Você está na página 1de 18

PRIMER

Acuteonchronic liver failure in cirrhosis


Vicente Arroyo13, Richard Moreau1,37, Patrick S.Kamath8, Rajiv Jalan1,3,9,10,
PereGins1,3,11, Frederik Nevens1,3,12, Javier Fernndez1,3,11, Uyen To13,14,
GuadalupeGarca-Tsao13,14 and Bernd Schnabl15,16
Abstract | The definition of acuteonchronic liver failure (ACLF) remains contested. In Europe and
North America, the term is generally applied according to the European Association for the Study of
the Liver-Chronic Liver Failure (EASL-CLIF) Consortium guidelines, which defines this condition as a
syndrome that develops in patients with cirrhosis and is characterized by acute decompensation,
organ failure and high short-term mortality. One-third of patients who are hospitalized for acute
decompensation present with ACLF at admission or develop the syndrome during hospitalization.
ACLF frequently occurs in a closed temporal relationship to a precipitating event, such as bacterial
infection or acute alcoholic, drug-induced or viral hepatitis. However, no precipitating event can be
identified in approximately 40% of patients. The mechanisms of ACLF involve systemic inflammation
due to infections, acute liver damage and, in cases without precipitating events, probably intestinal
translocation of bacteria or bacterial products. ACLF is graded into three stages (ACLF grades 13)
onthe basis of the number of organ failures, with higher grades associated with increased mortality.
Liver and renal failures are the most common organ failures, followed by coagulation, brain, circulatory
and respiratory failure. The 28day mortality rate associated with ACLF is 30%. Depending on the
grade, ACLF can be reversed using standard therapy in only 1651% of patients, leaving a considerable
proportion of patients with ACLF that remains steady or progresses. Liver transplantation in selected
patients with ACLF grade 2 and ACLF grade 3 increases the 6month survival from 10% to 80%.

Cirrhosis is a progressive chronic liver disease character Third, new mechanisms involved in the pathogenesis of
ized by diffuse fibrosis, severe disruption of the intra cirrhotic complications, such as dysbiosis of the micro
hepatic venous flow, portal hypertension and liver failure. biota6 and systemic inflammation7 have been recognized.
The course of cirrhosis is divided into two stages1 (FIG.1). Last, it is increasingly evident that patients rarely die as
Compensated cirrhosis defines the period between the a consequence of an end-stage irreversible destruction
onset of cirrhosis and the first major complication. of the liver. Rather, in most patients, the cause of death
During this period, which is relatively long in most is an acute deterioration in their clinical condition pro
patients (>10 years), symptoms are absent or minor, but moted by a precipitating event a s yndrome termed
liver lesions and portal p ressure steadily progress. The acuteonchronic liver failure (ACLF)8.
term decompensated cirrhosis defines theperiod follow More than 13 distinct definitions of ACLF have been
ing the development ofascites (thatis,the accumulation proposed. These definitions are generally based on
of large amountsof fluid within the peritoneal cavity), personal experience or consensus agreements915 (BOX1).
variceal haemorrhage and/or hepatic encephalo The Asian Pacific Association for the Study of the
pathy 24. This period is a ssociated with shortterm Liver (APASL) definition has received major attention11,12
survival(35years). (BOX1). This definition is based on positive and negative

Correspondence to V.A.
Concepts about cirrhosis are rapidly changing. First, criteria. The main positive criteria are: prior diagnosis of
European Foundation for the cirrhosis is no longer considered to be an irreversible chronic liver disease (cirrhotic or non-cirrhotic, exclud
Study of Chronic Liver Failure progressive disease. Indeed, decompensated cirrhosis ing isolated steatosis); a precipitating event that has a
(EFCLIF), Travessera de may return to compensated cirrhosis or even to pre direct effect on the liver; and acute hepatic insult that
Gracia 11, 08021Barcelona,
cirrhotic phases if the cause of the disease is removed5. causes acute liver failure. The main negative criteria in the
Spain.
vicente.arroyo@efclif.com Second, the list of organ or system dysfunctions in APASL definition are: no prior history of acute decom
cirrhosis (hepatic, renal, brain and circulatory) has been pensation in patients with cirrhosis (decompensated
Article number: 16041
doi:10.1038/nrdp.2016.41 expanded to include the immune system, intestines, cirrhosis would represent the presence of end-stage pro
Published online 9 June 2016 heart, lungs, adrenal glands, muscles and thyroid glands. gressive liver disease); and no extrahepatic precipitating

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 1



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Author addresses It has been suggested that differences between


APASL and EASL-CLIF Consortium definitions are
1
European Foundation for the Study of Chronic Liver Failure (EFCLIF), logical consequences of the distinct epidemiology of
TravesseradeGracia 11, 08021 Barcelona, Spain. liver diseases in the east and in the west 28,33. However,
2
Grifols Chair for the Study of Cirrhosis, Barcelona, Spain. the differences are more likely to be related to the dis
3
European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF)
tinct objectives by which both definitions were designed.
Consortium, Barcelona, Spain.
4
Inserm, U 1149, Centre de Recherche sur lInflammation (CRI), Paris, France. The ACLF definition by the APASL consensus group
5
Universit Paris Diderot, Facult de Mdecine, Paris, France. was designed to identify a condition that anticipates the
6
Dpartement Hospitalo-Universitaire (DHU) UNITY, Service dHpatologie, development of extrahepatic or multiple organ failure
HpitalBeaujon, APHP, Clichy, France. and death11,12. By contrast, the goal of the CANONIC
7
Laboratoire dExcellence (Labex) Inflamex, ComUE Sorbonne Paris Cit, Paris, France. study was to characterize a syndrome in which organ
8
Division of Gastroenterology, Hepatology and Internal Medicine, Mayo Clinic College failure (or failures) and high short-term mortality are
ofMedicine, Rochester, Minnesota, USA. central features8.
9
Institute of Hepatology, UCL Medical School, London, UK. Attempts to unify both definitions have not been
10
Royal Free Hospital, UCL Medical School, London, UK. successful34. Recent investigations from Asia have com
11
Liver Unit, Hospital Clinic, University of Barcelona, Barcelona, Spain.
pared the two definitions in a large series of patients
12
Department of Hepatology, University Hospitals KU Leuven, Leuven, Belgium.
13
Yale Digestive Diseases, Temple Medical Center, New Haven, Connecticut, USA. with cirrhosis23,26,35. FIGURE2 compares the results of
14
Veterans Administration, Yale-New Haven Hospital, New Haven, Connecticut, USA. the largest Asian series35 with those in the CANONIC
15
Department of Medicine, University of California San Diego, La Jolla, San Diego, study 8. Acoincident diagnosis by the APASL and the
California, USA. EASL-CLIF Consortium definitions was observed in
16
Department of Medicine, VA San Diego Health Care System, San Diego, California, USA. only a minority of patients in both series, indicating
that the two ACLF definitions selected different patient
populations (FIG. 2a) . The EASL-CLIF Consortium
event, such as bacterial infection. TheAPASL definition definition was significantly more accurate in predict
was based on a consensus conference. ing prognosis than the APASL definition in both the
The APASL proposal did not reach wide diffusion eastern and the western populations (FIG.2b). Significant
in Europe and North America for several reasons. First, differences in mortality depending on the diagnostic
the most common form of ACLF in these areas occurs criteria were also observed in two other cohorts of
in patients with decompensated cirrhosis in a closed patients from China23 and India26. This Primer on ACLF
temporal relationship with bacterial infections or active in cirrhosis uses the EASL-CLIF Consortium defin
alcoholism8,13 (FIG.1), and these patients are not included ition. The reader is referred to a review by Sarin and
in the APASL definition. Second, the concept that Choudhury 36 for a discussion of ACLF that is based on
decompensated cirrhosis represents a terminal phase of the APASL criteria.
the disease is not the experience of European centres.
Third, extrahepatic organ failure is the most character Epidemiology
istic differential feature between patients with ACLF and Worldwide prevalence and mortality
those with acute decompensation in European patients. ACLF is a major worldwide medical problem, with
Last, ACLF in patients with non-cirrhotic chronic liver prevalence rates in atrisk populations in the region
disease is exceptional in Europe and North America of2035% (TABLE1). The worldwide reported mortal
owing to the low prevalence of hepatitis A virus, ity of ACLF according to the EASL-CLIF Consortium
hepatitisB virus (HBV) and hepatitisE virus infections. definition ranges between 30% and 50% and correlates
For these reasons, in 2009, the European Association closely with the number of organ failures. In Europe,
for the Study of the Liver-Chronic Liver Failure the average 28day mortality rate without liver trans
(EASLCLIF) Consortium started a prospective, multi plantation reported by the CANONIC study was 1.9%
centre European observational study in 1,343 patients in patients with decompensated cirrhosis without ACLF
who were hospitalized for acute decompensation of and 32.8% in patients with ACLF (23% in patients with
cirrhosis (the CANONIC study). This study aimed to ACLF grade1, 31% in patients with ACLF grade2
define ACLF in cirrhosis, to assess the prevalence and and 74% in patients with ACLF grade 3; see BOX 2
clinical course of the syndrome and to improve the accu fordetails)8.
racy of the prognostic scores currently available8,1620 In the United States, a study using the North-
through an evidence-based pragmatic approach. The American Consortium for the Study of End Stage
analysis of this study lead to a new definition with three Liver Disease (NACSELD) criteria (BOX 1) reported
major characteristics (BOX1): acute decompensation that the 30day mortality rate associated with infected
of cirrhosis; the presence of organ failure (or failures, decompensated cirrhosis without ACLF was 8% and
which can be either hepatic or extrahepatic); and a high this rate increased to 27% in patients with one, 49%
probability of short-term (28day) mortality. Following inpatients with two, 64% in patients with three and
the publication of the main articles derived from the 77% in patientswith four organ failures13. In addi
CANONIC study, the definition, grading of severity of tion, in Asia, no significant reduction in mortality in
ACLF and prognostic scores proposed are widely used in patients with ACLF has been observed over the past
Europe, Asia and North America for the assessment and two decades, withmortality in the nationwide sample
treatment of patients with decompensated cirrhosis2132. approaching50%36.

2 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

In China, the average 28day transplant-free mor or hepatitis E virus infection38, acute alcoholic hepati
tality reported by Li etal.24 in patients with decompen tis and acute bacterial infection are the most frequent
sated cirrhosis due to chronic HBV infection was 2.6% in precipitating events of ACLF in Asia23. In the west, the
patients without ACLF and 44% in patients with ACLF. most common precipitating events are active alcohol
This study used the EASL-CLIF Consortium definition ism and bacterial infections, although in a considerable
of ACLF and found mortality rates of 23.6% in patients proportion of patients there is no recognizable precipi
with ACLF grade 1, 40.8% in patients with ACLF grade 2 tating event 8. The potential role of drug-induced liver
and 60.2% in patients with ACLF grade 3 (REF.24). Zhang injury (DILI) as a precipitating event in ACLF has been
etal.23 reported similar findings in Chinese patients with insufficiently explored in both the east and thewest.
decompensated cirrhosis of different aetiologies. The
90day mortality rate in patients without ACLF was 2.1% Organ failures
and in patients with ACLF grade 1 was 39.9%, ACLF In the CANONIC study8, among the different organ and
grade 2 was 54.1% and ACLF grade 3 was 84.7% (using system failures in ACLF, the most frequently affected
the EASL-CLIF Consortium definition)23. organs or systems were the kidneys (55.8% of patients),
followed by the liver (43.6% of patients), coagulation
Precipitating events (27.7% of patients), the brain (24.1% of patients), circula
Precipitating events of ACLF vary according to geo tion (16.8% of patients) and the lungs (9.2% of patients).
graphical areas and can be classified as hepatic or extra At first glance, it might be surprising that not all patients
hepatic depending on their site of origin14,34,3739 (FIG.1). with ACLF had liver failure, but there are two important
Reactivation of chronic HBV, acute hepatitis A virus issues that should be taken into account. First, thelevel

Acute decompensation Organ or system failure


Organ failure (or failures) Liver Coagulation
High short-term mortality Kidney Circulation
Brain Lung

Precipitating events Acute-on-chronic


Liver brosis (portal pressure) and liver failure

Hepatic liver failure


Excessive alcohol intake Organ or system
DILI dysfunction
Viral hepatitis (A, B, C, D and E) Liver
Ischaemic hepatitis Kidney
TIPS Brain
Liver surgery Coagulation
Extrahepatic Circulation
Acute bacterial infection Heart
Paracentesis without albumin Acute decomposition Intestine
Major surgery Ascites Thyroid gland
Non-identiable precipitating Gastrointestinal Lung
event (4050%) haemorrhage Immune
Encephalopathy Adrenal gland
Bacterial infection Muscle

Time

Precirrhotic disease Compensated cirrhosis Decompensated cirrhosis


Liver
1035 years 1015 years 35 years transplantation
or death

Treatment Treatment
Figure 1 | The clinical course of cirrhosis. Acuteonchronic liver failure (ACLF) can develop at any stage from
compensated to decompensated cirrhosis, and can involve hepatic or extrahepatic precipitating events. A| Disease
Nature Reviews considerable
Primers
proportion of patients have no identifiable triggering event. In this figure, paracentesis means large volume paracentesis
(>5 litres). Acute decompensation of cirrhosis defines the acute development of clinically evident ascites, hepatic
encephalopathy, gastrointestinal haemorrhage or any combination of these in patients with or without prior history of
these complications. Although bacterial infections are not specific complications of cirrhosis, they are considered as such
in patients with prior history of ascites, haemorrhage or encephalopathy because of their high prevalence and their
association with abnormalities related to cirrhosis, including bacterial translocation and impaired leukocyte function18.
DILI, drug-induced liver injury; TIPS, transjugular intrahepatic portosystemic shunt. Figure is adapted from an image
provided courtesy of Jordi Bozzo, Avinguda de la Generalitat, Barcelona, Spain.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 3



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

of bilirubin used to define liver failure was very high The development of complications, mainly ascites
(12mg per dl) and most (if not all) patients without liver and, less frequently, variceal haemorrhage or hepatic
failure also had abnormal bilirubin values, which implies encephalopathy, marks the onset of decompensated
a variable degree of impairment of liver function in these cirrhosis. Decompensated cirrhosis is characterized by
patients. Second, it is important to note that the definition impairment in the function of the liver and extrahepatic
of ACLF goes beyond the classic concept of decompen organs and systems, including: the brain (disturbances
sation of cirrhosis and includes the consequences of affecting cognitive, psychiatric and motor functions
cirrhosis on the function of otherorgans7. ranging from subclinical alterations to severe stupor and
coma); the kidneys (impairment in renal sodium and free
Mechanisms/pathophysiology water excretion, intrarenal haemodynamics, renal perfu
ACLF during the course of cirrhosis sion and glomerular filtration rate); circulation (splanch
As indicated, cirrhosis is a progressive disease that inevit nic arterial vasodilation leading to r eduction in systemic
ably leads to death unless the aetiological mechanism vascular resistances and high c ardiac output); the lungs
is suppressed by appropriate treatment or a liver trans (impairment in the ventilation/perfusion ratio leading
plantation is performed. Indeed, there is good evidence to hypoxia and hypocapnia); the heart (impairment in
that discontinuation of alcohol ingestion in alcoholic chronotropic and left ventricular systolic and diastolic
cirrhosis, antiviral treatment in chronic HBV-related functions); coagulation (as a result of impairment in
and hepatitisC virus-related cirrhosis and immuno the hepatic synthesis of coagulant and anticoagulant
suppressive therapy in autoimmune cirrhosis may trans factors and increased fibrinolysis); the adrenal glands
form decompensated cirrhosis to compensated cirrhosis (impaired ability to provide adequate cortisol release
or even to precirrhotic phases5. By contrast, if the aetio in response to stress); the intestines (reduced motility,
logical mechanisms persist in patients with compen bacterial overgrowth and increased permeability of the
sated cirrhosis, hepatic fibrosis increases progressively mucosal barrier leading to increased translocation of
as a consequence of continuous liver cell necrosis and bacteria and/or bacterial products from the intestinal
inflammation, giving rise to progressive distortion of lumen to the systemic circulation); the immune system
the liver architecture, reduction in liver parenchyma (systemic inflammation and impaired function of poly
cells, increase in the intrahepatic resistance to the portal morphonuclear leukocytes and monocytes); the thyroid
venous flow, portal hypertension, liver insufficiency and glands (impaired hormonal secretion); and muscles
acute decompensation of the disease (FIG.1). (sarcopaenia) (FIG.1).
ACLF may develop at any phase of the disease from
compensated to early or late decompensated cirrhosis
Box 1 | The main definitions of ACLF (FIG.1). Thus, it is not a terminal event of a long-standing
The APASL definition decompensated cirrhosis. As indicated above (BOX2),
For patients with compensated cirrhosis or with any kind of non-cirrhotic chronic liver organ failure is defined by an intense impairment in the
disease, except isolated steatosis (definition was first made in 2004 and revised in function of six specific organs or systems that are impor
2014)11,12, acuteonchronic liver failure (ACLF) is the result of an acute direct hepatic tant in determining prognosis (the liver, the kidneys and
insult (hepatotropic viral infections, active alcohol consumption or drug-induced liver the brain and the coagulation, circulatory and respiratory
injury) that causes liver failure. Liver failure is defined as jaundice (a serum bilirubin level systems)8. Organ failure is the feature that differentiates
of 5mg per dl) and coagulopathy (an international normalized ratio of 1.5 or ACLF from decompensated cirrhosis without ACLF.
prothrombin activity of <40%). This liver failure is complicated within 4weeks by clinical
Bycontrast, organ dysfunction, which defines a less severe
ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed
chronic liver disease (including cirrhosis). Both compensated cirrhosis and
impairment in the function of these (and other) organs
non-cirrhoticchronic liver disease (non-alcoholic fatty liver disease-related chronic and systems, is the differential feature of decompensated
hepatic injury or chronic hepatitis with fibrosis or fibrosis due to other reasons) qualify as cirrhosis versus compensated cirrhosis. For instance,
chronic liver disease. Bacterial infections are not considered hepatic insults. Patients according to the CANONIC study 8, brain failure is
with cirrhosis and known prior decompensation (jaundice, encephalopathy or ascites) defined by a hepatic encephalopathy grade3 or grade 4
who develop acute deterioration of their clinical status that is either related or unrelated of the West Haven classification, whereas brain dysfunc
to precipitating events are considered to have acute decompensation but not ACLF. tion is defined by a hepatic encephalopathy grade 1 or
The EASL-CLIF Consortium definition grade2. Similarly, renal dysfunction is defined by a serum
For patients with cirrhosis (2013)8, ACLF is the development of acute decompensation creatinine level of 1.51.9mg per dl, whereas renal failure
of cirrhosis (defined by the development of ascites, encephalopathy, gastrointestinal is defined be a serum creatinine level of 2mg perdl.
haemorrhage and/or bacterial infection) associated with either a single organ failure
(single renal failure or other single non-renal organ failure if associated with renal Inflammation in ACLF
and/or brain dysfunction) or multiple organ failures. ACLF is associated with features of systemic inflam
Other definitions mation. For example, white blood cell count and plasma
Jalan and Williams definition (2002)10 levels of Creactive protein and pro-inflammatory
The Chinese Medical Association definition (2013)15 cytokines and chemokines, such as IL6, IL1 and IL8,
The American Association for the Study of Liver Diseases and the EASL definition (2012)14 are higher in patients with ACLF than in patients with
North-American Consortium for the Study of End Stage Liver Disease definition (2014)13
cirrhosis without ACLF8,22. Moreover, among patients
with ACLF, the higher the ACLF severity, as estimated by
APASL, Asian Pacific Association for the Study of the Liver; EASL, European Association for the the number of organ failures, the higher the plasma pro-
Study of the Liver; EASL-CLIF, EASL-Chronic Liver Failure.
inflammatory cytokine or chemokine levels(R.M.andthe

4 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

a 100 b 1.2
Korean CANONIC

Proportion of patients diagnosed with ACLF (%)


90
1.0
80

Cumulative survival rate


70
0.8
60

50 0.6

40
0.4
30

20
0.2
10

0 0
Korean CANONIC 0 30 60 90 0 30 60 90
Study Survival time (days) Survival time (days)

APASL denition only


EASL-CLIF denition only No ACLF EASL-CLIF denition only
Both denitions APASL denition only Both denitions

Figure 2 | Different ACLF definitions capture different patient populations. a | The proportion of patients diagnosed
Nature Reviews | Disease Primers
with acuteonchronic liver failure (ACLF) according to the Asian Pacific Association for the Study of the Liver (APASL)
definition (green), the European Association for the Study of the Liver-Chronic Liver Failure (EASL-CLIF) Consortium
definition (red) and both definitions (blue). Data are from a large series of patients from Korea35 (1,470 patients, of which
1,352 patients had cirrhosis with or without prior history of decompensation) and from the CANONIC study8 carried out in
Europe. b | The 90day probability of survival in both series of patients depending on the ACLF diagnosis. Figures with
European data derive from unpublished results of the CANONIC study (R.M. and the CANONIC trialists, unpublished
observations). Partb (left panel) adapted from REF.35.

CANONICtrialists, unpublished observations). The Bacterial inducers of inflammation. Bacterial patho


excessive systemic production of pro-inflammatory gens can induce inflammation through two distinct
cytokines and chemokines or the cytokine storm classes of molecules: pathogen-associated molecular
by the patients immune system might cause collateral patterns (PAMPs)4244 and virulence factors42,45. PAMPs
tissue damage40, a process termed immunopathology 41. are recognized by the host via dedicated receptors called
As such, a cytokine storm might also be a prominent pattern recognition receptors (PRRs) and examples of
contributor to the development of organ failures in PRRs for bacterial ligands are detailed in FIG.3a4244. The
patients with cirrhosis. Of note, in patients with ACLF, engagement of PRRs results in the stimulation of signal
a subset of CD14+ monocytes show overexpression of ling cascades that activate transcription factors43. PRR-
the tyrosine-protein kinase MER (encoded by MERTK), activated transcription factors can induce an array of
which results in the inhibition of the production of genes that encode molecules involved in inflammation,
inflammatory cytokines by these cells22, suggesting that a including pro-inflammatory cytokines43,45,46 (FIG.3b).
form of c ompensatory immunosuppression develops in The second class of bacterial inducers of inflam
parallel to the systemic inflammatory response. mation includes a large number of virulence factors42,44.
There are two categories of ACLF: those in which Unlike PAMPs, most of these factors are generally not
the inducer (or inducers) of inflammation (for exam recognized by dedicated receptors but can be sensed by
ple, bacterial infection or excessive alcohol intake) the effects of their activity (a process called functional
are identified and those in which there is no clinically feature recognition)38,4648.
identifiable trigger (or triggers)8. In this Primer, the latter
category is called ACLF with no clinically identifiable Endogenous inducers of inflammation. Endogenous
trigger. Inducers of inflammation are either exogen inducers are released by necrotic cells or produced by
ous or endogenous42. Among exogenous inducers, we extracellular matrix (ECM) breakdown in an injured
discuss only bacterial inducers because the others are tissue (such as the diseased liver in the case of ACLF)42,43
beyond the scope of this Primer and have been described and are called damage-associated molecular patterns
elsewhere42. Although much of the molecular detail of (DAMPs)49. DAMPs can be recognized by certain recep
how inflammation triggers ACLF remains to be eluci tors of the host, with this recognition resulting in sterile
dated, it is likely that the following general processes inflammation. For example, high mobility group box1
play a key part. Bacterial inducers of inflammation and protein (HMGB1) engages the advanced glycosylation
endogenous inducers of inflammation are potential end product-specific receptor (RAGE), which cooperates
mechanisms of inflammation inACLF. with Toll-like receptors (TLRs; a class of PRRs) to induce

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 5



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Table 1 | Selected studies on the prevalence of ACLF elucidate the aetiological pathways of this syndrome.
Of all the recognized precipitating events in ACLF,
Country or Diagnostic Population Prevalence Refs the mechanisms underlying two sepsis and severe
region criteria of ACLF (%)
alcoholic hepatitis are the best characterized and
China EASL-CLIF 890 patients hospitalized with 34* 24 detailedbelow.
decompensated cirrhosis due to
chronic hepatitis B virus infection
Sepsis-induced ACLF. Organ dysfunction caused by a
China EASL-CLIF 1,397 patients hospitalized with 30* 97 dysfunctional host immune response to bacterial infec
decompensated cirrhosis due to
chronic hepatitis B virus infection tion defines sepsis-induced ACLF. 30% of patients with
cirrhosis and ACLF have bacterial sepsis as an identi
North NACSELD Patients with decompensated 24 13 fiable trigger of the syndrome8. However, ACLF can also
America cirrhosis and acute bacterial
infections predispose to bacterial infection; indeed, a proportion of
patients with ACLF develop bacterial infection during
Scandinavia EASL-CLIF Patients with cirrhosis 24 170
(from a population of 600,000) the course of the syndrome8. Among bacterial infec
tions, spontaneous bacterial peritonitis (SBP), sepsis
Europe EASL-CLIF 1,343 CANONIC study participants 30.9* 8 and pneumonia were more frequently associated with
ACLF, acute-on-chronic liver failure; EASL-CLIF, European Association for the Study of the ACLF than other infections in the CANONIC study 8.
Liver-Chronic Liver Failure; NACSELD, North-American Consortium for the Study of End Stage
Liver Disease. *At enrolment and during hospitalization. Patients with decompensated In patients with cirrhosis and ascites, viable intestinal
cirrhosis and bacterial infections who developed two organ failures. Infection-related ACLF bacteria can cross the intestinal barrier and migrate to
diagnosed between 2001 and 2010. the general circulation and colonize the ascitic fluid55,56.
During the first hours of bacterial infection,
an inflammatory response42,43,49. Additional factors that patients with cirrhosis have higher plasma levels of
might also be involved in ACLF include necrotic cells, pro-inflammatory cytokines than patients without
which may release members of the IL1 family such as cirrhosis.This finding suggests the existence of exces
IL1 and IL33 that trigger inflammation through their sive inflammation in cirrhosis57,58. The mechanisms that
respective myeloid differentiation primary response underlie this excessive inflammatory response to bac
protein 88 (MYD88)coupled cognate receptors50. terial infection are incompletely understood59. In fact,
most of our knowledge is based on experiments investi
Outcomes of the inflammatory response. The purpose gating the innate immune response to lipopolysacchar
of the inflammatory response to bacterial infection is to ide (LPS), a PAMP recognized by TLR4 (REFS5961)
promote host resistance by reducing bacterial b urden, (FIG.3). The response to LPS has been studied in exvivo
whereas that of sterile inflammation is to promote studies carried out in freshly isolated monocytes or
tissue repair 5154. However, when these two categories of peripheral blood mononuclear cells (PBMCs) from
inflammatory responses are excessive, they may induce patients with and without cirrhosis. LPS-stimulated pro
tissue damage52. During bacterial infection, the acute duction of pro-inflammatory cytokines and chemokines
phase of the inflammatory response can be excessive is higher in cells from patients with cirrhosis than in
and can cause immunopathology. For example, effec control cells6266. The mechanisms of the LPS-induced
tors of the immune response, such as recruited neutro cytokine storm associated with cirrhosis are poorly
phils and inflammatory monocytes, activated T helper1 understood. Ex vivo experiments have shown that
(TH1) and TH17 cells, and cytotoxic Tcells, are known PBMCs or monocytes from patients with cirrhosis show
to be associated with a high risk of immunopathology 44. defects in the following negative-feedback mechanisms
There are also some examples of DAMP-induced of TLR4 signalling: the activation of the phospho
excessive inflammatory response causing major tissue inositide 3kinase (PI3K)AKT pathway 61,65; inhibition
damage. Mice deficient for receptor-interacting serine/ of glycogen synthase kinase 3 activity 66; and the induc
threonine kinase 1 (Ripk1) develop RIPK3mixed tion of IL1 receptor-associated kinaseM (IRAKM;
lineage kinase domain-like protein (MLKL)-mediated also known as IRKA3)62 and of the anti-inflammatory
necroptosis resulting in systemic inflammation, multiple cytokine IL10 (REFS61,65). Nevertheless, several other
organ injury and death within 3days of birth50. In this crucial mechanisms known to downregulate the TLR-
model, IL33 (a DAMP) drives systemic inflammation mediated inflammatory response under non-cirrhotic
and severity. Therefore, the initial tissue injury caused by conditions (in particular, the induction of tumour
necroptosis may result in further tissue damage. Inthe necrosisfactor--induced protein3 (A20; also known as
context of severe bacterial infection, cell necrosis can TNFAIP3)) have not yet been investigated in the c ontext
occur (as a feature of immunopathology) and can result of cirrhosis.
in DAMP release. Inthis case, released DAMPs can per Following invivo LPS challenge, plasma tumour
petuate or accentuate inflammation originally triggered necrosis factor (TNF) levels are significantly higher in
by bacterial inducers (PAMPs and virulence factors)51. cirrhotic than in non-cirrhotic animals6771. Moreover,
in this setting, animals with, but not without, cirrhosis
ACLF with identified inducers of inflammation develop hepatocyte apoptosis and necrosis70. In addi
The relative contribution of these inflammatory pro tion, compared with normal livers, in cirrhotic livers,
cesses to ACLF probably differs depending on the LPS elicits prolonged endoplasmic reticulum stress and a
trigger, and considerable research is still needed to fully subsequent unfolded protein response that is responsible

6 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

for sustained phosphorylation of eukaryotic translation response to mtDNA stress might become an inflamma
initiation factor 2 subunit- (eIF2)70. eIF2 phosphoryl tory response at the tissue level and thereby might
ation is known to attenuate the translation of most contribute to liver failure.
RNAs72. In this context, hepatocyte TNF-mediated cell Recent results suggest that the inhibition of liver
death might occur in cirrhotic livers because of the lack regeneration might be involved in liver failure associ
of translation of nuclearfactor-B (NFB)dependent ated with severe alcoholic hepatitis85. Although hepatic
survival mRNAs into proteins. Insupport of this hypoth progenitor cells are activated in livers with severe
esis, normal hepatocytes exposed to high levels of TNF alcoholic hepatitis, these cells are committed to differ
are protected against cell death because of the induction entiate into cholangiocytes (epithelial cells lining the
of NFBdependent prosurvival proteins73. Together, bile duct) instead of hepatocytes85. Thus, it is possible
these findings led to the theory that, in cirrhosis, LPS that no replacement of hepatocytes that die as a result
recognition might result in severe liver damage that is of alcoholic hepatitis occurs. Together, these find
due not only to an excessive innate immune response ings suggest that severe alcoholic hepatitis might
but also to the impairment of mechanisms involved in be caused by both immunopathology and impaired
hepatocyte endoplasmic r eticulum homeostasis. hepatocyteregeneration.
Future studies should investigate the inflammatory
response and tissue damage induced by the recogni ACLF with no identifiable trigger
tion of PAMPs other than LPS. It should also be noted The trigger of ACLF is unknown in approximately
that the role of inducers of inflammation, other than 40% of cases8. Although these patients show features
PAMPs, such as virulence factors and DAMPs, have not of systemic inflammation8, one cannot clearly explain
yet been studied in the context of sepsis-inducedACLF. how the systemic inflammation is stimulated. Three
hypotheses might explain the mechanisms that under
Severe alcoholic hepatitis. Results of the CANONIC lie inflammation in ACLF with no clinically identifiable
study 8 suggest that 20% of cases of ACLF are caused trigger.
by severe alcoholic hepatitis. In alcoholic hepatitis, the The first hypothesis is based on the existence of dys
liver shows features of cell death and inflammation74,75. biosis of the gut microbiota in patients with cirrhosis
However, the underlying mechanisms that explain these (FIG.4). Dysbiosis associated with cirrhosis is typically
features are still poorly understood75 and most of the characterized by a decrease in diversity, a decrease in
following mechanisms require confirmation. Lachnospiraceae, Ruminococcaceae, Bacteroidaceae
Excessive alcohol consumption alters the gut micro and Family XIV incertae sedis at the family level and
biota and increases intestinal permeability 75. In addition, a decrease in Bacteroides spp. at the genus level6,8689.
chronic and excessive systemic inflammation causes Inaddition, dysbiosis associated with cirrhosis involves
damage to the intestinal barrier. These alterations might
favour the translocation of bacteria into the blood
stream7678 (FIG.4). Regardless of whether these b acteria Box 2 | ACLF grades
cause infection, they release PAMPs (such as LPS) that
No ACLF
can reach the liver where they are recognized by TLRs This category includes patients who either:
expressed in resident macrophages (called Kupffer cells).
Do not have any organ failure
This recognition stimulates the production of pro-
Have a single organ failure that does not involve the
inflammatory CXC chemokines, such as IL8 (REF.79),
kidneys with a serum creatinine level of <1.5mg per dl
that attract and activate neutrophils80. Neutrophil infil and no hepatic encephalopathy
tration is a hallmark of alcoholic hepatitis75. Hepatocyte
Have a single brain failure with a serum creatinine level
necrosis, which has been documented in severe alcoholic
of <1.5mg per dl
hepatitis81, might result in the release of DAMPs that
would be recognized by different receptors mediating ACLF grade 1
ACLF grade 1 is diagnosed with one of the following:
an inflammatory response, as describedabove.
Mitochondrial DNA (mtDNA) is a type of DAMP, Single kidney failure
and mtDNA stress might also contribute to inflam Single liver, coagulation, circulatory or lung failure
mation in the context of alcoholic hepatitis. Acetalde thatis associated with a serum creatinine level
hyde metabolism results in hepatocyte reactive oxygen of1.51.9mg per dl and/or hepatic encephalopathy
grade 1 or grade2
species (ROS) production68. ROS production is also
stimulated by TNF65. In the context of chronic a lcohol Single brain failure with a serum creatinine level of
1.51.9mg per dl
consumption82 or after LPS challenge83, ROS over
production induces mtDNA stress. In a mouse model of ACLF grade 2
moderate mtDNA stress, mtDNA was shown to escape ACLF grade 2 is diagnosed when there are two organ
to the cytosol where it engaged a cell-intrinsic response failures of any combination
involving the innate cytosolic DNA sensor cyclic GMP- ACLF grade 3
AMP synthase (cGAS) (FIG. 3a). cGAS engagement ACLF grade 3 is diagnosed when there are three or
with mtDNA, in turn, mediates typeI interferon (IFN) more organ failures of any combination
production and subsequent autocrine and paracrine
ACLF, acute-on-chronic liver failure.
induction of IFN target genes84. Thus, a cell-intrinsic

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 7



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

a Triacyl Diacyl LPS an increase in Gram-negative Enterob acteriaceae,


lipoproteins lipoproteins Fusobacteriaceae and Porphyromonadaceae and in
Flagellin
Gram-positive Streptococcaceae at the family level6,8689.
Plasma membrane Decompensation of cirrhosis results in additional distinct
TLR1 TLR2 TLR6 TLR4 TLR5
compositional changes of the microbiota compared with
compensated stages of liver disease87. There is a robust
Cytoplasm positive correlation between the abundance of certain
Peptidoglycan
fragments
LPS bacterial family members and plasma levels of inflam
ssDNA matory cytokines (including IL6 and TNF in patients
Caspase 4 with ACLF)90. These findings suggest that metabolites
and/or Endolysosome produced by gut microbiota might contribute to systemic
NOD1 NOD2 RIG-I NAIP5 caspase 5
ssRNA CpG DNA inflammation(FIG.4).
dsDNA The second hypothesis is that some patients might
have intestinal translocation of PAMPs, such as LPS or
TLR7 TLR9 bacterial CpG DNA91 (FIG.3a). These ligands might reach
IFI16 cGAS AIM2 the liver and systemic circulation and then be recognized
b by TLRs. Thus, TLR recognition is generally not depend
LPS
ent on microbial viability or invasiveness. During the
peak phase of ACLF, systemic levels of LPS are higher
than before the onset of ACLF and during remission
TLR4 of survivors87,91, suggesting that higher systemic LPS
levels correlate with disease severity. Interestingly,
TICAM2 TIRAP LPS small intestinal bacterial overgrowth is a risk factor for
TRIF MYD88 increased systemic LPS levels in patients with cirrho
Caspase 4 sis92. Increasedsystemic levels of CpG DNA are found
TRAF3 TRAF6 and/or in patients with decompensated cirrhosis and without
caspase 5 overt bacterial infection, and correlate with mortality 93,
IKK MAPK suggesting that increased levels of CpG DNA might be
involved in the development of ACLF in patients with
IRF3 NF-B AP-1 IRF5 NLRP3 acutely decompensated cirrhosis.
The third mechanism explaining inflammation in
TNF, IL6, IL1B, IL12B, CXCL8, Cleavage of IL-1 ACLF with no clinically identifiable trigger might be
Type 1 IFNs CXCL1, IL10 and IL1RN and IL-18 the release of DAMPs, for example, by necrotic hepato
cytes. In patients and animals with acute liver failure,
Figure 3 | Structural feature recognition of bacteria and induction of the inflammatory various DAMPs, such as HMGB1, that might contrib
response. a | Examples of pattern recognition receptors (PRRs)Naturethat
Reviews
detect| Disease
unique Primers
ute to inflammation are released83, but nothing is known
molecular structures of bacterial pathogen-associated molecular patterns (PAMPs) and
their subcellular localizations. PRRs for bacterial ligands include Toll-like receptors (TLRs), about DAMPs in patients withACLF.
nucleotide-binding oligomerization domain (NOD)-like receptors (NLRs), retinoic Finally, another possible explanation for a failure to
acid-inducible gene 1 (RIG-I; a member of the RIG-Ilike receptor family) and cytosolic DNA identify a precipitating event in ACLF could relate to a
sensors (including interferon- (IFN)-inducible protein 16 (IFI16), absent in melanoma 2 failure of current diagnostic tests or the testing protocol
(AIM2) and cyclic GMP-AMP synthase (cGAS))4348,167. b | An example of PRR-mediated to identify infection orDILI.
inflammation is the activation of inflammatory signalling pathways by extracellular and
intracellular lipopolysaccharide (LPS). Detection of extracellular LPS by TLR4 engages Diagnosis, screening and prevention
twointracellular signalling conduits: the myeloid differentiation primary response Defining organ failure and ACLF
protein88 (MYD88) pathway (grey), involving the adaptor TollIL1 receptor (TIR) Diagnostic criteria of organ failure. One of the assump
domain-containing adaptor protein (TIRAP); and the TIR domain-containing adaptor
tions made to define the EASL-CLIF criteria is that extra
protein-inducing IFN (TRIF) pathway (light green), involving the adaptor TIR
domain-containing adaptor molecule 2 (TICAM2)43. The MYD88 pathway via tumour hepatic organ failure (or failures) is a major differential
necrosis factor (TNF) receptor-associated factor 6 (TRAF6) stimulates different kinases feature of ACLF. The CLIF-Sequential Organ Failure
(darkgreen), including inhibitor of nuclear factor-B kinase (IKK) and mitogen-activated Assessment (CLIF-SOFA) score was the original scale
protein kinases (MAPKs), that activate master transcription factors (orange), NFB and used to define organ failure in the CANONIC study 8.
activator protein1 (AP1), respectively. The MYD88 pathway also activates the transcription Itwas derived from the SOFA score, a scale widely used
factor IFN regulatory factor 5 (IRF5). These activated transcription factors contribute to the in intensive care1619, which was then adapted to patients
induction of inflammatory genes (red), such as pro-inflammatory genes including TNF and with chronic liver disease on the basis of published stud
IL6 and anti-inflammatory genes such as IL10 and IL1RN. The TRIF pathway involves TRAF3 ies. Cut-off values were established after assessing the risk
activation of the transcription factor IRF3, which then contributes with other transcription increase of 28day mortality rates in each of the last four
factors to the induction of typeI IFNs43. Intracellular LPS is recognized by the inflammatory
CLIF-SOFA score categories compared with that of the
caspases (caspase 4 and caspase5 in humans and caspase 11 in mice) that stimulate the
non-canonical NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome167,168. previous one in the patients enrolled in the CANONIC
This results in the activation of caspase 1 (not shown), which promotes cleavage of IL1 study. A simplified version of the CLIF-SOFA score, the
and IL18 (REFS167,168). Activation of caspase 4 and caspase 5 by intracellular LPS can CLIF Consortium Organ Failure (CLIFC OF) score
trigger a programmed cell death called pyroptosis169. dsDNA, double-stranded DNA; (TABLE2) with identical criteria to diagnose organ failure
NAIP5, neuronal apoptosis inhibitory protein 5; ssRNA, single-stranded RNA. and similar prognostic accuracy, has been developed20.

8 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Mortality criteria. Another predefined criterion for the Grades of severity of ACLF
diagnosis of ACLF in the development of the EASL-CLIF Patients with decompensated cirrhosis can be strati
criteria was an expected 28day mortality rate of 15%. fied into four groups of severity no ACLF or ACLF
In the CANONIC series8, this criterion was present grades 13 on the basis of the type and the number
inpatients with two or more organ failures, but not in of organ failures they have (BOX2). Kidney failure is the
patients with one organ failure (a 28day mortality rate most prevalent organ failure in ACLF grade 1. For ACLF
of 14.6%). Additional risk factors were used to further grade 2, liver failure is the most prevalent organ failure
categorize patients in this low-risk subgroup. This analy followed by kidney, brain and coagulation failure. For
sis produced subgroups of patients that fulfilled the three ACLF grade3, the prevalence of all organ failures ishigh.
predefined criteria for ACLF (FIG.5): patients with two In the CANONIC study8, 23% of patients admitted
or more organ failures; patients with one organ failure to hospital had ACLF at admission. Furthermore, 11%
(specifically kidney failure); and patients with non-renal of patients with no ACLF at admission developed the
single organ failure if these failures are associated with syndrome during hospitalization, which gives a total
renal and/or brain dysfunction. prevalence of ACLF of 31%. Among patients with
ACLF, 51% had ACLF grade 1, 35% had ACLF grade 2
Healthy gut
and13% had ACLF grade 3. Besides providing the diag
microbiota Dysbiosis nosis of the syndrome, these criteria also provide data
for rapid prognostic information, with the ACLF grade
associated with different rates of mortality (TABLE3).
The usefulness of these classification criteria as well as
that of CLIF-SOFA and CLIFC OF scores in assessing
prognosis have been validated in independent series
Diet ofpatients26,2931,94,95.
Antibiotics
Bile ow
Motility
Natural history of ACLF
Microbial ACLF is a syndrome that has potential for reversibil
Gastric pH metabolites
Immunity Bacteria
ity 96. However, data from the CANONIC study clearly
PAMPs show that, despite this feature, mortality of patients with
Intestinal epithelium
ACLF increases cumulatively even after these patients
are discharged from the hospital. Specifically, mortality
increases from approximately 20% at 28days to >35%
Tight Disrupted at 90days in patients with ACLF grade 1 and from 30%
junction tight
junction
to approximately 50% at 90days in patients with ACLF
grade 2 (REF.8). Although there is considerable variability
between patients20,21, some broad principles regarding the
Lamina propria course of the condition can be put forward. In general, at
Cytokines
IL-6 days 37 from presentation, approximately 50% patients
Monocyte NO with ACLF grade 1 will improve to having no ACLF, with
TNF a consequent 28day mortality rate of approximately
IL-17 7%. In addition, 25% of patients with ACLF grade1 will
Macrophage T cell IFN
remain unchanged (that is, theirACLF grade will not
change) with a 28day mortality rate of 24%. By con
Blood vessel trast, approximately 25% of patients with ACLF grade1
progress to ACLF grade2 or ACLF grade3; their 28day
mortality rate is 53% and 88%, respectively. In patients
Figure 4 | Intestinal dysbiosis and bacterial translocation. Cirrhosis
Nature is associated
Reviews with
| Disease Primers
presenting with ACLFgrade2, only 35% improve to
quantitative differences (bacterial overgrowth) and compositional changes of the gut
microbiota, so called dysbiosis. Several factors might contribute to dysbiosis of the having no ACLF or ACLF grade1 at days 37 post
gutmicrobiota during cirrhosis including diet, use of antibiotics, decreased bile flow presentation. Those patients who do improve have low
andintestinal motility, changes in gastric pH and impaired mucosal immunity. A second 28day mortality rates of approximately 5%. In addi
important feature of patients with cirrhosis is the translocation of bacteria. Disruption of tion, approximately 50% of patients with ACLF grade2
tight junctions allows pathogen-associated molecular patterns (PAMPs) and possibly deteriorate to ACLF grade3(a 28day mortality rate
other microbial metabolites to use the paracellular route between adjacent intestinal of 90%) or remain the same (a28day mortality rate of
epithelial cells for translocation. Intestinal permeability is already increased in precirrhotic 26%). Inpatients presenting with ACLF grade3, mortal
stages, whereas translocation of viable bacteria is a characteristic of cirrhosis, particularly ity rates remain very high with only approximately 13%
during decompensation. Bacteria probably use the transcellular route (transcytosis) improving to no ACLF or ACLF grade 1. The factors
through epithelial cells. PAMPs might also activate immune cells, including monocytes,
that were independently related to progression to more-
macrophages and Tcells, in the lamina propria of the intestines, leading to secretion of
inflammatory mediators. Cytokines, such as tumour necrosis factor (TNF), IL6, IL17, nitric advanced grades were the CLIFC ACLF score (dis
oxide (NO) and interferon- (IFN), are increased in the intestines of patients or animal cussed below) and the presence of liver failure. These
models with cirrhosis7678. Several of these mediators are known to contribute to a data indicate that the syndrome is indeed very dynamic
dysfunction of tight junctions. Conversely, the intestinal immune surveillance response and that early intervention is crucial to minimize the
might be impaired to remove translocated bacteria in the lamina propria. risk ofdeath.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 9



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Clinical risk factors diagnosis of ACLF are extremely important to predict


There is evidence that the clinical course of ACLF clinical course since resolution; improvement or worsen
outlined above is true for all aetiologies of ACLF. Ina ing of ACLF following standard medical therapy occur
retrospective study from China in patients who predomi within this early time period in most patients96.
nantly had HBV-related cirrhosis, short-term outcomes, A prognostic model was developed and validated
which were the most closely associated with ACLF, were for patients with ACLF, referred to as the CLIFC ACLF
not affected by the nature of the precipitating illness97. score, and for patients with acute decompensation who
Patients with hepatic precipitants, such as reactivation did not fulfil criteria for the diagnosis of ACLF, which is
of HBV, had a short-term (28day and 90day) mortality called the CLIFC Acute Decompensation (CLIFC AD;
similar to patients with an extrahepatic precipitant, such www.clifconsortium.com) score. These two scores were
as infection. This pattern was also observed in a second designed because a single score was insufficient to satis
Chinese study24 in patients with cirrhosis due to chronic factorily delineate the prognosis associated with acute
HBV infection who developed ACLF. The 28day and decompensation andACLF8.
90day mortality rates for any given grade of ACLF The CLIFC ACLF score comprises the CLIFC
in this study 24 were similar to those reported by the OF score, age and white blood cell count 20,98. The score
CANONIC study 8 and were unrelated to the presence is a number from 0 to 100; the higher the number, the
and type of precipitating events (TABLE4). These studies, greater the risk of death. The score was validated using
therefore, suggest that it is the number of organ failures prospectively collected data from a series of patients not
and not the aetiology of cirrhosis or precipitating events included in the CANONIC study. The CLIFC ACLF
that is the main risk factor of mortality. score provided a significantly better estimate of the risk of
A previous history of episodes of acute decompen death at 28days, 90days, 6months and 12months post-
sation was absent in 23% of patients with ACLF in the presentation compared with the Model for End-Stage Liver
CANONIC study, indicating that the development of Disease (MELD) score, the MELD-Sodium score and the
ACLF as the initial manifestation of decompensated Child-Pugh score24,32,95,99101. Compared with the CLIFC
cirrhosis is a relatively common feature. These patients ACLF score, the MELD score underestimated the risk of
without prior history of decompensation were younger, death of patients by 2030%, implying that organ alloca
more-frequently alcoholics, had more-severe systemic tion for transplantations using the MELD score seriously
inflammation and ACLF grade, and had higher short- disadvantages the patient with ACLF20. The performance
term mortality (42% versus 30%) than patients with of the CLIFC ACLF score improved over the period of
ACLF with prior history of acute decompensation. follow-up, suggesting that it should be updated daily20.
The CLIFC AD score was developed in patients
Prediction of prognosis with acute decompensation without ACLF98. Variables
As ACLF is a dynamic syndrome, prognostic scores that were found to be independently associated with
need to be dynamic so that they can be updated sequen survivalwere age, serum sodium level, serum creatinine
tially on a daily basis, which would allow assessment level, white blood cell count and international normal
of response to intervention, escalation for the need for ized ratio. These generated a score between 0and 100,
urgent liver transplantation and determination of futility which was also significantly more accurate in predict
of ongoing treatment. The CANONIC study indicates ing prognosis than the MELD, MELD-Sodium and
that followup data within the first 37days following Child-Pugh scores24,98. Patients with a CLIFC AD score

Table 2 | The Chronic Liver Failure Consortium Organ Failure score


Organ or Subscore=1 Subscore=2 Subscore=3*
system (OR versus subscore=1) (95%CI)) (OR versus subscore=1) (95%CI))
Liver Bilirubin level of Bilirubin level of 6 and 12mg per dl Bilirubin level of >12mg per dl*
<6mg per dl (OR: 2.6 (1.64.3)) (OR: 7.1 (4.710.7))
Kidney Creatinine level Creatinine level of 2 and <3.5mg per dl* Creatinine level of 3.5mg per dl or
of <2mg per dl (OR: 3.8 (2.36.3)) renal replacement* (OR: 15.5 (8.926.8))
Brain West-Haven HE171 West-Haven HE grade 12 West-Haven HE grade 34*,
grade 0 (OR: 2.1 (1.43.2)) (OR: 9.7 (5.916.1))
Coagulation INR of <2 INR of 2 and <2.5 (OR: 5.2 (3.47.9)) INR of 2.5* (OR: 7.5 (4.612.3))
Circulation MAP of MAP of <70mmHg (OR: 2.6 (1.64.3)) Use of vasopressors*
70mmHg (OR:9.2(5.216.4))
Respiratory PaO2/FiO2 of >300 PaO2/FiO2 of >200 and 300 or SpO2/FiO2 PaO2/FiO2 of 200* or SpO2/FiO2
or SpO2/FiO2 of >214 and 357 (OR: 2.7 (1.74.2)) of214*, (OR: 6.4 (3.113.2))
of>357
The odds ratio (OR) describes the increase in the risk of 28day mortality compared with the low-risk category for each organ or
system and subscore. FiO2, fraction of inspired oxygen; HE, hepatic encephalopathy; INR, international normalized ratio; MAP,
mean arterial pressure; PaO2, partial pressure of arterial oxygen; SpO2, pulse oximetric saturation. *Criteria for diagnosing organ
failures. Patients submitted to mechanical ventilation due to HE and not to a respiratory failure were considered as presenting a
brain failure (cerebral subscore=3). Other patients enrolled in the study with mechanical ventilation were considered as
presenting a respiratory failure (respiratory subscore=3). Adapted with permission from REF.20, Elsevier.

10 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

80 Norfloxacin acts by selectively reducing the Gram-


70
negative microbiota, decreasing the permeability of the
No ACLF gut barrier via stimulation of IL10 release and modulat
60 ACLF ing the immune response to bacterial translocation111113.
Mortality rate (%)

50
In addition, treatment of patients with severe acute
alcoholic hepatitis with pentoxifylline, an inhibitor of
40 macrophage production of TNF, or with the combin
30 ation of prednisolone and intravenous Nacetylcysteine
has been shown to reduce the incidence of type1 HRS
20 in some studies114,115, presumably by modulating hepatic
10 inflammation, but this has not been confirmed in a recent
investigation116. Finally, short-term administration of
0 the combination of granulocyte colony-stimulating
No OF Single non-kidney Single Single non-kidney Two >3 OFs
OF without KD kidney OF with KD OFs factor (GCSF) plus darbepoetin (asynthetic analogue
and BD failure and/or BD of erythropoietin) has been shown to improve liver
Patient OF category function, to reduce the incidence of severe sepsis and
Figure 5 | Relationship between organ failure and mortality in ACLF. 28day mortality to increase 1year survival in comparison to placebo in
rates of patients with decompensated cirrhosis with (redNature Reviews | Disease Primers
bars) and without (green bars) patients with decompensated cirrhosis117.
acuteonchronic liver failure (ACLF) according to the diagnostic criteria proposed in the
CANONIC study8. Patients are divided into the following categories: patients with no organ Management
failure (OF); patients with a single non-kidney organ failure without kidney dysfunction Medical management
(KD; a serum creatinine level of 1.51.9mg per dl) or brain dysfunction (BD;grade 12
Medical management of ACLF consists of early recogni
hepatic encephalopathy); patients with a single kidney failure; patients with a single
non-kidney organ failure with kidney dysfunction and/or brain dysfunction; patients with
tion, treatment of the precipitating event and supportive
two organ failures; and patients with three or more organ failures. Data from REF.8. care8,14,118,119. Early treatment of the trigger is proven to
reduce mortality, for example, in treatment of reactivated
HBV infection with tenofovir or alcoholic hepatitis with
of<45had a 28day mortality rate of <3% and this steroids75,117,119121. However, most of ACLF management
category might identify a group of patients who could be is focused on supportive care118.
discharged early from the hospital. Conversely, patients
with a CLIFC AD score of >60 were at high risk of pro Antibacterial therapy. As discussed above, bacterial
gression to full-blown ACLF and had a 28day mortality infections are the precipitating event of ACLF in approx
rate of approximately 20%, indicating that this is prob imately 35% of patients14 (TABLE4). As such, there should
ably a pre-ACLF group. The CLIFC AD score was also be a low threshold for early initiation of antibiotics in
validated for sequentialuse. patientswith cirrhosis who have a bacterial infection.
Inpatients withseptic shock, every hour delay beyond
Prevention presentation is associated with an adjusted odds ratio of
Early diagnosis and treatment of potential precipitat overall death of 1.1 (REFS122,123). Broad spectrum anti
ing events are essential in the prevention of ACLF, and biotics should be used, particularly in patients with noso
several preventive measures have been shown to be comial or health care-associated infections or in those
effective5,55,102105. These all involve treating infections with septic shock, as inappropriate initial antimicrobial
before they can go on to trigger ACLF and include: therapy increases the adjusted odds ratio of death by
prompt administration of antibiotics tailored to the local tenfold122,123. Equally important to early initiation of anti
epidemiological pattern of resistance in patients with sus biotics is prompt deescalation of antibiotics once an
pected infections; long-term suppression of HBV infec organism is identified and/or the patient shows clinical
tion or sustained eradication of hepatitis C virus infection improvement. If no organism is identified and there is
in patients with compensated or decompensated cirrho persistent clinical deterioration in the setting of broad
sis; and intravenous administration of albumin at infec spectrum antibiotics, antifungals should be considered123.
tion diagnosis in patients with SBP. In patients with SBP, Measures to prevent superinfections (secondary infec
albumin is highly effective in preventing the development tions that occur on top of a primary infection) should be
of type1 hepatorenal syndrome (HRS), which is a special implemented in patients with ACLF, including bundles of
form of ACLF characterized by rapidly progressive renal prevention and control of ventilator-associated pneumo
failure. This effect is probably as a consequence of plasma nia, catheter-related bacteraemia and urinary tract infec
volume expansion and the modulatory effect of albumin tions, hand hygiene, barrier p recautions and avoiding
on the systemic inflammation associated with PAMPs unnecessary instrumentation124.
(such as LPS)104,105. There is no evidence that intravenous Infected and non-infected patients admitted with
albumin is effective in other bacterial infections106,107. ACLF are highly predisposed to developing new bac
There is also indirect evidence in support of other terial infections during hospitalization (R.M. and the
potential preventive measures for ACLF. For example, CANONIC trialists, unpublished observations). These
long-term oral norfloxacin administration reduces the rate infections act as a second hit of the syndrome. Thus, pre
of SBP (and of other bacterial infections) and type1HRS vention, early diagnosis and treatment of these s econdary
in patients with decompensated cirrhosis55,102,108110. infections are major issues inACLF.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 11



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Table 3 | ACLF grade and mortality ACLF14,131. The goal mean arterial pressure is >60mmHg
and careful attention should be made to volume admin
Category 28day 90day
mortality (%) mortality (%) istration with crystalloids given the predisposition of
volume overload in patients with cirrhosis118. Colloids,
No ACLF 1.9 10
including albumin, may also trigger volume overload.
ACLF (total) 33 51 Terlipressin or vasopressin can be used as an adjunc
ACLF grade 1 23 41 tive agent. There is also growing evidence that adrenal
ACLF grade 2 31 55 insufficiency in ACLF can further compromise haemo
dynamics132. Although still controversial, evaluation for
ACLF grade 3 74 78 adrenal insufficiency can be done by measuring random
ACLF, acute-on-chronic liver failure. Data from REF.8. cortisol levels in the morning. If these levels are indeter
minate, adrenal insufficiency can be confirmed with an
HBV-specific therapy. Reactivation of HBV is a frequent adrenocorticotropic hormone (ACTH) test (also called
precipitating event of ACLF in patients with cirrhosis the cosyntropin, tetracosactide or Synacthen test), which
in Asia. Antiviral treatment in patients with hepati estimates the response of the adrenal glands tostress.
tisB-related ACLF improves liver function and increases
short-term and long-term survival119121,125,126. Thus, early Brain dysfunction and failure. Treatment of encephalo
treatment with antiviral agents (such as lamivudine, teno pathy with tap water enemas, lactulose and oral non-
fovir, entecavir or telbuvidine) should be started as soon absorbable antibiotics (such as rifaximin and neomycin),
as possible121,127. by improving the level of consciousness, can prevent
bronchial aspiration, aspiration pneumonias and respir
Immunomodulation. Patients with ACLF might bene atory failure14. It is important to titrate lactulose dose
fit from treatments that aim to restore immune func and enemas appropriately to prevent hypovolaemia that
tion, such as albumin, Nacetylcysteine and G-CSF117,128. results from diarrhoea and to prevent hypernatraemia
Indeed, results from a recent randomized controlled trial (arise in serum sodium levels) that results from lactulose.
suggest that the administration of GCSF prevents the Goal stool output in a day should be 34 bowel move
development of sepsis and improves short-term survival ments133. Lower stool output is insufficient to reduce the
in patients without severe forms of ACLF, who did not intestinal production of ammonia and to increase ammo
have sepsis, brain failure or multiple organ failure128. nia clearance from blood. Higher stool output may induce
GCSF is thought to act by mobilizing stem cells from hypernatraemic dehydration. Patients with gradeIIIIV
the bone marrow to the periphery, including the liver, encephalopathy should be intubated, as they have a high
thus improving liver regeneration. risk of experiencing bronchial aspiration (of saliva or
gastric fluid). Intracranial pressure monitoring and the
Renal dysfunction and failure. Acute kidney injury use of mannitol is not recommended in these patients as
(AKI) is the most frequent organ failure in ACLF8,129. cerebral oedema and intracranial hypertension are excep
Common causes of AKI include pre-renal, intrinsic tional in patients with hepatic e ncephalopathy associated
causes and HRS129. Management of AKI differs depend withACLF12.
ing on the underlying aetiology, and urinary biomarkers
are helpful in identifying the cause of AKI129,130. Volume Coagulopathy. Coagulopathy in patients with ACLF is
resuscitation with crystalloids and/or albumin should be often difficult to manage in the setting of fluctuations
used in patients with pre-renal AKI (that is, impairment between a prothrombotic and an ineffective haemostatic
in renal function related to hypovolaemia caused by state134,135. In the setting of active bleeding and severe
excessive diuretic treatment). Terlipressin or noradrena coagulopathy, transfusion of platelets, cryoprecipitate
line are the first-choice treatment for HRS combined (a frozen blood product prepared from plasma used to
with volume expansion with albumin129. Terlipressin or increase fibrinogen levels) and blood should be consid
noradrenaline are given to reduce the splanchnic arterial ered. However, patients should not be prophylactically
vasodilation causing systemic circulatory dysfunction transfused with plasma for an increased international
and renal vasoconstriction in HRS. The effect of albumin normalized ratio. Patients with portal vein thrombosis
was initially thought to be due to plasma volume expan may require anticoagulant therapy to prevent recurrent
sion. However, a potential effect of albumin in modulat variceal bleeding.
ing the systemic inflammation of patients with ACLF has
recently been proposed7,105. Renal replacement therapy is Intensive care and liver support devices
used as a bridge to liver transplantation or liverkidney Admission to critical care units is mandatory in cases of
transplantation in patients with severe AKI, although the vascular, respiratory or brain failure and is recommended
dose and timing of dialysis has not been fully studied129. in those with renal failure. Patients with liver and coagu
lation failure can still be treated in regular wards, but
Cardiovascular failure. As in the management of sep require strict clinical monitoring. In the CANONIC
sis, aggressive volume resuscitation and the initiation of study 8, 50% of the patients with ACLF were admit
vasoconstrictor agents (that is, noradrenaline) to main ted to the intensive care unit (86% of those with ACLF
tain an adequate blood pressure for organ perfusion is grade3). Owing to the high mortality rate in patients
crucial to counter the vasodilatory state that occurs with with ACLF, treatments that are able to bridge the time

12 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

Table 4 | Potential precipitating events of ACLF of patients with cirrhosis and to reduce circulating
endotoxaemia is currently under evaluation140. Plasma
Precipitating event Patients without Patients with P value* exchange, a detoxification system that increases survival
ACLF (%) ACLF (%)
(n=1,040) (n=303) in patients with acute liver failure141, improves hepatic
encephalopathy and liver f unction in non-randomized
Bacterial infection 21.8 32.6 <0.0001
studies in patients withACLF.
Gastrointestinal bleeding 17.3 13.2 NS
Active alcoholism 14.9 24.5 0.0002 Liver transplantation
Other event
3.5 8.6 0.0002 Liver transplantation represents the only definitive
therapeutic option for patients with ACLF. However,
No event|| 58.9 43.6 <0.0001 very few studies have assessed its feasibility, selection
Any event ||
41.1 56.4 <0.0001 criteria (indications and contraindications), timing and
>1 event|| 5.7 13.5 <0.0001 efficacy 96,142148. In contrast to patients with acute liver
ACLF, acute-on-chronic liver failure; NS, not significant. *P value compares (Chi-square test) the failure, patients with ACLF cannot currently be included
prevalence of potential precipitating events between patients with and without ACLF at in the high-urgency transplantation list. Moreover, as
enrolment in the CANONIC study. Bacterial infection and active alcoholism were significantly the clinical course of ACLF evolves rapidly, the time
more frequent in patients with ACLF than in those without ACLF, suggesting that they were
associated with the development of the syndrome. This was not the case for gastrointestinal frame for evaluation and listing is frequently very short.
bleeding. Within 3months prior to inclusion. Other precipitating events include large volume Advanced age, active alcoholism, uncontrolled infec
paracentesis without intravenous administration of albumin (to prevent post-paracentesis
circulatory dysfunction), transjugular intrahepatic portosystemic shunt (which is used to treat
tions and multiple organ failure are the main reasons for
portal hypertension), major surgery, acute hepatitis (caused by viral infection, ischaemia or contraindication to transplantation or delisting. There is
drug-induced liver injury) and acute alcoholic hepatitis. Liver biopsy was required for general agreement in considering that transplantation
thediagnosis of acute alcoholic hepatitis in the CANONIC protocol, but many patients
with active alcoholism had a clinical picture suggestive of this diagnosis. ||Bacterial infections, must be avoided in patients with severe circulatory or
activealcoholism or other precipitating events. Adapted with permission from REF.8, Elsevier. respiratory failure and ongoing sepsis. By contrast, for
the majority of experienced centres, organ support (renal
between admission of patients with severe disease (ACLF replacement therapy and mechanical ventilation) does
grade2 or grade 3 at 37days following admission) to not contraindicate transplantation in ACLF. Current
liver t ransplantation are clearlyneeded. data indicate that less than half of patients with ACLF are
Extracorporeal liver support systems are potential listed andthat the procedure is feasible in only 1025% of
treatments for ACLF136,137. Bioartificial liver support sys patients, as >5070% of the listed patients die on the wait
tems use hollow-fibre bioreactors containing hepatic cells ing list147. A recent study in the United States showed that
to support the metabolic and synthetic function of the patients with cirrhosis, ACLF and a high MELD score
diseased liver. Currently, only tumour hepatocyte or por (>40) have higher waiting-list mortality(almosttwofold
cine hepatocyte lines (the Vital Therapies ELAD and the
Alliqua HepatAssist 2000 systems) are available. Arecent 28 days
randomized trial comparing ELAD versus standard 1.0 95.2%
90.5%
medical treatment did not find any significant effect
on survival136. Non-biological systems consist of albu 0.8 80.9%
min dialysis techniques and are based on the capacity of
Probability of survival

this molecule to remove water-insoluble substances and


0.6
pro-inflammatory molecules (such as PAMPs and ROS)
retained in plasma as a consequence of liver failure and
systemic inflammation105. Moreover, the physiology of 0.4
albumin function is markedly impaired in patients with
23.3%
decompensated cirrhosis because of severe oxidation 0.2
of the molecule by endogenous ROS, alterations in its 12.5%
10%
molecular structure and saturation of other binding sites
0
by water-insoluble substances produced and/or retained
0 30 60 90 120 150 180
as a consequence of liver failure (such as bilirubin, bile
Time (days)
salts and drugs). Three different albumin dialysis systems
are currently available: the Gambro molecular a dsorbent Patients who received a transplant
and recirculating system (MARS), the Prometheus Patients who did not receive a transplant
fractionated plasma separation and absorption (FPSA)
system and the Fresenius Medical Care single-pass Figure 6 | Liver transplantation increases survival of
albumin dialysis (SPAD). MARS, the system that is patients with ACLF. Survival
Nature Reviews curves
probability | Disease
of Primers
most extensively evaluated in ACLF, improves systemic patients with grade 2 or grade 3 acute-on-chronic liver
failure (ACLF) at days 37 following diagnosis who were
haemodynamics and severe hepatic encephalopathy 136,137.
submitted to early (<28 days) liver transplantation
However, two large randomized, multicentre studies (redcurve; n=21) and patients with the same ACLF grades
failed to show an improvement in survival using MARS who did not receive a liver transplant (green curve;
and FPSA138,139. Finally, an artificial liver device (the n=120)96. Percentages over the curves show the 28day,
University College London-Liver Dialysis Device) that 90day and 6month probability of survival. Adapted with
aims to remove and replace the dysfunctional albumin permission from REF.96, John Wiley and Sons.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 13



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

futility 20,98 (FIG.7). The prognosis in ACLF depends not


Diagnosis ACLF only on the number of organ failures or the CLIFC
ACLF score at diagnosis but also on the early response
Medical management to treatment 96. As nearly 20% of patients with ACLF
ICU for organ support
grade 3 improve after treatment, patients with three or
more organ failures should be admitted to the intensive
care unit and should receive unrestricted organ support
No ACLF ACLF ACLF ACLF
Days 37
grade 1 grade 2 grade 3
for a short period of time (37 days). The persistence of
three or more organ failures after this intervention may
Mortality rate lead to the need to consider a limitation in life-sustaining
Day 28 10% 21% 57% 87% treatments as a fatal outcome is almost invariable in
Day 90 24% 42% 74% 95% the absence of salvage liver transplantation19. A high
Day 180 38% 47% 79% 96% CLIFC ACLF score (>64 points) after initial interven
tion (at 37days) has also been suggested as a potential
futility rule in patients without possibilities of early liver
Assessment for Assessment for transplantation96. However, these criteria require further
liver transplantation liver transplantation validation. Patients who are potential candidates for
early liver transplantation, including living donor liver
Contraindication for
liver transplantation?
Yes No Yes transplantation, must not be limited in their treatment.
In those without options for transplantation, scores and
Survival rate
a pragmatic casebycase evaluation should be used for
<4 OFs and 4 OFs and the decision.
CLIF-C CLIF-C
ACLF of <64 ACLF of >64
Regenerative therapy
A few studies have evaluated the effect of GCSF ther
Day 180 58% 35% 0%
apy in small groups of patients with ACLF128,149,150. This
cytokine mobilizes bone marrow-derived stem cells,
Next step Continue treatment Withdrawal of care restores neutrophil function and promotes hepatic
regeneration. G-CSF administration in non-severe forms
Figure 7 | Proposed algorithm for the management of patients with ACLF or of ACLF reduces the risk of developing organ failure (or
decompensated cirrhosis. Aproposed management strategy for patients
Nature Reviews with Primers
| Disease failures) and sepsis and improves survival. GCSF ther
acuteonchronic liver failure (ACLF) based on mortality rate data from the CANONIC apy seems to be ineffective in patients with sepsis and in
study8. The first step is the assessment of ACLF grade at days 37 after initiation of those who have more-severe forms of ACLF. Hepatocyte
medical management, including organ support. Liver transplantation should be assessed
and stem cell transplantation have also been proposed as
in all patients with ACLF because of high 90day mortality rates (>20%). Liver
transplantation should be performed as early as possible in patients with ACLF grade 2 potential treatments in ACLF151.
and grade 3 as they are at considerable risk of short-term (28day) mortality. In the case of
contraindication of liver transplantation, the presence of four or more organ failures Quality of life
(OFs) or a Chronic Liver Failure Consortium (CLIF-C) ACLF score of >64 at days 37 after Following dismissal from hospital, patients recovering
diagnosis could indicate the futility of care. ICU, intensive care unit. Adapted with from ACLF may return to functioning in their com
permission from REF.96, John Wiley and Sons. munity, receive a liver transplantation, be sent to inter
mediate care facilities such as a nursing home or be
rehospitalized. The 30day hospital readmission rate
higher) than status1A candidates (that is, patients with is approximately 25%152. In the long-term followup of
acute liver failure)145. Defining criteria to select and 6months in the NACSELD study153, 27% of patients died,
prioritize patients with ACLF on the waiting list will 14% were transplanted and 59% were alive without liver
help to improve outcomes by providing timely liver transplantation. After discharge, 45% of patients had
transplantation. Several studies show that both living subsequent infections. Patients who had repeat infec
donor liver transplantation and deceased donor trans tions were older and were more likely to use proton pump
plantation offer similar results in this setting 146148. The inhibitors, rifaximin or prophylactic therapy for SBP
reported outcome of patients transplanted for ACLF is with norfloxacin154,155. In these last three circumstances,
good (FIG.6), ranging between 74% and 90% at 5years, a the predisposition to bacterial infections is probably
number similar to that observed in patients transplanted related to gut dysbiosis or colonization by drug multi
for other indications96,144148. resistant bacteria. Of crucial importance, patients with
infection-related ACLF were more likely to be delisted
Management algorithm for livertransplantation.
The three new scoring systems derived from the
CANONIC study the CLIFC OF score (or CLIF-SOFA Outlook
score), the CLIFC ACLF score and the CLIFCAD score ACLF definition
can be used to risk-stratify patients with cirrhosis The challenge of obtaining a universal definition of ACLF
and acute decompensation, to indicate early liver trans is an important issue. However, differences between the
plantation and to assess intensive care unit treatment APASL and western definitions are too important to

14 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

be solved by consensus agreements alone. These defin The mechanism of organ or system failure in ACLF
itions differ not only in terms of the characteristics of is of major interest. Renal failure in cirrhosis is consid
the patients, diagnostic criteria and clinical course but ered to be secondary to systemic circulatory dysfunction
also, and most importantly, in the conceptual view of and impaired renal perfusion. However, recent evidence
the disease. The APASL conference definition postulates from studies in sepsis suggest that renal failure might
that the sequence of events in ACLF starts with a hepatic also be a consequence of a direct effect of renal inflam
insult that causes acute liver failure and, as a consequence, mation, which impairs renal microcirculation and cell
extrahepatic organ failure (or failures). By contrast, the function159. In fact, there is evidence that inflammation
western definition relies on the concept that the acute might be involved in the pathogenesis of cardiac dys
impairment in liver function (which, if intense, is defined function, encephalopathy, relative adrenal insufficiency
as liver failure) develops simultaneously to an impair and pulmonary dysfunction in cirrhosis7.
ment in the function of other organs (which, if intense, A major difficulty for research in ACLF is the lack
are also defined as organ failures) as a consequence of of appropriate animal models. Carbon tetrachloride-
intrahepatic or extrahepatic mechanisms. These mech induced cirrhosis in rats is an excellent model of cirrhosis,
anisms could include intense systemic inflammation but animals die prior to the development of extrahepatic
related to a massive release of DAMPs from the diseased organ failure160. Bile duct-ligated rats represent an acute
liver (in the case of acute alcoholic hepatitis, viral hepa model of liver failure and ascites and, in combination
titis or DILI) or of PAMPs (by invading bacteria in the with the acute intraperitoneal administration of LPS,
case of sepsis or from the intestinal microbiota in patients have been used as a model of ACLF161. However, this
without clear precipitating events). Such controversy can model differs markedly from cirrhosis in humans and
only be solved by promoting research in this compelling no extrahepatic organ failure has been documented.
new syndrome.
Treatment
Clinical challenges The recognition of systemic inflammation as the main
Investigations of ACLF have generally been carried out mechanism of ACLF opens up new fields in the design
after the diagnosis of the syndrome. As such, there are few of new therapeutic procedures. This knowledge will
data within the critical period before ACLF development. promote the development of new artificial liver support
Prospective observational studies within this period are, systems capable of removing not only potentially harm
therefore, essential, particularly those assessing bio ful molecules retained as a consequence of organ failure
markers or panels of biomarkers of systemic inflam but also pro-inflammatory molecules that cause ACLF.
mation that could be of value as predictors of treatment Total plasma exchange141 is clearly an alternative method
response and survival. Liver pathology in ACLF has also to remove PAMPs, DAMPs and free radicals.
been insufficiently investigated. In patients with cirrho However, a major issue in the management of ACLF
sis due to HBV infection, ACLF occurs in the setting of is prevention. There are three potential effective treat
submassive hepatic necrosis27. In patients with alcoholic ments that should be explored. The first consists of the
cirrhosis and active alcoholism, severe alcoholic hepatitis prevention of bacterial translocation by long-term oral
superimposed on cirrhosis is probably the predominant administration of poorly absorbable antibiotics107,110,162.
liver histology. Finally, two recent studies have reported Long-term weekly administration of intravenous albu
severe ductular bilirubinostasis and cholestasis, a lesion min is the second approach. Preliminary data indicate
that is also seen in patients with sepsis who do not have that this technique prevented bacterial infections, AKI
cirrhosis, as a specific lesion in ACLF156,157. and hepatic encephalopathy and improved survival in
a large Italian randomized controlled trial in patients
Insights into pathophysiology with decompensated cirrhosis163. Last, recent investi
Sequential studies of the innate and adaptive immune gations have suggested a central role for defective bile
system function before and after ACLF are lacking. Such acid receptor (also known as farnesoid Xactivated
studies are essential to understand the mechanism of receptor) signalling in hepatic inflammation and intes
ACLF. Moreover, the immune system function might tinal bacterial translocation, factors that are known
change during the clinical course of the syndrome. Asit to shape ACLF164166. Obeticholic acid is a potent bile
occurs in sepsis158, an initial activation of the immune acid receptor agonist. Recent studies in animals have
system in ACLF might be followed by a period of demonstrated that obeticholic acid lowers portal hyper
immunosuppression, which would favour further bac tension and improves bacterial translocation165,166, sug
terial translocation and progression of organ failure gesting that it might be of potential benefit in patients
(orfailures). withACLF.

1. Gins,P. etal. Compensated cirrhosis: natural history 4. Polio,J. & Groszmann,R.J. Hemodynamic 6. Qin,N. etal. Alterations of the human gut
and prognostic factors. Hepatology 7, 122128 factorsinvolved in the development and rupture microbiome in liver cirrhosis. Nature 513, 5964
(1987). ofesophageal varices: a pathophysiologic (2014).
2. Schrier,R.W. etal. Peripheral arterial vasodilation approachtotreatment. Semin. Liver Dis. 6, 318331 7. Bernardi,M., Moreau,R., Angeli,P., Schnabl,B.
hypothesis: a proposal for the initiation of renal (1986). &Arroyo,V. Mechanisms of decompensation
sodium and water retention in cirrhosis. Hepatology 8, 5. Ramachandran,P., Iredale,J.P. & Fallowfield,J.A. andorgan failure in cirrhosis: from
11511157 (1998). Resolution of liver fibrosis: basic mechanisms and peripheralarterialvasodilation to systemic
3. Fraser,C.L. & Arieff,A.I. Hepatic encephalopathy. clinical relevance. Semin. Liver Dis. 35, 119131 inflammationhypothesis. J.Hepatol. 63, 12721284
N.Engl. J.Med. 313, 865873 (1985). (2015). (2015).

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 15



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

8. Moreau,R. etal. Acuteonchronic liver failure is 26. Amarapurkar,D. etal. Acuteonchronic liver failure: 53. Iwasaki,A. & Medzhitov,R. Regulation of adaptive
adistinct syndrome that develops in patients with aprospective study to determine the clinical profile, immunity by the innate immune system. Science 327,
acute decompensation of cirrhosis. Gastroenterology outcome, and factors predicting mortality. 291295 (2010).
144, 14261437.e9 (2013). IndianJ.Gastroenterol. 34, 216224 (2015). 54. Chovatiya,R. & Medzhitov,R. Stress, inflammation,
This article describes the first prospective 27. Li,H. etal. Submassive hepatic necrosis distinguishes and defense of homeostasis. Mol. Cell 54, 281288
investigation assessing the diagnostic criteria HBV-associated acute on chronic liver failure from (2014).
(EASL-CLIF Consortium definition of ACLF), cirrhotic patients with acute decompensation. 55. Jalan,R. etal. Bacterial Infections in cirrhosis.
prevalence, precipitating events, grading of severity J.Hepatol. 63, 5059 (2015). Aposition statement based on the EASL Special
and prognosis of ACLF in a large series of European 28. Singh,H. & Pai,C.G. Defining acuteonchronic liver Conference 2013. J. Hepatol. 60, 13101324
patients hospitalized with decompensated cirrhosis failure: east, west or middle ground? World J.Hepatol. (2014).
using a pragmatic approach. 7, 25712577 (2015). 56. Wiest,R., Lawson,M. & Geuking,M. Pathological
9. Wlodzimirow,K.A., Eslami,S., Abu-Hanna,A., 29. Agrawal,S., Duseja,A., Gupta,T., Dhiman,R.K. bacterial translocation in liver cirrhosis. J.Hepatol.
Nieuwoudt,M. & Chamuleau,R.A.F.M. A systematic &Chawla,Y. Simple organ failure count versus 60, 197209 (2014).
review on prognostic indicators of acute on chronic CANONIC grading system for predicting mortality 57. Byl,B., Roucloux,I., Crusiaux,A., Dupont,E.
liver failure and their predictive value for mortality. inacuteonchronic liver failure. J.Gastroenterol. &Devire,J. Tumor necrosis factor alpha and
Liver Int. 33, 4052 (2013). Hepatol. 30, 575581 (2015). interleukin6 plasma levels in infected cirrhotic
10. Jalan,R. & Williams,R. Acuteonchronic liver failure: 30. Lee,M. etal. CLIF-SOFA scoring system accurately patients. Gastroenterology 104, 14921497 (1993).
pathophysiological basis of therapeutic options. predicts short-term mortality in acutely 58. Navasa,M. etal. Tumor necrosis factor and
BloodPurif. 20, 252261 (2002). decompensated patients with alcoholic cirrhosis: interleukin6 in spontaneous bacterial peritonitis
11. Sarin,S.K. etal. Acuteonchronic liver failure: aretrospective analysis. Liver Int. 35, 4657 (2015). incirrhosis: relationship with the development of
consensus recommendations of the Asian Pacific 31. Dhiman,R.K., Agrawal,S., Gupta,T., Duseja,A. renalimpairment and mortality. Hepatology 27,
Association for the Study of the Liver (APASL). &Chawla,Y. Chronic Liver Failure-Sequential Organ 12271232 (1998).
Hepatol. Int. 3, 269282 (2009). Failure Assessment is better than the Asia-Pacific References 57 and 58 show for the first time
This article describes the results of a consensus Association for the Study of Liver criteria for defining aninvivo overproduction of pro-inflammatory
conference promoted by the APASL aiming to acuteonchronic liver failure and predicting outcome. cytokines in patients with cirrhosis.
assess the diagnostic definition of ACLF. World J.Gastroenterol. 20, 1493414941 (2014). 59. Gustot,T., Durand,F., Lebrec,D., Vincent,J.L.
12. Sarin,S.K. etal. Acuteonchronic liver failure: 32. Kim,H.Y. etal. Characterization of acuteonchronic &Moreau,R. Severe sepsis in cirrhosis. Hepatology
consensus recommendations of the Asian Pacific liver failure and prediction of mortality in Asian 50, 20222033 (2009).
Association for the Study of the Liver (APASL) 2014. patients with active alcoholism. J.Gastroenterol. 60. Devire,J. etal. Excessive invitro bacterial
Hepatol. Int. 8, 453471 (2014). Hepatol. 31, 427433 (2016). lipopolysaccharide-induced production of monokines
13. Bajaj,J.S. etal. Survival in infection-related 33. Kim,T.Y. & Kim,D.J. Acuteonchronic liver failure. in cirrhosis. Hepatology 11, 628634 (1990).
acuteonchronic liver failure is defined by extra-hepatic Clin. Mol. Hepatol. 19, 349359 (2013). This paper shows for the first time that the exvivo
organ failures. Hepatology 60, 250256 (2014). 34. Jalan,R. etal. Toward an improved definition of innate immune response to LPS is deregulated in
This study shows the prevalence of ACLF and acuteonchronic liver failure. Gastroenterology 147, monocytes from patients with alcoholic cirrhosis.
associated mortality in a large series of patients 410 (2014). 61. Le Moine,O. etal. Role of defective monocyte
with cirrhosis and bacterial infection from the 35. Kim,T.Y. etal. Characteristics and discrepancies in interleukin10 release in tumor necrosis factor-alpha
United States. acuteonchronic liver failure: need for a unified overproduction in alcoholics cirrhosis. Hepatology 22,
14. Jalan,R. etal. Acuteon chronic liver failure. definition. PLoS ONE 11, e0146745 (2016). 14361439 (1995).
J.Hepatol. 57, 13361348 (2012). This study is the first to show that the EASL-CLIF 62. Tazi,K.A. etal. Upregulation of TNF-alpha production
15. Liver Failure and Artificial Liver Group, Chinese Society Consortium definition and the APASL definition signaling pathways in monocytes from patients with
of Infectious Diseases, Chinese Medical Association; ofACLF include different populations of patients. advanced cirrhosis: possible role of Akt and IRAKM.
Severe Liver Diseases and Artificial Liver Group, 36. Sarin,S.K. & Choudhury,A. Acuteonchronic liver J.Hepatol. 45, 280289 (2006).
Chinese Society of Hepatology, Chinese Medical failure: terminology, mechanisms and management. This paper describes the intracellular mechanisms
Association. [Diagnostic and treatment guidelines Nat. Rev. Gastroenterol. Hepatol. 13, 131149 involved in the excessive innate immune response
forliver failure (2012 version)]. Zhonghua Gan Zang (2016). to LPS in monocytes from patients with
Bing Za Zhi 21, 177183 (in Chinese) (2013). 37. Olson,J.C. & Kamath,P.S. Acuteonchronic liver decompensated cirrhosis.
16. Vincent,J.L. etal. The SOFA (Sepsis-related Organ failure: concept, natural history, and prognosis. 63. Tazi,K.A. etal. Protein array technology to
Failure Assessment) score to describe organ Curr.Opin. Crit. Care 17, 165169 (2011). investigate cytokine production by monocytes from
dysfunction/failure. On behalf of the Working Group 38. Singh,K.K., Panda,S.K., Shalimar & Acharya,S.K. patients with advanced alcoholic cirrhosis: an exvivo
onSepsis-Related Problems of the European Society Patients with diabetes mellitus are prone to develop pilot study. Hepatol. Res. 39, 706715 (2009).
of Intensive Care Medicine. Intensive Care Med. 22, severe hepatitis and liver failure due to hepatitis virus 64. Galbois,A. etal. Exvivo effects of high-density
707710 (1996). infection. J.Clin. Exp. Hepatol. 3, 275280 (2013). lipoprotein exposure on the lipopolysaccharide-
17. Wehler,M., Kokoska,J., Reulbach,U., Hahn,E.G. 39. Verbeke,L., Nevens,F. & Laleman,W. Benchtobeside induced inflammatory response in patients with severe
&Strauss,R. Short-term prognosis in critically ill review: acuteonchronic liver failure linking the gut, cirrhosis. Hepatology 49, 175184 (2009).
patients with cirrhosis assessed by prognostic scoring liver and systemic circulation. Crit. Care 15, 233 65. Coant,N. etal. Glycogen synthase kinase 3
systems. Hepatology 34, 255261 (2001). (2011). involvement in the excessive proinflammatory
18. Das,V. etal. Cirrhotic patients in the medical intensive 40. Suntharalingam,G. etal. Cytokine storm in a phase1 response to LPS in patients with decompensated
care unit: early prognosis and long-term survival. trial of the antiCD28 monoclonal antibody TGN1412. cirrhosis. J.Hepatol. 55, 784793 (2011).
Crit.Care Med. 38, 21082116 (2010). N.Engl. J.Med. 355, 10181028 (2006). 66. Gandoura,S. etal. Gene- and exon-expression
19. Levesque,E. etal. Prospective evaluation of the 41. Medzhitov,R., Schneider,D.S. & Soares,M.P. profiling reveals an extensive LPS-induced response
prognostic scores for cirrhotic patients admitted to an Disease tolerance as a defense strategy. Science 335, inimmune cells in patients with cirrhosis. J.Hepatol.
intensive care unit. J.Hepatol. 56, 95102 (2012). 936941 (2012). 58, 936948 (2013).
20. Jalan,R. etal. Development and validation of 42. Medzhitov,R. Origin and physiological roles of 67. Heller,J. etal. Effects of lipopolysaccharide on TNF
aprognostic score to predict mortality in patients inflammation. Nature 454, 428435 (2008). production, hepatic NOS2 activity, and hepatic toxicity
withacute on chronic liver failure. J. Hepatol. 61, 43. Takeuchi,O. & Akira,S. Pattern recognition receptors in rats with cirrhosis. J.Hepatol. 33, 376381
10381047 (2014). and inflammation. Cell 140, 805820 (2010). (2000).
This study describes a prognostic score specifically 44. Iwasaki,A. & Medzhitov,R. Control of adaptive 68. Moreau,R. etal. Terlipressin inhibits invivo aortic
designed for patients with ACLF. The accuracy immunity by the innate immune system. iNOS expression induced by lipopolysaccharide in rats
ofthis score (CLIF-C ACLF score) is significantly Nat.Immunol. 16, 343353 (2015). with biliary cirrhosis. Hepatology 36, 10701078
higher than that of all scores currently used in 45. Wu,J. & Chen,Z.J. Innate immune sensing and (2002).
clinical practice. signaling of cytosolic nucleic acids. Annu. Rev. 69. Urbanowicz,W. etal. Tezosentan, an endothelin
21. Bernal,W. etal. Acuteonchronic liver failure. Lancet Immunol. 32, 461488 (2014). receptor antagonist, limits liver injury in endotoxin
386, 15761587 (2015). 46. Xu,H. etal. Innate immune sensing of bacterial challenged cirrhotic rats. Gut 53, 18441849
22. Bernsmeier,C. etal. Patients with acuteonchronic modifications of Rho GTPases by the pyrin (2004).
liver failure have increased numbers of regulatory inflammasome. Nature 513, 237241 (2014). 70. Tazi,K.A. etal. Invivo altered unfolded protein
immune cells expressing the receptor tyrosine kinase 47. Zhao,Y. etal. The NLRC4 inflammasome receptors response and apoptosis in livers from
MERTK. Gastroenterology 148, 603615.e14 (2015). forbacterial flagellin and typeIII secretion apparatus. lipopolysaccharide-challenged cirrhotic rats.
23. Zhang,Q. etal. Comparison of current diagnostic Nature 477, 596600 (2011). J.Hepatol. 46, 10751088 (2007).
criteria for acuteonchronic liver failure. PLoS ONE 48. Martinon,F., Mayor,A. & Tschopp,J. The This paper shows for the first time that
10, e0122158 (2015). inflammasomes: guardians of the body. Annu. Rev. LPS-induced hepatic endoplasmic reticulum stress
24. Li,H. etal. Characteristics, diagnosis and prognosis Immunol. 27, 229265 (2009). inhibits the accumulation of NFBdependent
ofacuteonchronic liver failure in cirrhosis associated 49. Kono,H. & Rock,K.L. How dying cells alert the anti-apoptotic proteins in livers from rats with
to hepatitis B. Sci. Rep. 6, 25487 (2016). immune system to danger. Nat. Rev. Immunol. 8, cirrhosis.
This study indicates that the EASL-CLIF Consortium 279289 (2008). 71. Thabut,D. etal. High-density lipoprotein
definition of ACLF designed for European patients 50. Rickard,J.A. etal. RIPK1 regulates RIPK3MLKL- administration attenuates liver proinflammatory
can also be used in Chinese patients with cirrhosis driven systemic inflammation and emergency response, restores liver endothelial nitric oxide
due to HBV infection with no major differences in hematopoiesis. Cell 157, 11751188 (2014). synthase activity, and lowers portal pressure in
prevalence, severity and prognosis. 51. Angus,D.C. & van der Poll,T. Severe sepsis and septic cirrhotic rats. Hepatology 46, 18931906 (2007).
25. Dirchwolf,M. etal. Immune dysfunction in cirrhosis: shock. N.Engl. J.Med. 369, 840851 (2013). 72. Malhi,H. & Kaufman,R.J. Endoplasmic reticulum
distinct cytokines phenotypes according to 52. Medzhitov,R. Inflammation 2010: new adventures stress in liver disease. J.Hepatol. 54, 795809
cirrhosisseverity. Cytokine 77, 1425 (2015). ofan old flame. Cell 140, 771776 (2010). (2011).

16 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

73. Chaisson,M.L., Brooling,J.T., Ladiges,W., Tsai,S. diagnosis. It shows that ACLF is an extremely adoubleblind, placebo-controlled trial.
&Fausto,N. Hepatocyte-specific inhibition of NFB dynamic syndrome that may improve, worsen Gastroenterology 119, 16371648 (2000).
leads to apoptosis after TNF treatment, but not after orfollow a steady course. Prognosis is highly 115. Nguyen-Khac,E. etal. Glucocorticoids plus
partial hepatectomy. J.Clin. Invest. 110, 193202 dependent on the clinical course within the Nacetylcysteine in severe alcoholic hepatitis. N.Engl.
(2002). firstweek after diagnosis. J.Med. 365, 17811789 (2011).
74. Louvet,A. etal. Infection in patients with severe 97. Shi,Y. etal. Acuteonchronic liver failure precipitated 116. Thursz,M.R. etal. Prednisolone or pentoxifylline for
alcoholic hepatitis treated with steroids: by hepatic injury is distinct from that precipitated by alcoholic hepatitis. N.Engl. J.Med. 372, 16191628
earlyresponse to therapy is the key factor. extrahepatic insults. Hepatology 62, 232242 (2015).
Gastroenterology 137, 541548 (2009). (2015). 117. Kedarisetty,C.K. etal. Combination of granulocyte
75. Lucey,M.R., Mathurin,P. & Morgan,T.R. Alcoholic This study confirms the results of the CANONIC colony-stimulating factor and erythropoietin improves
hepatitis. N.Engl. J.Med. 360, 27582769 (2009). study in European patients, showing that outcomes of patients with decompensated cirrhosis.
76. beda,M. etal. Obeticholic acid reduces bacterial short-term (28day and 90day) mortality in Gastroenterology 148, 13621370.e7 (2015).
translocation and inhibits intestinal inflammation in Asianpatients with ACLF depends on the number 118. Arroyo,V., Moreau,R., Jalan,R. & Gins,P.
cirrhotic rats. J.Hepatol. 64, 10491057 (2015). of organ failures and not on the aetiology Acuteonchronic liver failure: a new syndrome that will
77. Du Plessis,J. etal. Activated intestinal macrophages (thetypeofprecipitating events) of the syndrome. reclassify cirrhosis. J.Hepatol. 62, S131S143
in patients with cirrhosis release NO and IL6 that may 98. Jalan,R. etal. The CLIF Consortium Acute (2015).
disrupt intestinal barrier function. J.Hepatol. 58, Decompensation score (CLIFC ADs) for prognosis 119. Seto,W.K., Lai,C.L. & Yuen,M.F. Acuteonchronic
11251132 (2013). ofhospitalised cirrhotic patients without liver failure in chronic hepatitis B. J.Gastroenterol.
78. Francs,R. etal. Bacterial translocation is acuteonchronic liver failure. J.Hepatol. 62, Hepatol. 27, 662669 (2012).
downregulated by anti-TNF monoclonal antibody 831840 (2015). 120. Garg,H. etal. Tenofovir improves the outcome in
administration in rats with cirrhosis and ascites. 99. Kamath,P.S. & Kim,W.R. The model for end-stage patients with spontaneous reactivation of hepatitis B
J.Hepatol. 46, 797803 (2007). liver disease (MELD). Hepatology 45, 797805 presenting as acuteonchronic liver failure.
79. Dominguez,M. etal. Hepatic expression of CXC (2007). Hepatology 53, 774780 (2011).
chemokines predicts portal hypertension and survival 100. Durand,F. & Valla,D. Assessment of the prognosis 121. Philips,C.A. & Sarin,S.K. Potent antiviral
in patients with alcoholic hepatitis. Gastroenterology ofcirrhosis: Child-Pugh versus MELD. J.Hepatol. 42, therapyimproves survival in acute on chronic
136, 16391650 (2009). S100S107 (2005). liverfailure due to hepatitis B virus reactivation.
This paper shows that neutrophil-attracting 101. Biggins,S.W. Use of serum sodium for liver transplant WorldJ.Gastroenterol. 20, 1603716052 (2014).
chemokines are overexpressed in livers from graft allocation: a decade in the making, now is it The results of this study are a clear indication
patients with severe alcoholic cirrhosis. ready for primetime? Liver Transpl. 21, 279281 thatpotent antiviral therapy significantly
80. Charo,I.F. & Ransohoff,R.M. The many roles of (2015). improvesthe clinical course and survival of
chemokines and chemokine receptors in inflammation. 102. Fernandez,J. & Arroyo,V. Bacterial infections in patientswith ACLF due to reactivation of HBV.
N.Engl. J.Med. 354, 610621 (2006). cirrhosis: a growing problem with significant 122. Arabi,Y.M. etal. Antimicrobial therapeutic
81. Kubes,P. & Mehal,W.Z. Sterile inflammation in the implications. Clin. Liver Dis. 2, 102105 (2013). determinants of outcomes from septic shock among
liver. Gastroenterology 143, 11581172 (2012). 103. Sarin,S.K. etal. Asian-Pacific clinical practice patients with cirrhosis. Hepatology 56, 23052315
82. Larosche,I. etal. Prolonged ethanol administration guidelines on the management of hepatitis B: a 2015 (2012).
depletes mitochondrial DNA in MnSOD- update. Hepatol. Int. 10, 198 (2016). 123. Tandon,P. & Garcia-Tsao,G. Bacterial infections,
overexpressing transgenic mice, but not in their wild 104. Sort,P. etal. Effect of intravenous albumin on renal sepsis, and multiorgan failure in cirrhosis.
type littermates. Toxicol. Appl. Pharmacol. 234, impairment and mortality in patients with cirrhosis Semin. Liver Dis. 28, 2642 (2008).
326338 (2009). and spontaneous bacterial peritonitis. N.Engl. J.Med. 124. Fernndez,J., Tandon,P., Mensa,J. & Garcia-Tsao,G.
83. Choumar,A. etal. Lipopolysaccharide-induced 341, 403409 (1999). Antibiotic prophylaxis in cirrhosis: good and bad.
mitochondrial DNA depletion. Antioxid. Redox Signal. This randomized controlled trial was the first to Hepatology 63, 20192031 (2016).
15, 28372854 (2011). show that intravenous albumin administration 125. Chen,T. etal. Nucleoside analogues improve the
84. West,A.P. etal. Mitochondrial DNA stress primes (1.5g per kg of body weight at infection diagnosis short-term and long-term prognosis of patients with
theantiviral innate immune response. Nature 520, and 1g per kg of body weight at the third day) hepatitis B virus-related acuteonchronic liver failure.
553557 (2015). ishighly effective in preventing type 1HRS and Clin. Exp. Med. 12, 159164 (2012).
85. Dubuquoy,L. etal. Progenitor cell expansion and mortality in patients with cirrhosis and 126. Xie,F. etal. Effects of nucleoside analogue on patients
impaired hepatocyte regeneration in explanted livers spontaneous bacterial peritonitis. with chronic hepatitis Bassociated liver failure:
from alcoholic hepatitis. Gut 64, 19491960 (2015). 105. Arroyo,V., Garca-Martinez,R. & Salvatella,X. Human metaanalysis. PLoS ONE 8, e54773 (2013).
86. Brenner,D.A., Paik,Y.H. & Schnabl,B. Role of gut serum albumin, systemic inflammation, and cirrhosis. 127. Yang,J. etal. Initial combination anti-viral therapy
microbiota in liver disease. J.Clin. Gastroenterol. 49, J.Hepatol. 61, 396407 (2014). with lamivudine and adefovir dipivoxil decreases
S25S27 (2015). 106. Guevara,M. etal. Albumin for bacterial infections short-term fatality rate of hepatitis-Bvirus-related
87. Bajaj,J.S. etal. Altered profile of human gut other than spontaneous bacterial peritonitis in acuteonchronic liver failure. Virol.J. 12, 97 (2015).
microbiome is associated with cirrhosis and its cirrhosis. A randomized, controlled study. J.Hepatol. 128. Garg,V. etal. Granulocyte colony-stimulating factor
complications. J.Hepatol. 60, 940947 (2014). 57, 759765 (2012). mobilizes CD34+ cells and improves survival of
88. Bajaj,J.S. etal. Linkage of gut microbiome with 107. Thvenot,T. etal. Effect of albumin in cirrhotic patients with acuteonchronic liver failure.
cognition in hepatic encephalopathy. Am. J.Physiol. patients with infection other than spontaneous Gastroenterology 142, 505512.e1 (2012).
Gastrointest. Liver Physiol. 302, G168G175 (2012). bacterial peritonitis. A randomized trial. J.Hepatol. 129. Angeli,P. etal. Diagnosis and management of acute
89. Chen,Y. etal. Characterization of fecal microbial 62, 822830 (2015). kidney injury in patients with cirrhosis: revised
communities in patients with liver cirrhosis. 108. Gins,P. etal. Norfloxacin prevents spontaneous consensus recommendations of the International Club
Hepatology 54, 562572 (2011). bacterial peritonitis recurrence in cirrhosis: results of of Ascites. J.Hepatol. 62, 968974 (2015).
90. Chen,Y. etal. Gut dysbiosis in acuteonchronic liver adouble-blind, placebo-controlled trial. Hepatology This article provides the most modern clinical
failure and its predictive value for mortality. 12, 716724 (1990). guidelines on the diagnosis and treatment of AKI
J.Gastroenterol. Hepatol. 30, 14291437 (2015). 109. Soriano,G. etal. Norfloxacin prevents bacterial incirrhosis.
91. Pan,C. etal. Dynamic changes of lipopolysaccharide infection in cirrhotics with gastrointestinal 130. Belcher,J.M. etal. Urinary biomarkers and
levels in different phases of acute on chronic hemorrhage. Gastroenterology 103, 12671272 progression of AKI in patients with cirrhosis.
hepatitisB liver failure. PLoS ONE 7, e49460 (2012). (1992). Clin.J.Am. Soc. Nephrol. 9, 18571867 (2014).
92. Bauer,T.M. etal. Small intestinal bacterial 110. Fernndez,J. etal. Primary prophylaxis of 131. Rivers,E. etal. Early goal-directed therapy in the
overgrowth in human cirrhosis is associated with spontaneous bacterial peritonitis delays hepatorenal treatment of severe sepsis and septic shock. N.Engl.
systemic endotoxemia. Am. J.Gastroenterol. 97, syndrome and improves survival in cirrhosis. J.Med. 345, 13681377 (2001).
23642370 (2002). Gastroenterology 133, 818824 (2007). 132. Fede,G. etal. Adrenocortical dysfunction in liver
This paper shows an association between This randomized controlled trial was the first disease: a systematic review. Hepatology 55,
microbiota alterations and systemic endotoxaemia toshow that long-term oral administration 12821291 (2012).
in patients with cirrhosis. ofnorfloxacin prevents the development of 133. Vilstrup,H. etal. Hepatic encephalopathy in chronic
93. Zapater,P. etal. Serum and ascitic fluid bacterial spontaneous bacterial peritonitis and type 1HRS liver disease: 2014 Practice Guideline by the
DNA: a new independent prognostic factor in and improves survival in patients with cirrhosis American Association for the Study of Liver Diseases
noninfected patients with cirrhosis. Hepatology 48, andsevere liver and renal dysfunction. and the European Association for the Study of the
19241931 (2008). 111. Zapater,P. etal. Norfloxacin modulates the Liver. Hepatology 60, 715735 (2014).
94. McPhail,M.J.W. etal. Increased survival for patients inflammatory response and directly affects 134. Bianchini,M., De Pietri,L. & Villa,E. Coagulopathy in
with cirrhosis and organ failure in liver intensive care neutrophilsin patients with decompensated liver diseases: complication or therapy? Dig. Dis. 32,
and validation of the Chronic Liver Failure-Sequential cirrhosis.Gastroenterology 137, 16691679.e1 609614 (2014).
Organ Failure Scoring System. Clin. Gastroenterol. (2009). 135. de Franchis,R. & Baveno VI Faculty. Expanding
Hepatol. 13, 13531360.e8 (2015). 112. Gmez-Hurtado,I. etal. Interleukin10mediated consensus in portal hypertension: report of the
95. Silva,P.E.S.E. etal. Single-centre validation of the heme oxygenase 1induced underlying mechanism Baveno VI Consensus Workshop: stratifying risk
EASL-CLIF Consortium definition of acuteonchronic ininflammatory down-regulation by norfloxacin in andindividualizing care for portal hypertension.
liver failure and CLIF-SOFA for prediction of mortality cirrhosis. Hepatology 53, 935944 (2011). J.Hepatol. 63, 743752 (2015).
in cirrhosis. Liver Int. 35, 15161523 (2015). 113. Gmez-Hurtado,I. etal. Role of interleukin 10 in This article provides the most modern clinical
96. Gustot,T. etal. Clinical course of acuteonchronic liver norfloxacin prevention of luminal free endotoxin guidelines on the diagnosis management of portal
failure syndrome and effects on prognosis. Hepatology translocation in mice with cirrhosis. J.Hepatol. 61, hypertension and gastrointestinal haemorrhage
62, 243252 (2015). 799808 (2014). incirrhosis. There is a detailed description on
This study is the first investigation defining the 114. Akriviadis,E. etal. Pentoxifylline improves short-term themanagement of coagulopathy in patients
clinical course of ACLF within 28days following survival in severe acute alcoholic hepatitis: withportal vein thrombosis.

NATURE REVIEWS | DISEASE PRIMERS VOLUME 2 | 2016 | 17



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.
PRIMER

136. Lee,S.Y., Kim,H.J. & Choi,D. Cell sources, liver ameta-analysis based on seven controlled trials. 165. Verbeke,L. etal. Obeticholic acid, a farnesoid X
support systems and liver tissue engineering: Gastroenterol. Res. Pract. 2015, 908275 (2015). receptor agonist, improves portal hypertension by
alternatives to liver transplantation. Int. J.Stem Cells 152. Volk,M.L., Tocco,R.S., Bazick,J., Rakoski,M.O. twodistinct pathways in cirrhotic rats. Hepatology 59,
8, 3647 (2015). &Lok,A.S. Hospital readmissions among patients 22862298 (2014).
137. Struecker,B., Raschzok,N. & Sauer,I.M. Liver with decompensated cirrhosis. Am. J.Gastroenterol. 166. Verbeke,L. etal. The FXR agonist obeticholic acid
support strategies: cutting-edge technologies. Nat. 107, 247252 (2012). prevents gut barrier dysfunction and bacterial
Rev. Gastroenterol. Hepatol. 11, 166176 (2014). 153. Reddy,K.R. etal. High risk of delisting or death in translocation in cholestatic rats. Am. J.Pathol. 185,
This article contains a comprehensive review of liver transplant candidates following infections: results 409419 (2015).
theartificial liver support strategies in patients from the North American Consortium for the Study of This article reports a study in experimental
with acute liver failure and ACLF. End-Stage Liver Disease. Liver Transpl. 21, 881888 cirrhosisshowing that oral obeticholic acid
138. Baares,R. etal. Extracorporeal albumin dialysis (2015). improvesgut permeability, intestinal inflammation
withthe molecular adsorbent recirculating system 154. OLeary,J.G. etal. Long-term use of antibiotics and and bacterial translocation.
inacuteonchronic liver failure: the RELIEF trial. proton pump inhibitors predict development of 167. Kayagaki,N. etal. Noncanonical inflammasome
Hepatology 57, 11531162 (2013). infections in patients with cirrhosis. Clin. activation by intracellular LPS independent of TLR4.
139. Kribben,A. etal. Effects of fractionated plasma Gastroenterol. Hepatol. 13, 753759.e2 (2015). Science 341, 12461249 (2013).
separation and adsorption on survival in patients with 155. Battle,C.E., Davies,G. & Evans,P.A. Long term 168. Shi,J. etal. Inflammatory caspases are innate immune
acuteonchronic liver failure. Gastroenterology 142, health-related quality of life in survivors of sepsis in receptors for intracellular LPS. Nature 514, 187192
782789.e3 (2012). south west Wales: an epidemiological study. PLoS ONE (2014).
140. Lee,K.C.L. etal. Extracorporeal liver assist device 9, e116304 (2014). 169. Broz,P. Immunology: caspase target drives pyroptosis.
toexchange albumin and remove endotoxin in acute 156. Vanwijngaerden,Y.M. etal. Critical illness evokes Nature 526, 642643 (2015).
liver failure: results of a pivotal pre-clinical study. elevated circulating bile acids related to altered 170. Sargenti,K., Prytz,H., Nilsson,E. & Kalaitzakis,E.
J.Hepatol. 63, 634642 (2015). hepatic transporter and nuclear receptor expression. Predictors of mortality among patients with
141. Larsen,F.S. etal. High-volume plasma exchange in Hepatology 54, 17411752 (2011). compensated and decompensated liver cirrhosis:
patients with acute liver failure: an open randomised 157. Katoonizadeh,A. etal. Early features of therole of bacterial infections and infection-related
controlled trial. J. Hepatol. 64, 6978 (2016). acuteonchronic alcoholic liver failure: a prospective acuteonchronic liver failure. Scand. J.Gastroenterol.
142. Bahirwani,R., Shaked,O., Bewtra,M., Forde,K. cohort study. Gut 59, 15611569 (2010). 50, 875883 (2015).
&Reddy,K.R. Acuteonchronic liver failure before 158. Hotchkiss,R.S., Monneret,G. & Payen,D. 171. Blei,A.T. & Crdoba,J. Hepatic encephalopathy.
liver transplantation: impact on posttransplant Sepsisinduced immunosuppression: from cellular Am.J.Gastroenterol. 96, 19681976 (2001).
outcomes. Transplantation 92, 952957 (2011). dysfunctions to immunotherapy. Nat. Rev. Immunol.
143. Duan,B.W. etal. Liver transplantation in 13, 862874 (2013). Acknowledgements
acuteonchronic liver failure patients with high 159. Gomez,H. etal. A unified theory of sepsis-induced The European Association for the Study of the Liver-Chronic
model for end-stage liver disease (MELD) scores: acute kidney injury: inflammation, microcirculatory Liver Failure (EASL-CLIF) Consortium is endorsed by the
asingle center experience of 100 consecutive cases. dysfunction, bioenergetics, and the tubular cell European Association for the Study of the Liver and
J.Surg. Res. 183, 936943 (2013). adaptation to injury. Shock 41, 311 (2014). supported by an unrestricted grant from Grifols. The authors
144. Finkenstedt,A. etal. Acuteonchronic liver failure: This article contains a comprehensive review of thank D.J.Kim for the supply of the published Korean
excellent outcomes after liver transplantation but high themechanisms of AKI associated with systemic data and the Data Management Centre of the EASL-CLIF
mortality on the wait list. Liver Transpl. 19, 879886 inflammation in sepsis. Concepts might be Consortium for providing the unpublished European data
(2013). extended to AKI and other types of organ failure used in Figure 2.
145. Sharma,P., Schaubel,D.E., Gong,Q., Guidinger,M. inACLF.
&Merion,R.M. End-stage liver disease candidates 160. Jimnez,W., Clria,J., Arroyo,V. & Rods,J. Carbon Author contributions
atthe highest model for end-stage liver disease scores tetrachloride induced cirrhosis in rats: a useful tool for Introduction (V.A.); Epidemiology (P.S.K.); Mechanisms/
have higher wait-list mortality than status1A investigating the pathogenesis of ascites in chronic pathophysiology (R.M. and B.S.); Diagnosis, screening and
candidates. Hepatology 55, 192198 (2012). liver disease. J.Gastroenterol. Hepatol. 7, 9097 prevention (P.G., V.A. and J.F.); Management (R.J., G.G.T., U.T.
146. Chan,A.C. etal. Liver transplantation for (1992). and J.F.); Quality of life (P.S.K.); Outlook (F.N. and V.A.);
acuteonchronic liver failure. Hepatol. Int. 3, 161. Harry,D. etal. Increased sensitivity to endotoxemia Overview of Primer (V.A.). V.A. and R.M. contributed equally to
571581 (2009). inthe bile duct-ligated cirrhotic rat. Hepatology 30, this work.
147. Chan,A.C.Y. & Fan,S.T. Criteria for liver 11981205 (1999).
transplantation in ACLF and outcome. Hepatol. Int. 9, 162. Bass,N.M. etal. Rifaximin treatment in hepatic Competing interests statement
355359 (2015). encephalopathy. N.Engl. J.Med. 362, 10711081 V.A. has received research funding from Grifols and has served
148. Reddy,M.S., Rajalingam,R. & Rela,M. Liver (2010). on the scientific advisory board for Takeda. P.G. has received
transplantation in acuteonchronic liver failure: This article reports a randomized controlled trial research funding from Grifols, served on the scientific advisory
lessons learnt from acute liver failure setting. showing that oral rifaximin is highly effective in board for Ferring and Squana Medical and received research
Hepatol.Int. 9, 508513 (2015). preventing the recurrence of hepatic funding from Sequana Medical. R.J. has received research
149. Khanam,A. etal. Altered frequencies of dendritic cells encephalopathy in cirrhosis. funding from Vital Therapies, has served on the scientific
and IFNsecreting Tcells with granulocyte colony- 163. Bernardi,M. etal. Long-term use of human albumin advisory board for Conatus Pharma and Takeda, has ongoing
stimulating factor (GCSF) therapy in acuteon- chronic for the treatment of ascites in patients with hepatic research collaborations with Gambro and Grifiols and is the
liver failure. Liver Int. 34, 505513 (2014). cirrhosis: the interim analysis of the ANSWER study. principal investigator of an industry sponsored study (Sequana
150. Duan,X.Z. etal. Granulocyte-colony stimulating factor Dig. Liv. Dis. 47 (Suppl.1), e6 (2015). Medical). F.N. has served on the scientific advisory board of
therapy improves survival in patients with hepatitis B 164. Neuschwander-Tetri,B.A. etal. Farnesoid X nuclear Center Fract, Croix Rouge Belgium, Intercept, Gore, Bristol-
virus-associated acuteonchronic liver failure. receptor ligand obeticholic acid for non-cirrhotic, Myers Squibb, AbbVie, Novartis, MSD, Janssen-Cilag,
WorldJ.Gastroenterol. 19, 11041110 (2013). nonalcoholic steatohepatitis (FLINT): a multicentre, Promethera Biosciences and Gilead, and has received grants
151. Ma,X.R. etal. Transplantation of autologous randomised, placebo-controlled trial. Lancet 385, from Roche, Astellas, Ferring, Novartis, Janssen-Cilag and
mesenchymal stem cells for end-stage liver cirrhosis: 956965 (2015). AbbVie. All other authors declare no competing interests.

18 | 2016 | VOLUME 2 www.nature.com/nrdp



2
0
1
6
M
a
c
m
i
l
l
a
n
P
u
b
l
i
s
h
e
r
s
L
i
m
i
t
e
d
.
A
l
l
r
i
g
h
t
s
r
e
s
e
r
v
e
d
.