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 Clnic, University of Barcelona, Barcelona, Catalunya, Spain, Institut dInvestigacions Biomdiques
August-Pi-Sunyer (IDIBAPS), Centro de Investigacin Biomdica en Red de Enfermedades Hepticas yDigestivas (CIBEREHED), Spain; 3Division of
Gastroenterology and Hepatology, Mayo Clinic, College of Medicine, Rochester, MN, United States; 4INSERM, U773, Centre de Recherche
Biomdicale Bichat-Beaujon CRB3, Paris and Clichy, France; 5Section of Digestive Diseases, Yale University School of Medicine,
New Haven, CT, United States

Summary
Acute-on-chronic liver failure (ACLF) is an increasingly recognised entity encompassing an acute deterioration of liver function
in patients with cirrhosis, which is usually associated with a
precipitating event and results in the failure of one or more
organs and high short term mortality. Prospective data to dene
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.
2012 European Association for the Study of the Liver. Published
by Elsevier B.V. All rights reserved.

manifesting as jaundice and coagulopathy, complicated within

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 denitions are too imprecise to
allow homogeneous diagnostic criteria and clinical studies are currently underway to reach an evidence-based denition. The latter
denition implies that organ failure is a central component of this
syndrome and leads to the hypothesis that the organs may behave
differently to chronic decompensated liver disease. This review
focuses upon the current understanding of this syndrome from
the clinical, prognostic and pathophysiologic perspectives and
indicates potential biomarkers and therapeutic targets for intervention. It is the second denition that will be used in the description 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
specic precipitating event can be found. Although the exact pathophysiology of the development of ACLF remains to be elucidated,
unregulated inammation 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 5090% [1]. The condition
remains undened but two consensus working denitions for this
syndrome exist. The rst was put forward by the AsiaPacic
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 monitoring, 26,300 patients were identied. 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 signicant proportion of these patients had ACLF
but is difcult to conrm until evidence-based denition of ACLF
is derived.

Keywords: Acute-on chronic liver failure; Hepatorenal syndrome; Hepatic encephalopathy; Immune failure; Liver support; Liver transplantation.
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
Digestive Health, UCL Medical School, Royal Free Hospital, Rowland Hill Street,
London NW3 2PF, United Kingdom. Tel.: +44 2074332795.
E-mail address: r.jalan@ucl.ac.uk (R. Jalan).

Clinical and prognostic factors (P)

Data on the natural history of patients with cirrhosis progressing
to multiorgan failure and its outcome are limited. In a study
reported in a preliminary form, the group at UCL hypothesized

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JOURNAL OF HEPATOLOGY
Table 1. SOFA scoring system.

Acute insult

Liver function (%)

100

Organ

Measurement

Score

PaO2 to FIO2 ratio

400 mmHg

300 to 399 mmHg

200 to 299 mmHg

Threshold for organ failure

?Too late!
Chronic decompensation
of cirrhosis

Platelet count

Months
Fig. 1. Acute-on chronic liver failure: diagrammatic representation of the
clinical concept. This gure describes the clinical concept of ACLF to distinguish
it from chronic decompensated cirrhosis. The red line describes the course of a
patient with chronic decompensation of cirrhosis that during evolution of their
liver disease will at some point develop organ dysfunction. This is usually in
association with advanced liver disease where the only option for treatment is
liver transplantation and the chances of reversibility of liver disease are very
limited. This is in contradistinction to the patient with acute-on chronic liver
failure (depicted by the blue line) who may often have a good liver reserve and
can deteriorate acutely over a short period, usually in association with a
precipitating illness that results in organ failure and high risk of death. The
patient may also have advanced liver disease but be stable and deteriorate
acutely following a precipitating event, and progress to organ failure. By contrast,
this patient has a potential for reversibility and recovery to the state the patient
was in, prior to the acute event.

that in patients with cirrhosis who present with acute deterioration of cirrhosis due to a precipitating factor and progress to
develop a single organ dysfunction have signicantly different
outcome to those that do not develop a single organ dysfunction
[4]. In a prospective study to explore this hypothesis, a group of
patients with liver cirrhosis that were admitted to a single unit
over a 5.5-year period and managed according pre-dened management guidelines were analyzed. Organ failure was dened as
the need for support of any organ. The patients were followed-up
clinically and biochemically until death or transplantation.
Among the approximately 500 patients studied, about one third
developed a single organ failure, of which 53% died during the
rst hospital admission, also indicating that the occurrence of a
single organ dysfunction was reversible in nearly 50% of cases.
The study also showed that both the severity of inammation
and the occurrence of new infection were associated with a
higher risk of death [5].
The prognostic factors determining the outcome of patients
with cirrhosis and multiorgan failure are currently under evaluation, but it seems that the scoring systems addressing the severity of liver disease, such as Child-Pugh score [6] or Model of End
Stage Liver Disease (MELD) [7] perform less well than the scoring
systems addressing organ dysfunction such as the Sequential
Organ Failure Assessment (SOFA) (Table 1) [8] or the Acute Physiology, Age and Chronic Health Evaluation (APACHE) [9] scores.
The available data describing the outcome of patients with cirrhosis who develop organ failure and are admitted to the ICU
are summarized in Table 2 and 3 [1044]. Critical examination
of the data indicates two fundamentally important conclusions.
First, the data suggest that the occurrence of an organ failure in
patients with cirrhosis with a dened severity of liver disease
indicates a poor prognosis with very wide survival gures, which
is possibly related to criteria for ICU admission. This notion is
supported by the second conclusion that it is not the severity of

Serum bilirubin

Hypotension

100 to 199 mmHg

<100 mmHg

150,000 per l

100,000 to 149,999 per l

50,000 to 99,999 per l

20,000 to 49,999 per l

<20,000 per l

<1.2 mg/dl

1.2 to 1.9 mg/dl

2.0 to 5.9 mg/dl

6.0 to 11.9 mg/dl

12.0 mg/dl

MAP 70 mmHg

MAP <70 mmHg,

no pressor agents used
Dobutamine, any dose

Dopamine >5 to 15 g/kg/min

Dopamine >15 g/kg/min

Epinephrine 0.1 g/kg/min

Epinephrine >0.1 g/kg/min

Norepinephrine 0.1 g/kg/min

Norepinephrine >0.1 g/kg/min

Glasgow coma score 15

Serum creatinine or
urine output

Dopamine 5 g/kg/min

4
0

13-14

10-12

6-9

3-5

Serum creatinine <1.2 mg/dl

Serum creatinine 1.2 to 1.9 mg/dl 1

Serum creatinine 2.0 to 3.4 mg/dl 2
Serum creatinine 3.5 to 4.9 mg/dl 3
Urine output 200 to 499 ml/day

Serum creatinine >5.0 mg/dl

Urine output <200 ml/day

MAP, mean arterial pressure.

liver disease measured using conventional clinical and biochemical testing (Child-Pugh score) that is important, but the degree of
end-organ failure that determines outcome. In these complex
patients, a concept similar to the PIRO concept in sepsis (predisposition, infection/inammation, response, organ failure) [45] might
be useful in describing pathophysiology and clinical categories
(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

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

63

Gildea et al., 2004

420

Cirrhosis on ICU

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

Chen et al., 2006

102

Cirrhosis on ICU

Jenq et al., 2007

134

Cirrhosis on ICU

Cholongitas et al., 2008

128

Cirrhosis on ICU after 48 h

Fang et al., 2008

111

Cirrhosis on ICU, renal failure

Juneja et al., 2009

104

Cirrhosis on ICU

42

Cholongitas et al., 2009

412

Cirrhosis on ICU

61

69 (1-yr mortality)

58

88
68
68

55
82
56

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 background of established cirrhosis. The event may directly exaggerate liver injury such as alcoholic hepatitis, drug-induced liver
injury, superimposed viral hepatitis, portal vein thrombosis and
ischemic hepatitis or liver decompensation may be consequent
upon extra-hepatic insults such as trauma, surgery, variceal
bleeding or infection. In a proportion of patients, there may be
no identiable 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

1338

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 cirrhotics. Mortality rate between HEV infected vs. non-infected cirrhotics at 4 weeks was 43% vs. 22% (p = 0.001) respectively and
70% vs. 30% (p = 0.001) at one year [49]. Patients who acquire
acute HBV infection in the setting of chronic liver disease are

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JOURNAL OF HEPATOLOGY
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
Zauner et al., 1996

Number of Patient
patients
selection
198
Cirrhosis on ICU

Zimmerman et al., 1996

117

Singh et al., 1998

54

Cirrhosis on ICU,
MV
Cirrhosis on ICU

Kress et al., 2000

138

Cirrhosis on ICU

Afessa et al., 2000

111

Wehler et al., 2001

143

Cirrhosis on ICU,
bleeding
Cirrhosis on ICU

Ho et al., 2003

135

Cirrhosis on ICU

Tsai et al., 2003

111

Cirrhosis on ICU

Chen et al., 2003

76

Cirrhosis on ICU,
bleeding
Cirrhosis on ICU

Tsai et al., 2004

160

Chen et al., 2004

67

Rabe et al., 2004

76

Gildea et al., 2004

APACHE II
(AUROC)
0.75

APACHE III
(AUROC)
0.8

SOFA
OFS
Child-Pugh
(AUROC) (AUROC) score (AUROC)
-

Accurate for
risk stratification
Predicts
mortality
Predicts
mortality
0.78

Does not
predict mortality

0.76

0.79

0.94

0.74

0.833

0.75
0.901

0.887

0.900
0.892

0.66

420

Cirrhosis on ICU,
renal failure
Cirrhosis on ICU,
MV
Cirrhosis on ICU

0.878

Cholongitas et al., 2006

312

Cirrhosis on ICU

0.78

Chen et al., 2006

102

Cirrhosis on ICU

Jenq et al., 2007

134

Cholangitas et al., 2008

128

Fang et al., 2008

111

Juneja et al., 2009

104

Cirrhosis and
renal failure on ICU
Cirrhosis on ICU
after 48 h
Cirrhosis on ICU
with renal failure
Cirrhosis on ICU

Cholangitas et al., 2009

412

Cirrhosis on ICU

Thomson et al., 2010

Filloux et al., 2010
Juneja et al., 2011

137
86
73

Levesque et al., 2012

Cavallazzi et al.,
2012

377
441

Cirrhosis on ICU
Cirrhosis on ICU
Cirrhosis on ICU
requiring mechanical
ventilation
Cirrhosis on ICU
Cirrhosis on ICU

0.748
0.706

0.906

0.712

0.873
0.87

Predicts
mortality
0.72

0.83
0.91

0.91
0.92

0.78

0.88

0.90

0.93

0.85

0.78

0.84

0.77

0.94

0.83

0.92

0.79

ICU, intensive care unit; MV, mechanical ventilation.

more likely to suffer decompensation, which is common in carriers 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 tenofovir 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 targeting the precipitating event. This principle is also illustrated by
the demonstration that survival of patients with variceal bleeding
can be improved by the prompt use of antibiotics, which reduces
the risk of infection [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 inammatory response and immune dysfunction
increasing the susceptibility to infection [56].
Inammation and infection (R)
The role of a systemic inammatory response (SIRS), which is a
collection of simple and relatively crude clinical and hematological measure using heart and respiratory rate, white cell count,
and temperature, in determining the outcome of patients with
liver failure was rst 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
Pugh score
MELD
[Biomarkers]

Early identification
Risk stratification
Preventative strategies
[Novel interventions]

Injury

Precipitating event

Hepatic
Extra-hepatic
[Therapies]

Rapid intervention to treat event

Bundles of care
[Novel interventions]

Response

Inflammation

Inflammation
Immune failure
[Biomarkers]

Vigilance, monitoring
Goal directed approaches
[Biomarkers and novel interventions]

Organ

Organ failure

SOFA
APACHE
[Biomarkers]

Intensive care, organ support

Liver transplantation
[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 inammation and risk of infection. Organs by the extent of organ failure. Categorisation of patients into these entities allows denition of
interventions and helps dene prognosis at different levels.

where the presence of SIRS was associated with more severe

encephalopathy, associated infection, renal failure, and poor
outcome [5759]. Elevated levels of multiple pro- and antiinammatory 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 signicantly higher in the group with SIRS [62,63]. It is not surprising
that SIRS should be associated with increased inammatory cytokine response but the use of anti-TNF alpha strategies in patients
with alcoholic hepatitis who demonstrate an inammatory
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 signicant morbidity and
mortality [66]. About 4050% of hospital admissions of cirrhotic
patients are with sepsis and a further 2040% will develop nosocomial infections. Overall in-hospital mortality rates of cirrhotic
patients with infection are about 15%, which is about twice those
without infection. The mortality rate of cirrhotic patients with
severe bacterial infection with septic shock is about 60100%
[6670]. 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
1340

in-dwelling cannulas and very early treatment remain the cornerstones of therapy. The relationship between the SIRS response
and infection leads one to hypothesise that an inammatory
response may lead to immune dysregulation, which may predispose to infection that would then further aggravate a pro-inammatory 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-inammatory
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
[7173]. A recent study in cirrhotic patients suggested that a
genetic predisposition may underlie the risk of infection. The
investigators focussed on Toll-like receptor (TLR) 2 and nucleotide-binding oligomerisation domain (NOD) 2 which recognize
pathogen-associated molecular patterns (PAMS). In a multivariate analysis, they conrmed that TLR2 GT microsatellite polymorphism and NOD2 variants were independent predictors of
spontaneous bacterial peritonitis (SBP) when both risk factors
were present, the risk of SBP was dramatically increased (odds
ratio: 11.3; p = 0.00002) [74]. In alcoholic hepatitis patients,
neutrophil activation indicated by increased resting burst and
reduced phagocytic function was predictive of subsequent

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JOURNAL OF HEPATOLOGY
SIRS: Systemic inflammatory response

Liver failure/bacterial translocation

Immune paralysis

Innate immunity
Neutrophils: phagocytic defect
Monocytes: DR loss
NK cells

Normal
ACLF: survivor
ACLF: non-survivor

Immune response

Endotoxemia
Reduced protein/complement synthesis
Reduced immune surveillance
Reduced albumin function

Adaptive immunity
T-cell exhaustion
Inability to profilerate
Increased apoptosis

CARS: Compensatory anti-inflammatory response

Fig. 3. Immune dysfunction of acute-on chronic liver failure. This gure 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-inammatory to
an anti-inammatory state, making them susceptible to infection. It is likely that the patients that do not resolve the compensated anti-inammatory 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
and vasodilatation

Multiorgan failure

Decompensated
cirrhosis

Death

Hypotension
Renal failure
Jaundice
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 brosis 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 signicant 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 inammatory response. VH, variceal hemorrhage; HE, hepatic
encephalopathy.

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Review
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 signicantly reduced in ACLF
who also showed an inability to produce TNF-a, the severity of
which correlated with survival [7173]. These observations
provide potential biomarkers to predict infection risk and allow
individualisation of therapy. Modulation of enteric microora
with probiotic therapy has been shown to restore neutrophil 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 denition and the investigators showed a very high 2-month mortality
of 71% in the untreated group compared with about 30% in the
treated group. Clearly, this study will need to be repeated with
larger numbers of patients but provides the proof of concept
that modulation of immune paresis may prevent the progression
of ACLF.

The organs in ACLF (O)

Liver and hepatic hemodynamics
The hallmark of the liver manifestation of ACLF is hyperbilirubinemia and coagulopathy but the pathophysiological basis is
unclear. It is likely that the histopathological characteristics of
the liver during ACLF will be determined by the underlying cause
of cirrhosis and the nature of the precipitating event. The occurrence of ACLF due to a non-specic insults such as infection or a
variceal bleeding is likely to be different from the effect of direct
hepatotoxins such as drugs or superimposed viral hepatitis.
Recent studies in patients with acute deterioration of alcoholic
cirrhosis and resultant ACLF showed presence of SIRS and bilirubinostatis as early markers to identify these high-risk patients
[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 population, the role of bilirubinostasis was conrmed and the investigators also observed that K8/18 immunostaining was reduced
suggesting loss of cellular actin and microtubular structure,
which was associated with important prognostic information
[79]. At present, there is no clarity on the mechanism of celldeath 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 inammation 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 inammation and portal pressure [83,84]. Endotoxin

1342

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, dened according to APASL criteria, no differences in
the portal hemodynamics between decompensated cirrhosis and
ACLF were observed [87], but using the EASL-AASLD denition,
the portal pressure was markedly higher [88] in those with ACLF
pointing to the need to carefully dene the population under
study.
Hepatic eNOS activity has been shown to be reduced in the
context of cirrhosis with superadded inammation [89,90]. NOS
activity is subject to regulation by a number of inhibitors such
as asymmetric dimethylarginine (ADMA), which is increased during inammation 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 sildenal, which
increase cGMP, have been shown to have a benecial effect on
intrahepatic resistance [92]. Further studies are therefore needed
in ACLF in whom both liver blood ow and intrahepatic resistance are altered.
Kidney dysfunction
HRS is thought to be a functional disorder secondary to circulatory dysfunction in which there is splanchnic vasodilatation, a
lowering of arterial blood pressure, intense renal vasoconstriction, impaired cardiac function and marked activation of the sympathetic and neurohormonal systems [9395]. However, in
patients with ACLF who present with renal dysfunction, the characteristics may be widely variable. Thus, in some patients the circulatory changes may predominate, and in other patients there
may be increased synthesis of pro-inammatory mediators or
both. Administration of terlipressin and albumin remains the current gold standard for treatment of patients with HRS, but is
unsuccessful in 54% of patients [96]. It is likely that in these latter
patients different factors predominate in the development of
renal dysfunction. In about 3040% of patients with cirrhosis
who develop renal dysfunction, a bacterial infection is the precipitating 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 dysfunction has been suggested to be reversible with transplantation.
However, recent data suggests that patients that are transplanted
with evidence of renal tubular injury on the background of cirrhosis are more likely to require renal replacement therapy after
transplantation than patients undergoing transplantation with
HRS, suggesting that the basis of renal dysfunction in ACLF is
not the same as HRS [97]. The important pathophysiological role
of inammation in modulating renal dysfunction associated with
ACLF is highlighted by the benet of anti-inammatory 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-inammatory agent and has been shown to protect the kidney during spontaneous bacterial peritonitis and is associated

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JOURNAL OF HEPATOLOGY
with improved survival in patients with renal failure [100,101].
Administration of prophylactic noroxacin, a selective gut decontaminant reduced the incidence of renal failure and improved
survival [102]. The mechanism of the protective effect of noroxacin was explored in animal models of cirrhosis and AKI and
shown to result from modulation of renal NFkB and cytokines
possibly mediated through a TLR4-based mechanism. In a preliminary observation, increased TLR4 has been shown in renal
tubules in ACLF patients, which was not observed in HRS [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
reect 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 inammatory causes. The biomarkers of interest are markers of tubular injury such as kidney
injury molecule-1, pi and alpha glutathione S-transferase; markers of inammation such as NAG, NGAL, FABP, and IL-18 [104]. It
is possible that novel therapeutic approaches may be developed if
this hypothesis can be conrmed.

Acute on Chronic Liver Failure

Inflammation

Hyperammonemia

Astrocytic swelling

Activation of transcription factors

Activation of NFkB

Cytokines

Oxidative stress
iNOS; nitrotyrosine

Brain dysfunction
Hepatic encephalopathy (HE) is a common manifestation of ACLF
[1,105107]. Local and systemic changes have been implicated in
the pathophysiology of the development of this neurological syndrome. From the pathophysiological perspective, like the situation in acute liver failure, brain swelling is an important feature
of ACLF also [105108]. As the syndrome occurs on the background of existing cirrhosis and chronic portacaval shunting, a
degree of brain atrophy protects from this brain swelling, resulting in an increase in intracranial pressure. There are, however,
several reports of signicant increases in intracranial pressure
in patients with ACLF [105107]. Studies using MRI have shown
that this increase in brain swelling can be reversed with liver
transplantation supporting the notion that, like acute liver failure, the brain manifestation of ACLF is a reversible disorder
[109]. Ammonia is thought to play a key role in the development
of HE but no direct relationship between the severity of hyperammonemia and HE could be demonstrated [110]. On the background of this hyperammonemia, an added hepatic insult and/
or superimposed inammation leads to the development of brain
edema suggesting a synergy between ammonia and inammation. The synergy between ammonia and inammation 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 mechanism 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 deleterious effects of superimposed inammation by induction of
microglial cells, which have a huge repertoire for cytokine production; and a reduction in ammonia in cirrhotic models prevents the effect of superimposed inammation [108,111113].
Conversely, reduction in bacterial translocation using a nonabsorbable antibiotic, rifaximin was shown to prevent the occurrence of HE, suggesting that reducing inammation may be protective as well [114]. Cerebral blood ow is known to be
progressively reduced in cirrhosis but in ACLF may be paradoxically increased as seen in patients with acute liver failure. In a

Hepatic Encephalopathy
Fig. 5. Pathophysiological mechanisms of brain dysfunction in acute-on
chronic liver failure. This gure 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 inammatory 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 intrahepatic shunt, which is known to induce endotoxemia, was studied in patients with cirrhosis. The study demonstrated that TIPSSinduced endotoxemia led to an increase in the rate of production
of nitric oxide, which was associated with endothelial dysfunction and increased cerebral blood ow 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 cirrhotics without hepatic encephalopathy undergoing TIPSS was not
associated with a change in cerebral blood ow, stressing the
pathophysiologically distinct nature of ACLF from otherwise stable cirrhosis [116].
Cardiac and systemic hemodynamics
In patients with decompensated cirrhosis, a hyperdynamic circulation is the key hemodynamic feature. The increased cardiac
output observed in this situation is mainly due to a vasodilated
splanchnic bed but paradoxically, the blood ow 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
inammatory 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,

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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 denition
of ACLF was based upon the APASL criteria, no differences in
cardiac output were observed, highlighting the fact that the
designation is crucial in dening which patients are being
described. The mechanisms underlying the cardiac dysfunction
in ACLF are likely similar to those in severe sepsis, such as cardiovascular-active factors like TNF and nitric oxide which are
increased, and cortisol which is decreased [120]. The former
can further dilate the vasculature and the latter decreases the
sensitivity to vasoconstrictors. However, no study has yet demonstrated the benet of vasodilators/vasoconstrictors in the
management of ACLF. It is important to monitor the cardiac
situation using appropriate methods to guide uid replacement
and inotrope support. The choice of inotropes is also unclear
but vasopressin analogue in this situation should be used cautiously as it may further reduce cardiac perfusion and an
already compromised hepatic blood ow [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 cirrhotics with a rebalancing of pro- and anti-coagulant factors (providing there are sufcient 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]. Antibiotics 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 evidence-based [126]. Moreover, normalization of abnormal coagulation parameters is difcult to achieve, and creates volume
excess, increasing the risk of transfusion-related acute lung
injury and other transfusion reactions. Even recombinant factor VIIa, which corrects prothrombin time, does not reduce
blood loss during variceal bleeding [127]. Conversely, antibrinolytic agents do reduce blood loss during liver transplantation, but have not been evaluated prophylactically during
other procedures or for bleeding. Apart from increased brinolysis, 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 concentrates which have 20 times the concentration of factors than
FFP are now available [129]. Currently, prophylactic transfusions of any coagulation products are difcult to justify and
it is likely that more comprehensive, global tests of coagulation are needed to guide the correction of coagulation on an
individual basis [130].

1344

Hepato-adrenal axis
Adrenal insufciency is reported in 5168% of patients with
cirrhosis and severe sepsis, particularly in patients with high
Child-Pugh and MELD scores and hemodynamic instability.
Adrenal insufciency is associated with increased mortality
compared to patients without adrenal insufciency [131].
Administration of hydrocortisone to patients with septic shock
and adrenal insufciency was shown to improve the circulatory
function but routine use of hydrocortisone during sepsis has
not been conrmed to improve the outcome [132]. Interpretation of response to synacthen test in cirrhosis and ACLF is difcult 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 specic aspects
of treatment relevant to this group of patients are discussed
below [3].
Liver support devices are intended to provide detoxication
functions to patients with ACLF until liver transplantation, recovery or futility. The overall efcacy of liver support devices have
failed to reach a level sufcient to gain approval for widespread
use [133]. Liver support devices are of two main types; articial
livers-acellular devices such as albumin dialysis and plasmaexchange/dialtration, and bio-articial livers, which incorporate
cells from human, animal, or transformed sources. An unpublished study using the ELAD device which incorporates liver cancer cells, C3A cells, into the device, was shown in a preliminary
study to be useful in patients with ACLF, mainly induced by
HBV reactivation in a small randomised controlled study [134].
A pivotal clinical trial in USA and Europe has been stopped. None
of the bioarticial liver devices as far as we know, are in clinical
trials for ACLF patients at present.
The best studied articial liver support devices are the
molecular adsorbents recirculating system (MARS) and Prometheus devices, which are based upon the principles of albumin
dialysis [135]. These devices are based on the concept that albumin 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 modications that
negatively affect its biological activity [136]. These devices are
designed to provide additional detoxication functions. Several
studies have conrmed that the use of these devices can remove
inammatory 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 signicant survival
benet at 28 days. Subgroup analysis suggested that patients
with a MELD score of >30 and those with hepatorenal syndrome
may have some benet. MARS was tested in a similar cohort,

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JOURNAL OF HEPATOLOGY
the RELIEF trial, which has been reported in a preliminary communication and again failed to show any survival benet [138].
A better denition of ACLF would allow the study of a more
homogenous cohort, but it is likely that modications to the
current devices will be necessary to improve their efcacy and
capacity.
Liver transplantation in patients with ACLF has not been systematically analysed but a recent retrospective study was performed in 332 patients of whom 157 patients had ACLF and
175 patients had no ACLF pre-transplant [139]. Thirty-four
patients received a liver-kidney transplant, of whom 10
(29.4%) had ACLF. The denition 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 transplantation is crucial as patients with ACLF may provide a window of opportunity. Therefore, living-donor transplantation is
an attractive option, the experience of which has been reported
extensively from South-East Asia, mainly in patients with ACLF
resulting from re-activation of hepatitis B virus infection. The
data from Hong Kong suggests that although the patients with
ACLF and HRS had stormier post-operative course, living donor
transplantation could be performed safely and overall there
were no signicant differences in survival with 5-year survivals
of about 80% [140]. Similar observations have been made
regarding the safety and feasibility of living donor transplantation from the Chinese groups [141]. Currently, in most countries there is no priority for ACLF patients who have
signicantly higher short-term mortality. A better understanding of the natural history and prognostic criteria will allow
ACLF to be incorporated as a possible new indication for high
urgency allocation.

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

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

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 dened. In order to ll 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 nished the recruitment of 1400
patients prospectively; the results of the study are eagerly
awaited [142]. It is likely that a better denition 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
dene which patients with ACLF should be transplanted and
dene new allocation policy. Finally, it is likely that there will
be a resurgence of research activity in cirrhosis to allow the
determination of modiable factors that predispose to ACLF,
and likely to personalise their management based on clinical
and genetic factors.

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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