More recently, the mortality of patients presenting
with renal dysfunction of cirrhosis has been shown to be signifi-
cantly higher in the group with SIRS [62,63]. It is not surprising
that SIRS should be associated with increased inflammatory cyto-
kine response but the use of anti-TNF alpha strategies in patients
with alcoholic hepatitis who demonstrate an inflammatory
response is associated with an increased risk of infection and
mortality [64,65].
Infection is a common feature of ACLF, which complicates the
natural history and is associated with significant morbidity and
mortality [66]. About 40–50% of hospital admissions of cirrhotic
patients are with sepsis and a further 20–40% will develop noso-
comial infections. Overall in-hospital mortality rates of cirrhotic
patients with infection are about 15%, which is about twice those
without infection. The mortality rate of cirrhotic patients with
severe bacterial infection with septic shock is about 60–100%
[66–70]. In cirrhotic patients, sepsis is a common precipitating
event resulting in hepatic encephalopathy, renal dysfunction
and rebleeding, and mortality associated with variceal bleeding.
Vigilance, repeated cultures from various sites, cautious use of
in-dwelling cannulas and very early treatment remain the cor-
nerstones of therapy. The relationship between the SIRS response
and infection leads one to hypothesise that an inflammatory
response may lead to immune dysregulation, which may predis-
pose to infection that would then further aggravate a pro-inflam-
matory response resulting in a vicious cycle [56]. This
immunopathology of ACLF is reminiscent of the multimodal
immunological response observed in patients with severe sepsis,
which is characterised by an initial SIRS response followed by a
mixed (MARS) and subsequently compensated anti-inflammatory
response (CARS) (Fig. 3 and 4).
The associated mechanisms of this phenomenon are not clear
but immune paresis has been suggested as a possible mechanism
[71–73]. A recent study in cirrhotic patients suggested that a
genetic predisposition may underlie the risk of infection. The
investigators focussed on Toll-like receptor (TLR) 2 and nucleo-
tide-binding oligomerisation domain (NOD) 2 which recognize
pathogen-associated molecular patterns (PAMS). In a multivari-
ate analysis, they confirmed that TLR2 GT microsatellite polymor-
phism and NOD2 variants were independent predictors of
spontaneous bacterial peritonitis (SBP) when both risk factors
were present, the risk of SBP was dramatically increased (odds
ratio: 11.3; p = 0.00002) [74]. In alcoholic hepatitis patients,
neutrophil activation indicated by increased resting burst and
reduced phagocytic function was predictive of subsequent

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Liver failure/bacterial translocation SIRS: Systemic inflammatory response

• Endotoxemia
• Reduced protein/complement synthesis
• Reduced immune surveillance Normal

Immune response
• Reduced albumin function ACLF: survivor
ACLF: non-survivor

Immune paralysis

Innate immunity Adaptive immunity

• Neutrophils: phagocytic defect • T-cell exhaustion
• Monocytes: DR loss • Inability to profilerate CARS: Compensatory anti-inflammatory response
• NK cells • Increased apoptosis

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

Bacterial translocation
Bacterial infection

SIRS

Worsening systemic and

hepatic hemodynamics/
liver function

Compensated
cirrhosis

Increasing portal
pressure, fibrosis Multiorgan failure Death
and vasodilatation • Hypotension
• Renal failure
Decompensated • Jaundice
cirrhosis • Coagulopathy
• Encephalopathy
• VH
• Ascites
• HE

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

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infection, organ failure and mortality [72]. Importantly, data from
ex vivo studies showed that this neutrophil dysfunction was
reversible and possibly due to a circulating humoral factor that
was hypothesised to be endotoxin [72]. In another study,
monocyte HLA-DR expression was significantly reduced in ACLF
who also showed an inability to produce TNF-a, the severity of
which correlated with survival [71–73]. These observations
provide potential biomarkers to predict infection risk and allow
individualisation of therapy. Modulation of enteric microflora
with probiotic therapy has been shown to restore neutro-
phil phagocytic capacity [75]. In a randomised clinical trial,
administration of the granulocyte-colony stimulating factor was
associated with improved survival of patients with ACLF [76].
The study included 47 patients with ACLF using the APASL defini-
tion and the investigators showed a very high 2-month mortality
of 71% in the untreated group compared with about 30% in the
treated group. Clearly, this study will need to be repeated with
larger numbers of patients but provides the proof of concept
that modulation of immune paresis may prevent the progression
of ACLF.
The organs in ACLF (O)
Liver and hepatic hemodynamics
The hallmark of the liver manifestation of ACLF is hyperbilirubi-
nemia and coagulopathy but the pathophysiological basis is
unclear. It is likely that the histopathological characteristics of
the liver during ACLF will be determined by the underlying cause
of cirrhosis and the nature of the precipitating event. The occur-
rence of ACLF due to a non-specific insults such as infection or a
variceal bleeding is likely to be different from the effect of direct
hepatotoxins such as drugs or superimposed viral hepatitis.
Recent studies in patients with acute deterioration of alcoholic
cirrhosis and resultant ACLF showed presence of SIRS and biliru-
binostatis as early markers to identify these high-risk patients
[77,78]. The investigators made the important observation that
the presence of bilirubinostasis was associated with an increased
risk of subsequent infection. In another study, in a similar popu-
lation, the role of bilirubinostasis was confirmed and the investi-
gators also observed that K8/18 immunostaining was reduced
suggesting loss of cellular actin and microtubular structure,
which was associated with important prognostic information
[79]. At present, there is no clarity on the mechanism of cell-
death or capacity for regeneration of ACLF livers. Early biopsy
may help in both the management of patients and providing an
understanding of the mechanisms involved, as new drugs, such
as pan-caspase inhibitors or stimulators of hepatic regeneration,
may be useful [80].
Liver inflammation is an important determinant of portal
pressure and prognosis in cirrhosis. Patients with ACLF that
occurs on the background of alcoholic hepatitis have increased
plasma TNF-a level and also the highest portal pressures [81].
Indeed anti-TNF-a therapy has been shown to reduce portal
pressure in patients with severe alcoholic hepatitis and cirrhosis
[81]. Several lines of evidence exist implicating gut-derived
endotoxemia in the pathogenesis of portal hypertension [82].
Modulation of the portal bacterial load using antibiotics such
as quinolones and rifaxamin has been associated with a
reduction in inflammation and portal pressure [83,84]. Endotoxin
1342 Journal of Hepatology 2012 vol. 57 j 1336–1348
neutralisation with high density lipoprotein administration has
been associated with a reduction in portal pressure [85]. An
increase in reactive oxidant species, in particular superoxide, is
also observed in ACLF, contributing to an increase in intrahepatic
resistance by reducing nitric oxide bioavailability [86]. In patients
with ACLF, defined according to APASL criteria, no differences in
the portal hemodynamics between decompensated cirrhosis and
ACLF were observed [87], but using the EASL-AASLD definition,
the portal pressure was markedly higher [88] in those with ACLF
pointing to the need to carefully define the population under
study.
Hepatic eNOS activity has been shown to be reduced in the
context of cirrhosis with superadded inflammation [89,90]. NOS
activity is subject to regulation by a number of inhibitors such
as asymmetric dimethylarginine (ADMA), which is increased dur-
ing inflammation resulting in high ADMA levels [91]. This has
been suggested as both a prognostic marker and a possible target
of therapy. Evidence suggests that in addition to decreased nitric
oxide generation, there is also a reduced response to nitric oxide
in cirrhotic livers likely caused by dysfunction of the cyclic GMP
system. Phosphodiesterase-5 inhibitors such as sildenafil, which
increase cGMP, have been shown to have a beneficial effect on
intrahepatic resistance [92]. Further studies are therefore needed
in ACLF in whom both liver blood flow and intrahepatic resis-
tance are altered.
Kidney dysfunction
HRS is thought to be a functional disorder secondary to circula-
tory dysfunction in which there is splanchnic vasodilatation, a
lowering of arterial blood pressure, intense renal vasoconstric-
tion, impaired cardiac function and marked activation of the sym-
pathetic and neurohormonal systems [93–95]. However, in
patients with ACLF who present with renal dysfunction, the char-
acteristics may be widely variable. Thus, in some patients the cir-
culatory changes may predominate, and in other patients there
may be increased synthesis of pro-inflammatory mediators or
both. Administration of terlipressin and albumin remains the cur-
rent gold standard for treatment of patients with HRS, but is
unsuccessful in 54% of patients [96]. It is likely that in these latter
patients different factors predominate in the development of
renal dysfunction. In about 30–40% of patients with cirrhosis
who develop renal dysfunction, a bacterial infection is the precip-
itating cause (SBP) [94]. Indeed, the presence of SIRS in patients
with renal dysfunction was associated with infection in 56% of
the subjects, which was a major independent prognostic factor
for mortality in these patients [63]. Traditionally, renal dysfunc-
tion has been suggested to be reversible with transplantation.
However, recent data suggests that patients that are transplanted
with evidence of renal tubular injury on the background of cir-
rhosis are more likely to require renal replacement therapy after
transplantation than patients undergoing transplantation with
HRS, suggesting that the basis of renal dysfunction in ACLF is
not the same as HRS [97]. The important pathophysiological role
of inflammation in modulating renal dysfunction associated with
ACLF is highlighted by the benefit of anti-inflammatory agents
such as albumin, pentoxifylline and N-acetylcysteine, which
decreased the risk of renal dysfunction in patients with alcoholic
hepatitis [98,99]. Albumin in this situation probably acts as an
anti-inflammatory agent and has been shown to protect the kid-
ney during spontaneous bacterial peritonitis and is associated

with improved survival in patients with renal failure [100,101].
Administration of prophylactic norfloxacin, a selective gut decon-
taminant reduced the incidence of renal failure and improved
survival [102]. The mechanism of the protective effect of norflox-
acin was explored in animal models of cirrhosis and AKI and
shown to result from modulation of renal NFkB and cytokines
possibly mediated through a TLR4-based mechanism. In a preli-
minary observation, increased TLR4 has been shown in renal
tubules in ACLF patients, which was not observed in HRS [103].
These data provide potential novel insights into pathophysiology
and the potential for the development of novel biomarkers and
therapeutic approaches. Thus, the use of urinary biomarkers that
reflect renal injury may allow early diagnosis of renal dysfunction
of cirrhosis and allow the functional causes of renal dysfunction
to be better distinguished from the inflammatory causes. The bio-
markers of interest are markers of tubular injury such as kidney
injury molecule-1, pi and alpha glutathione S-transferase; mark-
ers of inflammation such as NAG, NGAL, FABP, and IL-18 [104]. It
is possible that novel therapeutic approaches may be developed if
this hypothesis can be confirmed.
Brain dysfunction
Hepatic encephalopathy (HE) is a common manifestation of ACLF
[1,105–107]. Local and systemic changes have been implicated in
the pathophysiology of the development of this neurological syn-
drome. From the pathophysiological perspective, like the situa-
tion in acute liver failure, brain swelling is an important feature
of ACLF also [105–108]. As the syndrome occurs on the back-
ground of existing cirrhosis and chronic portacaval shunting, a
degree of brain atrophy protects from this brain swelling, result-
ing in an increase in intracranial pressure. There are, however,
several reports of significant increases in intracranial pressure
in patients with ACLF [105–107]. Studies using MRI have shown
that this increase in brain swelling can be reversed with liver
transplantation supporting the notion that, like acute liver fail-
ure, the brain manifestation of ACLF is a reversible disorder
[109]. Ammonia is thought to play a key role in the development
of HE but no direct relationship between the severity of hyperam-
monemia and HE could be demonstrated [110]. On the back-
ground of this hyperammonemia, an added hepatic insult and/
or superimposed inflammation leads to the development of brain
edema suggesting a synergy between ammonia and inflamma-
tion. The synergy between ammonia and inflammation has been
demonstrated in animal models of cirrhosis where acute brain
swelling was observed following administration of endotoxin
mimicking the clinical situation seen in ACLF [108]. The mecha-
nism is likely to be related to generation of cytokines in the brain,
increased iNOS expression, oxidative stress and formation of
nitrated protein adducts [108,111]. Studies in animal models
have suggested that ammonia may prime the brain to the delete-
rious effects of superimposed inflammation by induction of
microglial cells, which have a huge repertoire for cytokine pro-
duction; and a reduction in ammonia in cirrhotic models pre-
vents the effect of superimposed inflammation [108,111–113].
Conversely, reduction in bacterial translocation using a non-
absorbable antibiotic, rifaximin was shown to prevent the occur-
rence of HE, suggesting that reducing inflammation may be pro-
tective as well [114]. Cerebral blood flow is known to be
progressively reduced in cirrhosis but in ACLF may be paradoxi-
cally increased as seen in patients with acute liver failure. In a
Journal of Hepatology 2012 vol. 57 j 1336–1348
JOURNAL OF HEPATOLOGY
Acute on Chronic Liver Failure
Inflammation Hyperammonemia
Astrocytic swelling
Activation of transcription factors
Activation of NFkB Cytokines
Oxidative stress
iNOS; nitrotyrosine
Hepatic Encephalopathy
Fig. 5. Pathophysiological mechanisms of brain dysfunction in acute-on
chronic liver failure. This figure describes the possible mechanisms underlying
the pathogenesis of hepatic encephalopathy in acute-on chronic liver failure. It is
likely that similar mechanisms are operative in other organs, where susceptibility
to an inflammatory insult is provided by organ characteristics that are a feature of
that particular organ in cirrhosis.
recent study, the acute effect of insertion of a transjugular intra-
hepatic shunt, which is known to induce endotoxemia, was stud-
ied in patients with cirrhosis. The study demonstrated that TIPSS-
induced endotoxemia led to an increase in the rate of production
of nitric oxide, which was associated with endothelial dysfunc-
tion and increased cerebral blood flow supporting the hypothesis
that multiple hits and brain swelling is a feature of ACLF [115]
(Fig. 5). However, the insertion of TIPSS in relatively well cirrho-
tics without hepatic encephalopathy undergoing TIPSS was not
associated with a change in cerebral blood flow, stressing the
pathophysiologically distinct nature of ACLF from otherwise sta-
ble cirrhosis [116].
Cardiac and systemic hemodynamics
In patients with decompensated cirrhosis, a hyperdynamic cir-
culation is the key hemodynamic feature. The increased cardiac
output observed in this situation is mainly due to a vasodilated
splanchnic bed but paradoxically, the blood flow in other
organ, such as kidneys, brain and peripheral organs, is
decreased [117]. Additionally, patients with cirrhosis may have
an underlying cirrhotic cardiomyopathy, which may make
them susceptible to cardiovascular collapse during an acute
inflammatory insult, but data supporting that hypothesis does
not exist [118]. The hallmark of ACLF is cardiovascular collapse
akin to the patients with acute liver failure and severe sepsis,
often requiring large doses of inotropes. Unlike decompensated
cirrhosis, where the cardiac output remains elevated, in ACLF,
1343
Review
despite splanchnic vasodilation, the cardiac output can be
reduced and both systolic and diastolic functions are affected.
This cardiovascular abnormality is associated with increased
risk of death, particularly in those patients who present with
renal dysfunction [119]. In another study, where the definition
of ACLF was based upon the APASL criteria, no differences in
cardiac output were observed, highlighting the fact that the
designation is crucial in defining which patients are being
described. The mechanisms underlying the cardiac dysfunction
in ACLF are likely similar to those in severe sepsis, such as car-
diovascular-active factors like TNF and nitric oxide which are
increased, and cortisol which is decreased [120]. The former
can further dilate the vasculature and the latter decreases the
sensitivity to vasoconstrictors. However, no study has yet dem-
onstrated the benefit of vasodilators/vasoconstrictors in the
management of ACLF. It is important to monitor the cardiac
situation using appropriate methods to guide fluid replacement
and inotrope support. The choice of inotropes is also unclear
but vasopressin analogue in this situation should be used cau-
tiously as it may further reduce cardiac perfusion and an
already compromised hepatic blood flow [121].
Coagulation
Routine diagnostic tests of coagulation are usually abnormal
in patients with cirrhosis due to multiple defects. An
increased bleeding tendency has been attributed to the degree
of abnormalities in these tests, but this has not been formally
proven [122]. Thrombin generation is normal in stable cirrho-
tics with a rebalancing of pro- and anti-coagulant factors (pro-
viding there are sufficient platelets >50,000  109/L). Since
hypercoagulation may exist [123], bleeding abnormalities are
far less frequent than it would be expected [124]. In cirrhosis
with sepsis, endogenous low-molecular weight heparinoids are
detected, and disappear with resolution of infection [68]. Anti-
biotics are known to reduce early variceal rebleeding rates
[125]. The use of prophylactic blood products to correct
abnormalities to prevent bleeding is empirical and often
guided by local protocols; virtually none of these are evi-
dence-based [126]. Moreover, normalization of abnormal coag-
ulation parameters is difficult to achieve, and creates volume
excess, increasing the risk of transfusion-related acute lung
injury and other transfusion reactions. Even recombinant fac-
tor VIIa, which corrects prothrombin time, does not reduce
blood loss during variceal bleeding [127]. Conversely, antifibri-
nolytic agents do reduce blood loss during liver transplanta-
tion, but have not been evaluated prophylactically during
other procedures or for bleeding. Apart from increased fibrino-
lysis, which is seen in ACLF, defective platelet function is the
other major abnormality [128]. The thrombopoietin analog
eltrombopag may be thrombogenic at least in stable cirrhosis
(there has been a suspended trial in this area), probably
because of the interaction with the very high levels of vWF
in cirrhosis. The use of fresh frozen plasma is limited by the
volume of transfusions; safer prothrombin complex concen-
trates which have 20 times the concentration of factors than
FFP are now available [129]. Currently, prophylactic transfu-
sions of any coagulation products are difficult to justify and
it is likely that more comprehensive, global tests of coagula-
tion are needed to guide the correction of coagulation on an
individual basis [130].
1344 Journal of Hepatology 2012 vol. 57 j 1336–1348
Hepato-adrenal axis
Adrenal insufficiency is reported in 51–68% of patients with
cirrhosis and severe sepsis, particularly in patients with high
Child-Pugh and MELD scores and hemodynamic instability.
Adrenal insufficiency is associated with increased mortality
compared to patients without adrenal insufficiency [131].
Administration of hydrocortisone to patients with septic shock
and adrenal insufficiency was shown to improve the circulatory
function but routine use of hydrocortisone during sepsis has
not been confirmed to improve the outcome [132]. Interpreta-
tion of response to synacthen test in cirrhosis and ACLF is dif-
ficult due to methodological constraints, so no conclusions can
be made.
Intensive care management, organ support and
transplantation
Intensive care management of patients with ACLF has been
recently reviewed and a full description is beyond the scope
of this review. The essential principles are those of multiple
organ support to allow the treatment of the precipitating
event and the recovery of the liver. The two specific aspects
of treatment relevant to this group of patients are discussed
below [3].
Liver support devices are intended to provide detoxification
functions to patients with ACLF until liver transplantation, recov-
ery or futility. The overall efficacy of liver support devices have
failed to reach a level sufficient to gain approval for widespread
use [133]. Liver support devices are of two main types; artificial
livers-acellular devices such as albumin dialysis and plasma-
exchange/diafiltration, and bio-artificial livers, which incorporate
cells from human, animal, or transformed sources. An unpub-
lished study using the ELAD device which incorporates liver can-
cer cells, C3A cells, into the device, was shown in a preliminary
study to be useful in patients with ACLF, mainly induced by
HBV reactivation in a small randomised controlled study [134].
A pivotal clinical trial in USA and Europe has been stopped. None
of the bioartificial liver devices as far as we know, are in clinical
trials for ACLF patients at present.
The best studied artificial liver support devices are the
molecular adsorbents recirculating system (MARS) and Prome-
theus devices, which are based upon the principles of albumin
dialysis [135]. These devices are based on the concept that albu-
min is a complex molecule with a plethora of physiological
functions besides providing oncotic properties [136]. Studies
have demonstrated that during hepatic failure, the circulating
albumin undergoes structural and functional modifications that
negatively affect its biological activity [136]. These devices are
designed to provide additional detoxification functions. Several
studies have confirmed that the use of these devices can remove
inflammatory molecules, reduce NO and improve systemic and
hepatic hemodynamics, severe hepatic encephalopathy leading
to large clinical trials [61]. The randomised controlled trial of
the Prometheus device in patients with ACLF has been recently
published [137]. The data show that the approach is safe and
well tolerated, although there is no overall significant survival
benefit at 28 days. Subgroup analysis suggested that patients
with a MELD score of >30 and those with hepatorenal syndrome
may have some benefit. MARS was tested in a similar cohort,

the RELIEF trial, which has been reported in a preliminary com-
munication and again failed to show any survival benefit [138].
A better definition of ACLF would allow the study of a more
homogenous cohort, but it is likely that modifications to the
current devices will be necessary to improve their efficacy and
capacity.
Liver transplantation in patients with ACLF has not been sys-
tematically analysed but a recent retrospective study was per-
formed in 332 patients of whom 157 patients had ACLF and
175 patients had no ACLF pre-transplant [139]. Thirty-four
patients received a liver-kidney transplant, of whom 10
(29.4%) had ACLF. The definition was based on a rapid increase
in MELD by >5 points. The results showed that the group with
ACLF had a 26% mortality compared with a mortality of 17% in
the non-ACLF group. The difference was statistically different in
univariate analysis, but when only single organ transplants
were analysed, the results were not statistically different. On
multivariate analysis, ACLF was not an independent predictor
of post-transplant mortality, arguing strongly that this is a
good indication for transplantation [139]. The timing of trans-
plantation is crucial as patients with ACLF may provide a win-
dow of opportunity. Therefore, living-donor transplantation is
an attractive option, the experience of which has been reported
extensively from South-East Asia, mainly in patients with ACLF
resulting from re-activation of hepatitis B virus infection. The
data from Hong Kong suggests that although the patients with
ACLF and HRS had stormier post-operative course, living donor
transplantation could be performed safely and overall there
were no significant differences in survival with 5-year survivals
of about 80% [140]. Similar observations have been made
regarding the safety and feasibility of living donor transplanta-
tion from the Chinese groups [141]. Currently, in most coun-
tries there is no priority for ACLF patients who have
significantly higher short-term mortality. A better understand-
ing of the natural history and prognostic criteria will allow
ACLF to be incorporated as a possible new indication for high
urgency allocation.
Conclusions and future perspectives
In conclusion, ACLF is a devastating syndrome with inordinately
high mortality, which is clinically, pathophysiologically and
prognostically a distinct clinical entity, but the condition has
not yet been defined. In order to fill this knowledge gap, groups
in Europe, US and Asia have started to study this entity as part
of large consortia. One such consortium in Europe, the EASL
CLIF-Consortium, has just finished the recruitment of 1400
patients prospectively; the results of the study are eagerly
awaited [142]. It is likely that a better definition will require
new biomarkers, which will allow the development of new
drugs and devices and, therefore, engagement with the industry
will be crucial to bring these emerging treatments to patients.
The liver transplant community will need to be engaged to
define which patients with ACLF should be transplanted and
define new allocation policy. Finally, it is likely that there will
be a resurgence of research activity in cirrhosis to allow the
determination of modifiable factors that predispose to ACLF,
and likely to personalise their management based on clinical
and genetic factors.
Journal of Hepatology 2012 vol. 57 j 1336–1348
JOURNAL OF HEPATOLOGY
Key Points
• Acute-on chronic liver failure is a syndrome that defines
a subgroup of cirrhotic patients who develop organ
failure following hospital admission with or without an
identifiable precipitating event and have increased
mortality rates
• Altered host response to injury such as deranged
systemic inflammatory response plays an important
pathophysiological role
• Bacterial infection that occurs on the background of
varying degrees of immune paralysis plays an important
role in determining the outcome of this syndrome
• Systemic, cardiac and hepatic hemodynamics are
important determinants of outcome
• The end-organs such as the kidney and the brain show
evidence of inflammation
• Survival of patients is dependent upon the severity of
organ failure
• Treatment strategies are limited to organ support but
better understanding of the pathophysiology is likely to
lead to discovery of novel biomarkers and therapeutic
strategies
Conflict of interest
The authors declared that they do not have anything to disclose
regarding funding or conflict of interest with respect to this
manuscript.
Acknowledgements
A lot of the manuscript is based around the discussions during a
meeting that took place at Atlanta, 2010; ‘Intensive Care of the
Patient with Acute-on Chronic Liver Failure: Summary of an
American Association for the Study of Liver Diseases and
European Association for the Study of the Liver Single Topic
Conference.’
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