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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
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
Time
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.
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
a 100 b 1.2
Korean CANONIC
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)
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.
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
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
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.
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.
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
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
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.
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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.
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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
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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.