REVIEWS

Acute‑on‑chronic liver failure:

terminology, mechanisms and
management
Shiv K. Sarin and Ashok Choudhury
Abstract | Acute-on-chronic liver failure (ACLF) is a distinct clinical entity and differs from acute
liver failure and decompensated cirrhosis in timing, presence of acute precipitant, course of
disease and potential for unaided recovery. The definition involves outlining the acute and chronic
insults to include a homogenous patient group with liver failure and an expected outcome in a
specific timeframe. The pathophysiology of ACLF relates to persistent inflammation, immune
dysregulation with initial wide-spread immune activation, a state of systematic inflammatory
response syndrome and subsequent sepsis due to immune paresis. The disease severity and
outcome can be predicted by both hepatic and extrahepatic organ failure(s). Clinical recovery is
expected with the use of nucleoside analogues for hepatitis B, and steroids for severe alcoholic
hepatitis and, possibly, severe autoimmune hepatitis. Artificial liver support systems help remove
toxins and metabolites and serve as a bridge therapy before liver transplantation. Hepatic
regeneration during ongoing liver failure, although challenging, is possible through the use of
growth factors. Liver transplantation remains the definitive treatment with a good outcome.
Pre-emptive antiviral agents for hepatitis B before chemotherapy to prevent viral reactivation
and caution in using potentially hepatotoxic drugs can prevent the development of ACLF.

Department of Hepatology,
Institute of Liver and Biliary
Sciences, D-1, Vasant Kunj,
New Delhi 110070, India.
Correspondence to S.K.S.
sksarin@ilbs.in
doi:10.1038/nrgastro.2015.219
Published online 3 Feb 2016
Liver failure is a frequent and often fatal medical emer-
gency. The incidence is rising with the increasing use
of alcohol, overuse of drugs and the growing epidemic of
obesity and diabetes mellitus1. Liver failure can present
as acute liver failure (ALF; in the absence of any pre-­
existing liver disease), acute‑on‑chronic liver failure
(ACLF; in the presence of chronic liver disease (CLD)
or cirrhosis), or an acute worsening of decompensated
cirrhosis. The former and the latter are well-defined
disease entities. However, owing to overlap of termin­
ologies, more than a dozen definitions have emerged
to describe ACLF. The two most widely accepted ones
are from the Asian Pacific Association for the Study
of the Liver (APASL)2 and the European Association
for the  Study of the Liver (EASL) Chronic Liver
Failure (EASL-CLIF) consortium3. Terms such as late-­
onset liver failure, sub-acute hepatic failure, impaired
regener­ation syndrome, acute‑on‑chronic liver disease,
sub-fulminant hepatic failure and so on have become
less relevant and are not often used. ACLF is one of
the most challenging fields in hepatology today, with
intense research underway to decipher the mechanisms
of progressive liver failure and to develop therapeutic
strategies to suppress ­ongoing injury and supplement
hepatic regeneration. This Review discusses the concept,
mechanisms, manage­ment and prevention of ACLF
and ­highlights the ­controversies and future directions
of the field.
The concept of ACLF and critical mass
ACLF is a clinical syndrome manifesting as acute and
severe hepatic dysfunction resulting from varied insults2.
The term was coined in 1995 to describe a condition in
which an acute and a chronic hepatic insult are operating
simultaneously4 (FIG. 1). An acute severe hepatic insult
in a healthy liver can lead to ALF, and with aggressive
critical care, a non-transplantation survival of up to
60% can be achieved5. In the presence of CLD, an acute
insult can lead to rapid and progressive liver failure,
with a high short-term mortality as the liver’s functional
reserve is limited4. However, potential for reversing pro-
gressive liver failure exists in a c­ rucial ‘golden window’
period, by ameliorating the acute insult, preventing
development of sepsis and extra­hepatic organ failure
and supporting hepatic regeneration (FIG. 2). The prime
drivers of patient outcome at different time points are a
combination of the critical functional hepatic reserve,
and the nature and severity of the acute insult2.

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Key points
• Acute‑on‑chronic liver failure (ACLF) is a distinct clinical syndrome characterized by
liver failure due to an acute hepatic injury on an underlying chronic liver disease with
high 28-day mortality
• Acute insults include alcohol, hepatotropic viruses and drugs whereas the underlying
chronic liver disease is generally cirrhosis due to alcohol, hepatitis B or C, or NASH
• After an acute insult, persistent inflammation, systemic inflammatory response
syndrome and the cytokine storm have a central role in the pathogenesis of liver
failure and subsequent organ failure
• A short ‘golden window’ precedes sepsis development and organ(s) failure, providing
opportunity for immunomodulation with granulocyte-colony stimulating factor and
other interventions; extrahepatic organ failure indicates severity of illness, prognosis
and helps guide management
• Abstinence, antiviral therapy and withdrawal of harmful drug are specific therapies
that could help ameliorate or reverse the liver failure
• Liver transplantation is the definitive treatment and a good outcome is achieved with
early transplantation in carefully selected patients; liver dialysis and plasmapheresis
can help as ‘bridge therapies’
Definition of ACLF
To identify the acute insult, one needs to answer issues
related to what constitutes an acute insult. First, is the
insult hepatic or extrahepatic? As the primary affected
organ and the nominal organ of the syndrome, arguably
the insult should be targeted to the liver. If liver failure
in a patient with cirrhosis is a consequence of kidney,
lung or circulatory failure, it would constitute a different
clinical scenario. Recent clinical worsening of a patient
with chronic pancreatitis due to urospesis would not
be called acute‑on‑chronic pancreatitis. Acute hepa-
titis in a patient with chronic obstructive pulmonary
disease (COPD) would not be called acute‑on‑chronic
ACLF
Acute insult Chronic injury
• Ethanol • Chronic liver
disease
• Hepatitis B reactivation
• Viral hepatitis • Cirrhosis
• Autoimmune hepatitis • Asymptomatic
• Compensated
• Drug-induced liver injury
• No prior
• Wilson’s disease flare
decompensation
• Unknown
Liver failure
• Jaundice
• Coagulopathy
• Ascites or hepatic encephalopathy
Reversibility
Figure 1 | Definition and concept of ACLF. The acute
Natureone.
insult is hepatic Reviews | Gastroenterology
This insult & Hepatology
to a patient with chronic
liver disease (and chronic injury) could result in ACLF. In a
patient with ACLF, the nature and severity of acute insult
needs to be identified and defined, the background
chronic liver disease (chronic hepatitis or compensated
cirrhosis) also needs to be assessed and defined. Both lead
to liver failure and determine the reversibility of this
syndrome. ACLF, acute-on-chronic liver failure.
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obstructive pulmonary disease. Similarly, an infection
resulting in pneumonia in a patient with cirrhosis, with
subsequent worsening of liver functions, is very dif-
ferent than a hepatic insult causing liver failure with
­subsequent failure of other organs.
Second, the chronology of events should be well
defined. In ALF, although hepatic encephalopathy is
part of the definition, it must follow or closely coincide
with liver failure. Renal or pulmonary failures that might
develop during ALF are not included in the definition of
ALF, although they do influence mortality. Thus, should
one define ACLF after or before extrahepatic organ fail-
ure sets in? Furthermore, the event must be evident in all
patients to be part of the definition to achieve uniform-
ity. From the point of view of intensive care physicians,
it is well known that as the number of dysfunctional or
failed organs increases, mortality cumulatively increases;
as is also shown by the CLIF sequential organ failure
assessment (SOFA) score for ACLF3.
Third, whether sepsis per se could directly lead
to liver failure without affecting extrahepatic organs
or whether sepsis is a result of severely compromised
hepatic immune function in ongoing liver failure should
be defined. Sepsis often follows systematic inflamma-
tory response syndrome (SIRS) and is an integral, but
usually late event in the development of multiorgan fail-
ure, for example in acute pancreatitis. Inclusion of both
extrahepatic organ failure and sepsis in the definition
of ACLF would therefore definitely delay diagnosis in
all cases and permit the inclusion of a heterogeneous
group of patients. These three points are the main con-
ceptual differences concerning the ‘acute insult’ between
the EASL-CLIF consortium and APASL definitions of
ACLF6,7. In most patients, sudden worsening of decom-
pensated end-stage liver disease is irreversible. By con-
trast, if the first acute hepatic insult can be treated, the
condition of patients with compensated cirrhosis leading
to ACLF could be improved8. Thus, including a worsen­
ing of decompensated cirrhosis in the definition of
ACLF would add to the heterogeneity of patient popu­
lation9 and hinder development of specific therapies,
such as approaches for hepatic regeneration or immune
modulation2. Furthermore, patients with cirrhosis who
require admission to hospital with acute decompensa-
tion (such as due to gastrointestinal bleeding and hepatic
encephalopathy) have variable outcomes depending on
whether they have underlying liver failure or not9. The
initial CLIF Acute‑on‑Chronic Liver Failure in Cirrhosis
(CANONIC) definition of ACLF was quite broad due
to these inclusions. Subsequently, proposals have been
put forward to create several subtypes of ACLF7,9. The
Western ACLF definition has become a bit more confus-
ing by including terms such as hepatic ACLF and extra-
hepatic ACLF10, infection-related ACLF11, and types A, B
and C ACLF12,13. A need for simplicity, clarity and homo-
geneity certainly exists. As new-onset liver failure is at
the core of the term ACLF and is a distinctly different
presentation of cirrhosis or chronic liver disease than,
for example, variceal bleeding, sepsis and renal failure,
it should not be adulterated to include aspects of these
clinical entities.

100
Relative threshold for:
Golden window
Injury
ACLF Spontaneous recovery
Heptatic reserve (%)
DC
Liver failure and liver transplantation
Multi organ failure
Death
0
0 1 2 3 4 5 6 7 8 9
Time (weeks)
Figure 2 | The concept of the hepatic reserve and ACLF. This model describes the
outcome of an acute insult to the liver depending upon the hepatic reserve. The hepatic
reserve is markedly reduced in patients with ACLF and much lower in those with
decompensated cirrhosis. After acute insult orReviews
Nature injury, the condition of a patient
| Gastroenterology & Hepatology
with ACLF is likely to rapidly deteriorate and in the first 1–2 weeks after injury onset,
the patient could also develop sepsis. This intervening period is a therapeutic ‘golden
window’, in which there are opportunities to ameliorate the acute injury and modulate
the patient’s immune response to prevent the development of sepsis, and supplement
liver regeneration to reverse the decline towards multiorgan failure and death.
A progressive downhill course often occurs in a patient with decompensated cirrhosis
compared with ACLF. After mitigating the acute injury, spontaneous recovery is more
likely in those with ACLF than decompensated cirrhosis because of a higher baseline
hepatic reserve. Liver transplantation should preferably be done before the onset of
multiorgan failure to achieve good outcomes. ACLF, acute‑on‑chronic liver failure;
DC, decompensated cirrhosis.
Although a lack of agreement on an acceptable
definition for ACLF exists, the community is in agree-
ment that ACLF is a distinct clinical entity. The 2009
APASL consensus definition of ACLF4 was developed
by analysis of data from 200 patients. The APASL
ACLF Research Consortium published a revised and
updated consensus statement2 in 2014 after a prospec-
tive f­ ollow‑­up of 1,363 patients across the Asia–Pacific
region. According to this APASL consensus, ACLF is
an acute hepatic insult manifesting as jaundice (serum
bilirubin ≥5 mg/dl (≥85 µmol/L)) and coagulopathy
(INR ≥1.5 or prothrombin activity <40%) complicated
within 4 weeks by clinical ascites and/or encephalo­pathy
in a patient with previously diagnosed or undiagnosed
chronic liver disease or cirrhosis, and is associated
with a high 28‑day mortality2. The APASL definition
is a simple bedside tool, which enables a clinician to
stratify a patient presenting with liver failure for early
intervention to slow the progress or reverse the failure
and improve survival. Moreau et al.3 in the CANONIC
study described ACLF as “an acute deterioration of
pre-existing chronic liver disease, usually related to a
precipitating event and associated with increased mor-
tality at 3 months due to multi-system organ failure”. The
CANONIC ACLF definition was developed from data
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on 1,343 patients across eight European countries and
includes a high 28‑day mortality and the occurrence of
or­gan failure3,6,13. The CLIF-SOFA score is endorsed to
assess severity of the ACLF syndrome, considers hepatic
and extrahepatic organ failure and makes a precise prog-
nostication6. The CLIF-SOFA score has been found use-
ful in the West12,14, however, some studies in the past few
years have shown that a simple organ failure score (con-
sidering only the number of organ failures) is easier for
clinicians to recall and superior to the CLIF-SOFA score
in predicting mortality in ACLF patients from different
populations15. Other studies also corroborate the use of
simple scores16,17. Superiority of CLIF-SOFA score over
the other score has been shown in a few small studies18,19.
The differences and similarities in the definition of
ACLF by these organizations are highlighted in TABLE 1.
When the same patient population is analysed, one
would diagnose ACLF when extrahepatic organ dysfunc-
10 tion or failure develops with the CANONIC definition,
and earlier than this stage using the APASL defini-
tion20. Moreover, in the natural history of ACLF, failure
of other organs is quite variable, and might come late,
so considering liver failure as the primary event will
identify the cohort more precisely and earlier whereas
incorpor­ation of extrahepatic organ failure will guide
the overall treatment options as well as prognostica-
tion20. Studies are needed to address which of the two
interpretations of ACLF (inclusion or exclusion of extra­
hepatic organ failure in the definition) is more relevant
to patient management21.
Aetiopathogenesis of acute injury
The development and progression of ACLF broadly
depends on the nature and severity of the acute insult,
the stage of underlying CLD or cirrhosis, and the rapid-
ity and degree of liver failure2. The nature of the acute
event causing ACLF varies with geographical region.
The time between insult to hepatic failure and its con-
sequences in those with CLD has been determined
as 28 days2. Hepatic failure resulting in ascites and/or
hepatic encephalopathy was found to be accompanied
within this period by high mortality in large Asian
(51%)2 and European cohorts (33.9%)3, respectively.
HBV infection
HBV-related ACLF generally develops in two clinical
scenarios: first, HBV reactivation on a background of
chronic HBV infection and CLD and second, acute
HBV infection on a background of CLD of any aetio­
logy. Up to 8% of patients with hepatitic flares develop
decompensation22. Although, the frequency is compar­
able in hepatitis B e antigen (HBeAg) positive or nega-
tive patients, decompensation is more frequent in those
infected with HBV genotypes B and D23. Reactivation
of HBV is probably due to changes in the immuno­
logical control of viral replication and reconstitution
of host defences. Liver injury is mediated by expanded
numbers of T cells that react with HBeAg and hepati-
tis B core antigen (HBcAg). This crossreaction leads
to HBcAg-specific and HBeAg-specific T cells that are
immunologically over-active. HBV-specific CD8+ T-cell
REVIEWS

Table 1 | The similarities and differences in Western and Eastern approach to ACLF
APASL-ACLF EASL and AASLD-ACLF
Definition
Acute hepatic insult manifesting as jaundice and An acute deterioration of pre-existing chronic liver disease usually
coagulopathy, complicated within 4 weeks by related to a precipitating event and associated with increased
ascites and/or encephalopathy in a patient with mortality at 4 weeks due to multisystem organ failure
previously diagnosed or undiagnosed chronic liver
disease associated with a high 4‑week mortality
Differences
Acute insult or precipitant should be hepatic only Acute insult or precipitant can be hepatic or extrahepatic
Variceal bleeding, only if it results in liver failure is Variceal bleeding is considered a precipitant leading to ACLF
considered a precipitant
Sepsis is a complication of liver failure, persistent Sepsis as a primary precipitant leading to ACLF, hence diagnosis
inflammation, SIRS and CARS, which leads to of ACLF is delayed with little potential for recovery of organ
immune paresis, hence diagnosis of ACLF is made failure (s)
early with potential of recovery
Duration between acute insult and development No duration specified
of ACLF is 4 weeks
CLD includes patients with and without cirrhosis, CLD includes those with (ACLF type B & C) and without (ACLF
but not those with decompensated cirrhosis type A) cirrhosis with or without prior decompensation
A defined cut-off for liver failure; both jaundice No defined cut-off for liver failure. Defined by organ failure cut-off
(bilirubin >85 μmol/L) and coagulopathy (INR >1.5 values in CLIF-SOFA score. Either bilirubin or INR levels can
or prothrombin activity of <40%) independently define liver failure
Disease severity score not defined Disease severity score not defined, but indirectly interpreted
through organ failure scores, as CLIF-SOFA score and represent
both hepatic and nonhepatic ACLF
Similarities
• ACLF defined as a distinct entity that is different from ALF
• Duration showing high mortality at 4 weeks
• Needs early consideration of liver transplant
• Organ failure and sepsis are the most common cause of high mortality
AASLD, American Association for the Study of Liver Disease; ACLF, acute‑on‑chronic liver failure; ALF, acute liver failure; APASL,
Asian Pacific Association for the Study of the Liver; CARS, compensatory anti-inflammatory response syndrome; CLD, chronic liver
disease; CLIF, chronic liver failure; EASL, European Association for the Study of the Liver; SIRS, systematic inflammatory response
syndrome; SOFA, sequential organ failure assessment.

numbers increase along with decreased expression of
programmed cell death protein 1 (PD‑1; also known
as PDCD1) after HBV reactivation24. PD‑1 upregula-
tion might efficiently mitigate pathogenic CD8+ T‑cell
responses and liver damage leading to recovery25.
Acute viral hepatitis
Hepatitis E virus (HEV) infection is a leading cause
of ALF in Asia and Africa, where it is endemic, with a
median incidence of 21% (range 4–72%)26. Although
large studies from India report a high mortality in
patients with HEV-related ACLF and ALF26,27, the
contrib­ution of HEV in precipitating ACLF in the West
is not known as these patients are not routinely tested
for HEV and the prevalence of HEV infection is gen-
erally sporadic28. In the general population, the sero-
prevalence of HEV has been reported as 5–52.5% and
6–26% in Europe and the US, respectively29. A French
study considering 343 patients with cirrhosis showed the
incidence of HEV to be 3.2% (11 of 343) in patients with
decompensated cirrhosis, without any substantial effect
on liver failure and mortality30. HEV infection causes
cell-mediated immune injury and hepatocyte damage,
with high cytokine levels produced by type 1 T helper
cells (TH1; IFNγ, IL‑2 and TNF) and type 2 T helper cells
(TH2; IL‑10)31,32. An increase in the median percentage
of CD4+CD25+Foxp3+ regulatory T (TREG) cells and
CD4+CD25−Foxp3+ effector TREG cells occurs along
with increased IL‑10 levels, suggesting a role for TREG
cells in liver injury and recovery33. Acute hepatitis due
to new HEV infection can contribute up to 20% of acute
­exacerbations of chronic hepatitis B34.
Super-infection with hepatitis A virus (HAV)35 and
HEV36 lead to the development of ACLF. HEV infection
is associated with a more severe form of ACLF with
higher mortality than those infected with HAV. The poly­
morphisms in the gene encoding the receptor for HAV,
HAVCR1 (also known as TIM1) predispose the host to
severe hepatitis37. During HAV infection the size of the
TREG pool is contracted owing to apoptosis of TREG cells
induced by a Fas-mediated mechanism38. A decrease in
TREG-cell numbers leads to reduced suppressive activity
and consequently results in severe liver injury38.
Alcohol
The dose and duration of alcohol consumption
determines the stage of CLD; however, recent alco-
hol intake and/or binge drinking behaviour is what

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contributes to rapid liver failure2. The presence of ­obesity
and/or ­diabetes mellitus increases disease severity39.
Liver injury occurs because of ethanol hepatotoxicity;
enhanced apoptosis, activation of innate and adaptive
immunity and impaired hepatic regeneration40. Ethanol-
mediated gut dysbiosis and increased intestinal perme-
ability leads to increased release of endotoxins to the
liver. Ethanol metabolism leads to accumulation of
reac­tive oxygen species (ROS) and subsequent mito-
chondrial endo­plasmic reticulum stress leading to
hepatocyte apoptosis41. Apoptosis is due to inhibition
of survival genes (Met) and induction of proapoptotic
signalling mol­ecules (TNF and tumour necrosis factor
ligand superfamily member 6 (FASLG; also known as
FasL))40. Release of danger-associated molecular pat-
terns (DAMPs) after cellular necrosis cause macrophage
and neutrophil activation42 and mammaglobin‑A and
microRNA‑122 mediated cell death. Complement C3
and C5 activation, increased neutrophilic infiltration
(upregulated by IL‑8, CXCL1 and IL‑1), activation
of Toll-like receptor (TLR)-2 and TLR‑6 (recognize
bacte­r ial lipopeptides), TLR‑9 (recognize bacterial
DNA-containing unmethylated CpG motifs), lead to
an increase in the proinflammatory cascade mediated
mainly by Kupffer cells43. Ethanol induced injury leads
to an increase in pro-inflammatory drivers (TNF, IL‑1,
IL‑6, IL‑17) and a decrease in anti-inflammatory driv-
ers (mainly adiponectin and adenosine)44. TNF and
tumour necrosis factor receptor superfamily member
1B (TNFRSF1B) closely correlate with disease severity,
hepatocyte ­apoptosis, ­endotoxaemia and mortality44.
Ethanol causes impaired liver regeneration by limit-
ing DNA synthesis and normal microRNA signalling in
mature hepatocytes45. At a cellular level, chronic alcohol
con­sumption induces senescent replication of hepato-
cytes and impaired proliferation of liver progenitors46.
This effect has been indirectly evidenced from patients
with severe alcoholic hepatitis who do not respond to
medical treatment as they have low hepatic expression
of TNF and IL‑6 with an aberrant regeneration process47.
Hepatotoxic drugs
The liver is the main organ for biotransformation of
drugs and metabolites, which involves cytochrome P450
(CYP; phase 1), conjugation (phase 2) and transport­
ation (phase 3). Drugs are, therefore, one of the common
precipitants of liver failure. However, most data relates
to drug-induced ALF and information on ACLF is lim-
ited. Devarbhavi et al.48 reported high mortality (17.1%)
in a cohort of patients with severe drug-induced liver
injury (DILI), having ascites and encephalopathy, which
is akin to ACLF. In a multinational Asian study of 660
patients, DILI contributed as an acute insult in 9.1%
of patients and in 53.3% of these patients the acute insult
was attributed to anti-tubercular drugs followed by com-
plementary alternative medications49. Antibiotics and
anti-epileptic drugs account for >60% of patients with
DILI in the West50. The baseline model for end-stage
liver disease (MELD) score (29 in survivors versus 34
in non-survivors; P <0.006) and hepatic encephalopathy
(23% grade 3 versus 96% grade 4; P <0.01) were strong
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REVIEWS
predictors of mortality and early consideration for trans-
plantation51. Patients with cirrhosis are more vulner­able
and less likely to recover from DILI due to reduced
hepatic drug clearance, aberrant metabolism, altered
excretion and/or impaired adaptive responses and high
free-circulating drug levels due to low albumin50.
Acute variceal bleeding
Liver failure in patients with acute variceal bleeding is
mainly due to hepatic ischaemia, increased b ­ acterial
translocation from the gut and subsequent bac­
terial infections52. Whether to consider acute variceal
bleeding as an acute event of ACLF or a form of decom-
pensation of underlying CLD is debatable. Acute variceal
bleeding was considered a precipitating event in 13.8%
of patients in the CANONIC study3 and 28% of cases in
another study53. In fact, if the acute variceal bleed results
in hepatic ischaemia, ischaemic hepatitis and jaundice,
and fulfils the criteria of liver failure in the given time
frame, it could then be included as a precipitating event
for ACLF2.
Sepsis and ACLF
Bacterial infections are more frequent in patients with
cirrhosis than in the general population54. Cirrhosis-
associated immune deficiency syndrome, an emerging
concept, relates to a relative inefficiency of the innate
and adaptive immune system in patients with cirrhosis
to prevent or clear infectious agents in comparison with
those without cirrhosis55. In this context, an acute insult
and ongoing hepatocellular injury, as seen in ACLF,
would lead to an aberrant host inflammatory response,
SIRS and infection (FIG. 3).
Reduced expression of HLA‑DR in monocytes and an
inability to produce TNF increases the risk of infection
and its severity, and correlates with survival in patients
with ACLF56. A substantial reduction in numbers of both
plasmacytoid dendritic cells (pDCs) and myeloid DCs
(mDCs) in addition to increased IFNγ-producing CD8+
T cells in patients with ACLF, further increases the risk
of sepsis and death57. In alcoholic hepatitis, neutrophil
activation, indicated by increased resting respiratory
burst and reduced phagocytic function, was predictive
of subsequent infection, organ failure and mortality58.
Genetic predisposition for increased risk of infections in
cirrhosis has been seen with the TLR2 GT microsatellite
polymorphism (16934 (rs4696480)) and NOD2 vari-
ants particularly for spontaneous bacterial peritonitis
(OR 11.3; P = 0.00002)59.
Whether sepsis is a consequence or a cause of liver
failure is not clear from the current data on ACLF.
Large cohort studies including patients with ACLF and
infection at baseline and comparing them with those
who develop infection subsequently could address
this issue. One viewpoint considers sepsis as a com-
mon extra­hepatic precipitant of ACLF60 and as such
ACLF has been subclassified as infection-related ACLF
(I‑ACLF)11. However, liver failure is a late event in this
group of patients with cirrhosis often concomitant
with other organ failures and has a different clinical
course11. So the I‑ACLF term adds to confusion and
REVIEWS

Gut

Dysbiosis or leaky gut

Inflammatory mediators
1
Necrosis DAMPS

1 PV
Acute insult
(alcohol, Activation 2
virus,drug,
cryptogenic)
4 TNF,
3 IL-1β, IL-6
6 Activation
5
NOS, eNOS

Elevated inflammatory cytokines

(TNF, IL-6, IL-1β, IL-8, IL-10. IL-12,
IL-17, IL-22, IFNγ, IFNα, TGFβ
8

• Inflammation
• Hepatocyte death

SIRS, CARS
Systemic circulation

Organ failure

Stellate Dendritic Kuppfer

Monocyte Neutrophil TREG cell TH17 cell
cell cell cell
Endotoxin or LPS Toxins, cytokines, inflammatory mediators

Figure 3 | The mechanism of injury in ACLF. (1) An acute hepatic insult from viral infection or alcohol activates Kupffer
cells present in hepatic sinusoids, through TLR4, complement receptors (C3R Nature
andReviews
C5R) and| Gastroenterology & Hepatology
DAMPs and results in
increased release of inflammatory mediators, regulatory cytokines, eicosanoids, and lysosomal and proteolytic enzymes.
(2) Increased gut permeability in the altered milieu allows immune cells as well as endotoxins and LPS to migrate towards
the liver. (3) Activation of hepatic stellate cells by Kupffer cells produces endothelin‑1, thromboxane A2, nitric oxide and
prostaglandins leading to hepatic microcirculatory dysfunction and an increase in portal pressure. (4) Release of nitric
oxide causes inflammation-induced hepatocyte cell death via necrosis or apoptosis, which damages neighbouring
parenchymal as well as nonparenchymal cells. (5) A relative deficiency of DCs, more so of myeloid DCs, exists in response
to endotoxin resulting in inefficient immune modulation and injury containment. (6) Neutrophil infiltration, leads to
release of reactive oxygen species (ROS) and in combination with the cytokine burst, leads to mitochondrial stress and
hepatic apoptosis and necrosis. Inhibition of IFNγ production from CD8+ T cells and TREG cells, directly and indirectly
deactivates monocytes and macrophages, resulting in fewer TH17 cells. Neutrophils are also dysfunctional, with poor
phagocytic functions and increased ROS generation. (7 and 8) Ongoing hepatocyte loss and cytokine release leads to
persistent injury, immunoparalysis, with SIRS, CARS and high probability of sepsis. Unabated hepatic injury, sepsis leads to
MODS and eventually, to organ failure. Abrogation of hepatic injury along with immune modulation could prevent sepsis
and or MODS and improve patient survival. ACLF, acute‑on‑chronic liver failure; CARS, compensatory anti-inflammatory
response syndrome; DAMP, damage-associated molecular pattern; DCs, dendritic cells; eNOS, endothelial nitric oxide
synthase; LPS, lipopolysaccharide; MODS, multiorgan dysfunction syndrome; PV, portal vein; SIRS, systemic inflammatory
response syndrome; TGFβ, transforming growth factor beta; TH17 cell, type 17 T helper cell; TREG cell, regulatory T cell.

should be discouraged from routine use. The other Transarterial chemoembolization

school of thought supports the concept that sepsis is
a result of liver failure and proposes that prevention
of SIRS or the development from SIRS to sepsis by
immune modulation in a ‘golden window’ period could
decrease the i­ncidence of organ failure and improve
survival61 (FIGS 2,3).
In a patient with Child–Pugh stage B or C cirrhosis and
HCC, acute deterioration leading to ACLF can develop
after locoregional anticancer therapy (such as TACE or
RFA)62. Quantitative liver function tests such as indo­
cyanine green retention ratio at 15 min or monoethyl­
glycinexylidide test63 can assess hepatic functional

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 REVIEWS

reserve and predict development of ACLF. A model
using risk factors such as portal vein thrombosis, high
levels of aspartate transaminase and bilirubin, raised
α‑fetoprotein levels, and low serum albumin and sodium
levels can reliably predict post‑TACE liver failure64.
Aetiology and diagnosis of CLD
As with the acute insult, the aetiology of CLD and
cirrhosis varies in different parts of the world. The
functional hepatocyte mass is difficult to quantify and
the current methods are rather primitive, especially to
evaluate the percentage of parenchymal loss when an
acute insult precipitates ACLF. CLD includes patients
with moderate to severe hepatic fibrosis and cirrho-
sis. Quite often CLD is detected for the first time after
the development of ACLF. The earlier definition of
ACLF from EASL and the American Association for
the Study of Liver Disease (AASLD) in 2011 included
only patients with cirrhosis65, but now it is proposed
to include patients with or without cirrhosis in three
categories; type‑A (patients with ACLF but without
cirrhosis), type‑B (patients with cirrhosis and ACLF)
and type‑C (patients with ACLF, cirrhosis and prior
hepatic decompensation; TABLE 1)7,12. This proposal is
a way forward to achieve a common ground between
the APASL and EASL-CLIF definitions (type A and B
ACLF from EASL-CLIF are same as in the existing
definition of APASL) as proponents of both groups
agree that CLD and cirrhosis will result in a poorer
outcome than that which results from acute insult on
a healthy liver.
Diagnosis of CLD in the setting of ACLF is difficult
unless previously confirmed or when overt signs of
cirrhosis are present. A detailed history, signs of portal
hypertension such as an enlarged spleen, laboratory
test results (low platelet levels, evidence of synthetic
dysfunction and altered aspartate aminotransferase
(AST): alanine transaminase (ALT) ratio) and endo-
scopic or radiological investigations are required to
confirm the diagnosis66. If these parameters are not
conclusive, a histopathological evaluation, often by
transjugular biopsy, is recommended67.
The aetiology of underlying CLD and cirrhosis is
nearly similar in most parts of the world, except in the
Far East where HBV dominates16. Only hepatosteatosis
is not considered as a CLD as no or minimal fibrosis
exists. On the other hand, NASH is an important cause
of CLD and patients >45 years of age, with diabetes,
obesity and dyslipidaemia do have a high chance of
having stage ≥2 fibrosis68. The APASL ACLF Research
Consortium data using liver biopsy studies has shown
that a proportion of patients presenting with ACLF
have advanced fibrosis without cirrhosis2.
Mechanisms from acute injury to ACLF
Liver failure in ACLF is multifactorial and self-­ immune system is substantially dysfunctional involv-
perpetuating. The acute insult or pathogen (inducer), ing monocytes, DCs, neutrophils and macrophages
directly or indirectly activates different cell types (sen- (FIG. 3). Kupffer cells, the resident macrophages in the
sors) and inflammatory cytokine pathways (medi­ators) liver, which occur in two phenotypes (M1 and M2), are
leading to tissue injury, and the release of DAMPs among the first line of defence for gut-derived patho-
and other cytokines from dying parenchymal and gens77. In response to acute injury and in the presence
non-parenchymal cells69. Tissue damage as a result of
infection is caused by three factors: first, direct action
of virulence factors that induce marked alterations in
tissue homeo­stasis; second, an excessive host immune
response; and third, failed host immune-mediated
tolerance mechanisms70.
Pathogens, such as bacterial products and toxins,
reach the liver mainly by translocation from the gut into
the portal circulation60. This inducer-sensor-­mediator
tissue damage sequence and immune deregulation
cause continued inflammatory injury. The range and
sequence of events, that is, the acute insult, inflamma-
tory injury, immune deregulation, SIRS, compensatory
anti-inflammatory response syndrome (CARS) and the
regenerative response, lead to either recovery of liver
failure or progression with sequential involvement of
extrahepatic organs71,72.
Bacterial translocation and immune response
Bacterial translocation is responsible for life-threaten-
ing infections, such as spontaneous bacterial peritoni-
tis. Gut flora release endotoxins and lipopolysaccharide
(LPS), which contribute to high levels of IL‑6 and TNF
in portal blood as well as in the liver73. Increased intes-
tinal permeability is due to venous congestion of the gut
due to portal hypertension, altered gut flora, the direct
effects of alcohol (in severe alcoholic hepatitis) and
ROS-mediated damage to the gut barrier. Studies show
a linear increase in bacterial translocation with worse
Child–Pugh score, (3.4%, 8.1% and 30.8%, respectively,
in Child–Pugh A, B and C74). Portal hypertension also
aggravates bacterial translocation75. Bacterial trans­
location induces and perpetuates the activated state of
the innate immune system leading to ongoing hepatic
injury. Bacterial trans­location has special relevance in
ACLF, in which both CLD and portal hypertension
coexist accompanied by severe hepatic failure and intes-
tinal dysbiosis. Chen et al.73 outlined the influence of gut
dysbiosis on ACLF and showed that the abundance of
Pasteurellaceae species was an independent predictor
of mortality. Altered innate immune functions, that is,
reduced phagocytic activity of intestinal macrophages
for translocated micro­organisms, and gut-derived
bacterial products lead to unregulated inflammation
as a major contributing factor in ACLF76. A negative
correlation of Ruminococcaceae and Lachnospiraceae
species with TNF and IL‑6 levels indicates a protective
role of these bacterial families and provides a rationale
for modulation of gut flora as a ­preventive strategy in
liver diseases73.
Immunopathology of liver failure in ACLF
The immunopathology of ACLF is a multimodal
immunological response involving alterations in both
the innate and adaptive immunity. In ACLF, the innate

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REVIEWS
of increased intestinal permeability, Kupffer cells are
activated through the LPS and TLR4, or complement
C3 and C5 receptor signalling pathways. The activation
of M1 Kupffer cells occurs via TLRs and DAMPs in
response to LPS stimulation77. The subsequent assem-
bly of the TLR4–CD14–Lymphoctye antigen 96 (Ly‑96
also known as MD2) receptor complex and recruitment
of the adaptor molecules, myeloid-differentiation fac-
tor 88 (MYD88) and TIR domain-containing adaptor
molecule 1 (TRIF), and the downstream signalling cas-
cades, lead to continued inflammatory response78. TNF
and IL‑6 have dual actions of induc­ing hepatocyte death
as well as stimulating hepatocyte proliferation79. TNF
is the first cytokine to be released and net production
increases (despite decreased production by monocytes),
and levels correlate with liver injury and development
of SIRS80. Simultaneously, M2 Kupffer cells are activated
by an alternative pathway in response to IL‑4 and IL‑10
released from TH2 cells77. The M2 phenotype has anti-­
inflammatory effects via cytokines such as transform-
ing growth factor-β (TGFβ) and favours progression to
CARS81. Kupffer cells modulate the transformation of
quiescent hepatic stellate cells to activated myofibro-
blasts, thereby linking immune activation to hepatic
microcirculatory dysfunction82. Hepatic stellate cells,
upon activation by LPS, release endothelin‑1 (ET‑1),
thromboxane A2, nitric oxide, and prostaglandins,
which leads to hepatic microcirculatory dysfunction
and an increase in portal pressure. Nitric oxide released
by hepatic stellate cells causes inflammatory cell death
of hepatocytes via necrosis or apoptosis83,84.
Neutrophils are increased in the liver of those with
ACLF; however, these are predominantly dysfunctional
neutrophils with an increased resting respiratory burst,
but reduced phagocytic function58. This process pre­
disposes patients to infections58, and also correlates with
the severity of liver failure85. Monocytes and DCs are
central mediators that present antigens bound to MHC
class II molecules to T cells, leading to T‑cell activation
and proliferation. With exposure to LPS, monocytes
secrete IL‑1 and TNF, which function in an autocrine
and paracrine fashion86. In patients with ACLF and
monocytes that have a reduced ability to produce TNF
an early reduction in HLA‑DR expression is observed,
which might represent a physiological downregulation
of monocyte function. The persistent or long-term sup-
pression of HLA‑DR is associated with a poor overall
outcome in terms of increased sepsis, organ failure and
death86. A subsequent rebound increase in expression of
HLA‑DR correlates with clinical recovery86.
DCs are potent antigen-presenting cells and pDCs
are particularly tolerogenic and immunosuppressive87.
DCs migrate from the blood to the liver, modulate CD8+
T cells and reduce IFNγ production, which in turn
reduces hepatocellular damage87,88. The low numbers
of mDCs at baseline are associated with high mortal-
ity. Survivors exhibit an initial rapid decline in mDCs
numbers followed by an increase in the circulating as
well as intrahepatic number of mDCs57,88. The altered
hepatic microenvironment, recruitment of mDCs or
mDC generation in the bone marrow does account for
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the subsequent increase in mDCs in liver. This increase
in mDCs correlates with recovery as seen in studies con-
sidering use of granulocyte-colony stimulating factor
(G-CSF)57 and methylprednisolone88.
Tyrosine-protein kinase Mer (MERTK) is a trans-
membrane protein expressed on immune cells and is a
negative regulator of the immune system (innate immu-
nity in particular). MERTK-positive monocytes are
unable to mount a response on exposure to pathogen89.
MERTK inhibition in ACLF monocytes in vitro leads
to upregulation of HLA‑DR, and enhanced response to
microbial challenge; a key mechanism to the monocyte
and/or macrophage dysregulation and immuneparesis89.
MERTK expression is increased in patients with ACLF
and positively correlates with development of SIRS and
increased predisposition to infection and development
of sepsis 89,90. Immune suppression in ACLF is also
mediated by increased population of TGFβ‑secreting
TREG cells81. TREG cells also exhibit substantial inhibi-
tion of IFNγ production, which directly or indirectly
deactivates monocytes and macrophages89. The pool
of TGFβ and IL‑6 secreted from monocytes helps in
generating IL‑17A-secreting CD4+ T cells known as
type 17 T helper (TH17) cells. The ratio of TH17 to TREG
cells is inversely associated with survival in patients
with ACLF91.
In brief, a severely dysregulated immune system
exists in patients with ACLF, from antigen processing
to effector cell functions and cytokine release. The
activated immune cells seem to be dysfunctional, para­
lysed and energy-depleted. This situation results in an
exaggerated SIRS, defective CARS and ultimately to
an increased susceptibility to infections81. Moreover,
even in the absence of overt infection, patients with
ACLF display sepsis-like characteristics such as reduced
ex vivo TNF secretion, monocyte HLA‑DR expression
and increased IL‑6 production81.
From SIRS to organ failure in ACLF
Occurrence and persistence of SIRS is associated with
a hyperdynamic circulation, low mean arterial pres-
sure, microcirculatory disturbances owing to capillary
leak and tissue hypoperfusion66,92. This situation leads
to organ dysfunction in up to 40% of patients with
ACLF even in the absence of any overt infection65,66,72.
SIRS is associated with more severe encephalopathy,
an increased incidence of bacterial infections, renal
failure and poor survival than those without it. In a
large study, the persistence of SIRS for up to 7 days
or new-onset SIRS within the first week of hospital-
ization, correlated with progressive liver failure and
high mortality (82% with SIRS versus 48.7% without
SIRS; P <0.05)61.
Liver histology in management of ACLF
Performing liver biopsy in the presence of coagulo­
pathy and ascites in patients with ACLF is challenging
and should be undertaken cautiously on an individual
basis. Transjugular biopsy in patients with ACLF is quite
safe. In addition, the transjugular approach enables the
­measurement of the hepatic venous pressure gradient93.

Histopathology helps to establish the aetiology of
both acute and chronic causes, particularly Wilson
disease, autoimmune hepatitis or DILI. Rastogi et al.67
have proposed two patterns to predict patient outcome
comparing those who survived to those who died
(BOX 1; FIG. 4); pattern I, which is associated with high
mortality and pattern II, which is associated with ­better
survival, irrespective of the aetiology67. Histology has
also been found to predict poor outcome and early
need for transplantation67,94. Submassive hepatic necro-
sis character­ized by extensive and confluent necrosis,
cholestasis and ductular bilirubinostasis are predictive
of poor outcome in patients with HBV-related ACLF95.
In those with severe alcoholic hepatitis, fibrosis stage,
polymorpho­nuclear infiltration and bilirubinostasis
indicate unfavour­able course96. Whereas bilirubino­
stasis correlates with the development of bacterial infec-
tions (OR 1.57, 95%CI: 1.00–2.47; P = 0.04), advanced
fibrosis predicts poor regeneration capabilities in any
aetiology of ACLF96. In patients with alcoholic steato­
hepatitis on biopsy, the presence of SIRS further
increases the mortal­ity (P <0.01)97. High portal pressure
correlates with the presence of alcoholic steato­hepatitis
and mortal­ity98. Liver biopsy can also help in selec-
tion of patients for steroid therapy, as the response is
­better in those with severe alcoholic hepatitis96. So early
liver biopsy can identify the patients with ASH, with
bilirubino­stasis and indirectly might help to s­ tratify
steroid non-responders99,100.
Management of ACLF
Multiple strategies exist in the management of ACLF.
These strategies include general measures, specific
therapies, bridging and definitive treatments and
emerging therapies.
General measures
Nutrition. Although the majority of patients with cir-
rhosis have moderate to severe malnutrition, many with
ACLF have fairly well-preserved nutritional status101,102.
In fact, obesity is one of the risk factors for ACLF102.
However, if such patients become acutely and severely
ill, their nutritional reserves do not last long to support
the crisis and the regenerating liver. Optimal nutritional
support in patients with ACLF has not been well defined.
Anorexia resulting in increased circulating TNF and
leptin, delayed gastric emptying, ascites leading to early
satiety, high bilirubin and cholestasis, altered hepatic bile
composition and synthesis, and high catabolic demands,
add to nutritional compromise and poor outcomes101,103.
Enteral tube feeding and the use of nutrient dense for-
mulas (1.5–2.0 kcal/ml) help ill patients who are ­unable
to meet their nutrient needs independently. A target
of 1.5–2.0 g protein/kg per day and 39 kcal/kg per day
has been shown to improve hepatic encephalopathy
and overall survival104,105. Carbohydrate-predominant
late evening snack has been shown to be helpful in a
few studies103,104. Limited data exists on the composi-
tion101 and utility of parenteral nutrition in patients
with ACLF and should be used carefully in those with
intestinal ileus.
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REVIEWS
Intensive care. Patients with ACLF need close monitor-
ing to detect the development of components of SIRS,
hypotension and shock. Use of prophylactic antibiotics
might help in prevention of infection if given at the onset
of SIRS, as it is difficult to differentiate SIRS from early
sepsis. However, to date, no prospective or randomized
control trial has been conducted on use of prophylactic
antibiotics in ACLF and in fact, most other studies did
not assess the use of antibiotics. Louvet et al.98 showed
that nonresponders to steroid treatment have poor
survival and an increased risk of infection. Mookarjee
et al.97 showed that even though infection cannot be
detected in the majority of patients, the presence of SIRS
is associated with high mortality. This data strongly sug-
gests that SIRS could be a manifestation of occult sepsis.
The choice of antibiotics depends on the type, severity
and origin of infection (community acquired or noso-
comial), and local epidemiological data about antibiotic
resistance2. Patients with ACLF and septic shock are
extremely ill with mortality exceeding 80%61,106. Septic
shock is fluid responsive in only ~12% and vasopressor
responsive in 50% of patients106. Terlipressin alone or
in combination with noradrenaline helps reverse septic
shock, improve microcirculation and reduce the risk of
variceal bleeding and nosocomial spontaneous bacterial
peritonitis (SBP). However, one needs to closely monitor
for adverse effects of terlipressin, which can be seen in
up to one-third of treated patients106.
Despite the data being limited, the use of albumin
is suggested by the authors to improve intravascular
volume, and prevent and manage acute kidney injury
(AKI) and infections. Cyclooxygenase (COX)-derived
prostaglandin E2 (PGE2) is one of the main drivers
for immunosuppression in patients with acute decom-
pensation of cirrhosis and its level increased in ACLF.
Albumin binds to PGE2 and reduces its bioavailability,
which in turn increases circulating TNF levels, reduces
monocyte anergy and reduces the risk of infections107.
The beneficial effects of albumin could also be due to
its ROS-scavenging activities, protection of endo­thelial
integrity and binding of toxic molecules. Albumin
administration in patients with ACLF could be help-
ful in managing complications such as SBP, hepato-
renal syndrome (HRS), hepatic encephalopathy and
Box 1 | Histological patterns associated with prognosis
Pattern 1
• Marked ductular proliferation
• Coarse inspissated ductular bile plugs
• Eosinophilic degeneration of hepatocytes
• Foci of confluent or bridging necrosis
• Higher apoptosis
• Pericellular fibrosis
• Mallory’s hyaline
• Higher stage of fibrosis
Pattern II
• Prominent hepatocyte ballooning
• Less fibrosis and necrosis than in pattern I
REVIEWS

Pattern I: poor prognosis

a b c d

100× 40× 200× 100×

Pattern II: good prognosis

e f g h

200× 200× 100× 100×

Figure 4 | Histological pattern in ACLF. Pattern I with poor prognosis:Nature

a | ductular billirubinostasis,
Reviews b | extensive
| Gastroenterology necrosis,
& Hepatology
c | eosinophilic degeneration, d | advanced fibrosis with nodule formation. Pattern II with good prognosis: e | ballooning
degeneration, f | ballooning degeneration of hepatocyte with cellular cholestasis, g | acinar disarray with hepatocellular
and canalicular bile, h | thin septa and mild fibrosis.

non-SBP infections, based on data from those with Specific therapies

­decompensated cirrhosis108.
About 40% of patients with ACLF develop hepatic
encephalopathy and require intensive care2. Although
little evidence exists at present for targeted ammonia
reduction therapies, such as lactulose and rifaximin, they
can be given empirically2.
Renal impairment occurs in about one-quarter
of patients with ACLF and AKI is often preceded by
SIRS109. The various factors leading to AKI include
type 1 HRS, acute tubular necrosis, hypovolaemia, sep-
sis or bile pigment nephropathy109,110. Presence of AKI
is associated with increased 7‑day mortality (38% ver-
sus 7%; P <0.05)111. Use of terlipressin with albumin is
effect­ive at treating AKI in only 35% of patients of ACLF,
and the responders do have a survival advantage111.
Nonresponders to terlipressin treatment might require
renal replacement therapy in the form of intermittent
haemodialysis, slow low-efficient dialysis or continuous
renal replacement therapy. Besides reducing urea and
creatinine levels from the blood, dialysis also reduces
ammonia and glutamine levels112. Continuous renal
replacement therapy might offer several advantages:
less fluctuation in the mean arterial pressure; mainten­
ance of stable cerebral perfusion pressure without a rise
in intracranial pressure; and a reduction in cerebral
oedema by preventing rapid osmolar shifts or fluctu-
ations in the mean arterial pressure113. Despite scant
evidence in the literature, continuous renal replacement
therapy is preferred over conventional haemodialysis or
slow low-efficient dialysis in critical care units in patients
with ALF and ACLF114.
HBV treatments. Early and rapid reduction of HBV
DNA levels supresses hepatocellular necrosis and associ­
ated cytokine storm115. Reducing HBV DNA level by
>2‑logs from baseline within 2 weeks using tenofovir
improved transplant-free survival from 17% to 57% in
a randomized controlled trial116. Other potent antiviral
agents such as entecavir or telbivudine could also be
used. Combination of telbivudine and tenofovir substan-
tially improved glomerular filtration rate, but without
increased antiviral potency in HBV-related ACLF117.
Treatments for alcohol-related injuries. Management
of a patient with severe alcoholic hepatitis presenting as
ACLF includes tailored nutrition, psychosocial rehabilita-
tion, anti-craving treatments (for example, baclofen) and
treatments aimed at suppressing inflammation or TNF
production (such as corticosteroids or pentoxy­filine)118.
Nutritional intervention is compar­able to cortico­steroid
therapy for survival at 1 month119. As ­limited data exists,
it is difficult to recommend one approach over the other;
however, in patients who are not eligible for steroid treat-
ment, nutrition therapy could be the obvious choice119.
Thus, the role of nutrition is emphasized, and steroid-­
eligible patients should receive both nutrition as well as
corticosteroid for maximal benefit.
Autoimmune hepatitis. Approximately 20% of patients
with autoimmune hepatitis present with severe jaun-
dice, encephalopathy and coagulopathy, with or with-
out ascites, which resembles ALF or ACLF120. In one
series, 11% of 89 patients presented with acute-severe

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autoimmune hepatitis, with 60% requiring transplan-
tation121. Use of steroids is controversial: a UK study
showed a benefit122, and a US ALF study reported bene-
fit in a selective cohort, that is, those with lower MELD
scores (20 versus 26, P = 0.02) and UK‑MELD score (57
versus 59, P = 0.01)123. Patients with a high MELD score
have greater treatment failure rates than those with
low scores122, and lack of large studies on use of tacroli-
mus124 or mycophenolate125 leaves limited options for
­intervention except early transplantation.
Corticosteroids. Steroid therapy is known to suppress
inflammatory and immune-mediated hepatocyte
injury. The benefit of steroid therapy in patients with
alcohol-related ACLF has not been studied and its role in
severe alcoholic hepatitis has been somewhat controver-
sial in presence of ascites, risk of sepsis, high mortality
upon failure of steroid therapy and ineligibility for liver
transplantation with uncontrolled sepsis that devel-
ops after the start of steroid treatment. Approximately
60% of patients with severe alcoholic hepatitis showed
improved short-term survival with steroids126, however,
6‑month mortality remained at ~40%127. Antibiotic
cover­age is suggested by most of the studies as infection
is seen in 25% patients at admission and another 25%
get infected during corticosteroid treatment98. Sensitivity
to corticosteroids improves as liver function recovers128.
Pentoxyfiline. A weak inhibitor of TNF synthesis, pen-
toxyfiline, has antioxidant properties129. In patients
with severe alcoholic hepatitis, pentoxyfiline improved
6‑month survival compared with placebo in some130,131,
but not in other studies132,133. In the STOPAH trial, con-
sisting of 1,103 patients, pentoxyfiline was comparable
to placebo. The corticosteroid therapy showed survival
benefit only at 28 days, but not at 90 days or 1 year134.
Experimental therapies. Therapy with N-acetyl cysteine,
modulation of gut flora75,76 anti-TNF agents135 and fae-
cal microbial transplantation136 are emerging therapeutic
Table 2 | ACLF and artificial liver support systems in ACLF
Study Study population n Trial design
Ash et al. (1994) Mixed (some with ACLF 56 Liver dialysis versus SMT
(REF. 190) and others with ALF)
Sen et al. (2004) ACLF — severe alcoholic 18 MARS + SMT versus SMT
(REF. 191) hepatitis (9 MARS; 9 control)
Laleman et al. ACLF — severe alcoholic 18 MARS + SMT versus
(2006) (REF. 192) hepatitis Prometheus + SMT or
SMT alone (3 d)
Banares et al. ACLF: bilirubin >20 mg/dl 189 • MARS + SMT versus SMT
(2013) (REF. 144) and/‌or HE greater than • Up to 10 sessions (6–8 h)
grade II and/or HRS
Kribben et al. ACLF 145 • Prometheus + SMT
(2012) (REF. 145) versus SMT
• Up to 8–11 sessions
ACLF, acute on chronic liver failure; ALF, acute liver failure; DIC, disseminated intravascular coagulation; HE, hepatic encephalopathy; HRS, hepatorenal syndrome;
MARS, molecular adsorbent recirculating system; SMT, standard medical therapy.
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REVIEWS
options for the treatment of ACLF. Despite their poten-
tial, probiotics137, thalidomide138 and plasma exchange
are only considered as experimental therapies owing to
the lack of data at this time.
Artificial liver support
The rationale behind artificial liver support is to remove
possible toxins and prevent further aggravation of liver
failure, stimulate liver regeneration and support hepatic
functions139. Liver failure in patients with ACLF leads
to the accumulation of toxic concentrations of biliru-
bin, bile acids, ammonia, protein breakdown products
(aromatic amino acids, phenol and mercaptans), lactate,
glutamine, various mediators of oxidative stress, free
fatty acids, endogenous benzodiazepines, iron metabo-
lites and inflammatory cytokines both in blood and tis-
sues140. An artificial liver support system (ALSS) using
albumin dialysis, leads to removal of these vasoactive
substances, improves systemic and splanchnic circula-
tion141, liver regeneration142,143 and serves as a bridge to
liver transplantation139,140.
At present, there are two main devices providing
ALSS; the Molecular Adsorbent Recirculating System
(MARS® (Gambro, Sweden)) and the Fractionated
plasma separation and adsorption (FPSA; the Prome­
theus System® (Fresenius Medical Care, Germany)).
Studies on the use of ALSS in patients with ACLF as
per the current APASL or EASL definition are limited
(TABLE 2). The published RELIEF study144 using MARS®
reported a decrease in serum creatinine and bilirubin
levels with improvement of hepatic encephalopathy on
the fourth day of treatment, but without survival bene­
fits. The FPSA (Prometheus System®) device used in
the HELIOS study (n = 145) reported a ­notable reduc-
tion in serum bilirubin levels145. The survival benefit
was limited to patients with type I HRS and a MELD
score of >30 (REF.  145) . A meta-analysis showed a
decrease in mortality in those with ACLF when treated
with ALSS (RR 0.80; 95% CI 0.66–0.96; P = 0.018)146.
Decreasing the MELD score to <30 with ALSS before
Device Clinical results
Hemodiabsorption • Improved HE and haemodynamic profile
• Increased bleeding in patients with DIC
MARS • Improvement of HE
• No haemodynamic changes
• No changes in plasma cytokines and
ammonia levels
MARS and Better haemodynamic improvement in
Prometheus MARS with less bilirubin reduction than
Prometheus or SMT alone
MARS • No changes in survival
• Improvement in HE
• Improvement in HRS
• No differences in overall adverse events
Prometheus • No changes in overall survival
• Survival benefit in post-hoc analysis in
type I HRS and MELD score>30
REVIEWS

Table 3 | Liver transplantation in patients with ACLF

Study n % patients with Mean MELD Graft type Hospital Overall Overall % survival 5-year
grade III‑IV HE score mortality (%) mortality survival at 1 year survival (%)
Finkenstedt et al. 33 N/A 28 DDLT NA 5 28 84.8 82
(2013) (REF. 148)
Duan et al. (2013) 100 20 32 DDLT & 20 20 80 80 74.1
(REF. 152) LDLT
Xing et al. (2013) 133 11.3 28 DDLT 21.8 29 104 78.1 72.8
(REF. 150)
Lin et al. (2013) 54 14.8 24 LDLT NA 4 50 92.6 NA
(REF. 193)
Liu et al. (2003) 32 NA 36 LDLT 6.3 4 28 88 84
(REF. 194)
Ling et al. (2012) 126 NA N/A LDLT & 16.7 34 92 73 NA
(REF. 147) DDLT
Bahirwani et al. 157 NA 32.8 DDLT 25.5 40 117 74.5 NA
(2011) (REF. 195)
Chan et al. (2009) 149 42.3 37 DDLT & 4.7 7 142 95.3 90
(REF. 153) LDLT
Wang et al. (2007) 42 NA 33 DDLT & 16.7 7 35 83.3 NA
(REF. 196) LDLT
Total 826 150 676 83.3 80.6
DDLT, deceased donor liver transplant; HE, hepatic encephalopathy; LDLT, live donor liver transplant; NA, data not available.

liver transplantation, leads to reduced overall mortal-
ity147. ALSS therefore remains a useful tool in a selected
group of patients with ACLF to improve their clinical
and biochemical status before transplantation.
Liver transplantation in ACLF
Patients with ACLF are relatively sick in comparison
to those with decompensated cirrhosis or patients
with acute hepatitis, and often have sepsis and multi­
organ failure leading to a 4‑week mortality close to
50%2. Liver transplantation is a potentially curative
treatment option, with a good outcome irrespective of
aetiology (TABLE 3). Priority transplantation is required
for the ACLF patient population as SIRS and sepsis
generally develop within 7 days of hospitalization61.
Transplantation is only feasible in ~25% of patients
with ACLF on the deceased donor liver transplant­
ation waiting list, owing to progressive liver failure
and onset of multiorgan failure14,148. Disease severity
scores such as MELD have been considered to deter-
mine organ allocation to those who need the organs
most in a scenario of increased demands for organs;
however, it is a solution that is far from perfect. Disease
severity scores do not take into account cerebral, cir-
culatory and respir­atory failures, giving no priority
for patients with ACLF 14,149. Using the EASL-CLIF
definition, liver failure (bilirubin ≥204 μmol/L) and a
high CLIF‑C score at baseline, have been shown to be
associated with a transplantation-free survival of only
12.8%. Early liver transplantation upon diagnosis of
ACLF, that is, within a median of 11 (1–28) days led
to a 75% 1‑year survival14. However, the presence of
≥4 organ failures at admission, or CLIF‑C ACLF score
of >64 at 3–7 days, in the absence of liver transplant­
ation, is associated with a 100% mortality by 28 days14.
Pamecha et al.149 proposed serial assessment of disease
severity with CLIF‑C score of patients with ACLF in the
first week of hospitalization for prioritization for liver
transplantation. In general, patients with a MELD score
of >30, discovery of HBV reactivation with cirrhosis on
biopsy and serum bilirubin levels of ≥170 μmol/L, pro-
thrombin index >40%, a platelet count of <1 × 105/L and
presence of encephalopathy should be listed for early
transplantation150–153. Although, many prediction mod-
els of early transplantation listing exist, none ­reliably
predicts chances of reversibility of ACLF.
In one series from Germany, 101 of 111 (91%)
patients with ACLF (as defined by APASL) who could
not undergo liver transplantation died owing to being
too ill, whereas 28 of 33 (85%) who underwent trans-
plantation survived for a median of 29 months148. Chan
et al.153 in a series of 149 patients with ACLF defined by
the APASL criteria who received either deceased or liv-
ing donor transplants, showed a 5‑year survival of 90%.
In a series from China, patients with ACLF as defined
by APASL definition, the 1‑year, 3‑year and 5‑year sur-
vival rates were 76.8%, 75.6% and 74.1%, respectively152.
Overall, the results of transplantation in patients with
ACLF are encouraging (TABLE 3). However, the min­
imum duration of abstinence to prevent recidivism in
patients with severe alcoholic hepatitis is undecided. Of
note, early liver transplantation does improve survival
in those with alcohol-related ACLF that is unrespon­
sive to steroids154. Although early transplantation in
carefully selected patients with alcohol-related ACLF
improves clinical outcomes, an ethical dilemma remains
if the patient has been drinking until the last 6 months
from index presentation. The decision becomes
even more challenging in a related living donor liver
­transplantation scenario155.

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 REVIEWS

The emergence of regenerative therapy
Some special concerns related to improving hepatic
regeneration as a therapeutic approach in those with
ACLF are: the status of liver regeneration during o
­ ngoing
liver injury; the role of growth factors in augmenting
hepatic regeneration; and the development of in vivo or
ex vivo approaches to modulate hepatic regeneration.
Liver regeneration in a failing liver
Liver regeneration is a complex process and it depends
upon the extent and type of parenchymal injury156.
In  ALF, regeneration occurs by self-replication of
quiescent differentiated hepatocytes and cholangio-
cytes156. In ACLF, it occurs by activation and differen-
tiation of hepatic progenitor cells (HPCs; FIG. 5)156,157.
The tumour necrosis factor ligand superfamily mem-
ber 12 (TNFSF12, also known as TWEAK) and tumour
necrosis factor receptor superfamily member 12A
(TNFRSF12A, also known as FN14) pathway, stimulated
by macrophages, T cells and M2 Kupffer cells is associ-
ated with the differentiation of HPCs into hepatocytes in
ACLF158,159. Dying hepatocytes engulfed by macrophages
activate WNT3 signalling, which promotes differenti­
ation of HPC into hepatocytes by inhibition of Notch–
Hedgehog signalling160. Lineage tracing experiments in
various mouse models of liver injury have shown both
hepatic and nonhepatic cellular origins of HPCs in adult
liver regeneration depending on the extent of hepatic
injury161,162. Hepatic nonparenchymal cells might also
actively participate to repopulate the liver, as suggested
by an increase in the proportion of activated hepatic stel-
late cells per 1,000 cells in patients with ACLF (231 ± 91)
than those with cirrhosis (73 ± 35) and healthy individ-
uals (25 ± 10; P <0.0001)163. The number of HPCs also
positively correlates with patient survival163,164. However,
whether the expanded number of activated stellate
cells dedifferentiate into HPCs164 or provide paracrine
­support for liver regeneration needs to be defined (FIG. 5).
After the hepatocytes, HPCs and hepatic stellate
cells, the bone marrow is the third tier of regenerative
response and has a synergistic effect on intrahepatic
regeneration165. In response to hepatic injury, stromal
cell-derived factor‑1 increases in bone marrow and in
the repopulated liver along with its ligand CXCR4 for

Liver Bone marrow

Hepatic injury Impaired hepatocyte replication Restoration of hepatic mass by HPC BM support
activation and maturation

Myofibroblast
HPC
Macrophage

Hh IH
? Phagocytosis
of dying NOTCH
hepatocytes ? ?
TWEAK Bone
WNT marrow

HPC differentiation Cholangiocyte

to hepatocyte

Hepatic ? ?
injury HPC
activation
DAMP ? HSC
Newly formed IH
TNF, IL-6 MSC
Other
cause EPC
Paracrine support for parenchymal
Kupffer cell and non-parenchymal regulation Therapeutic
or macrophage mobilization
activation of bone
Gut-derived marrow stem
factor cells

Figure 5 | Hepatic regeneration in ACLF. Acute hepatic injury, release Nature Reviewsfrom
of endotoxins | Gastroenterology & Hepatology
gut to the liver, production
of DAMPs by ongoing parenchymal and nonparenchymal cell injury, activates Kuppfer cells and macrophages to
release IL‑6 and TNF. These cytokines act together to perpetuate hepatic injury in chronic liver disease or stable
cirrhosis. Regenerative effects of TNF and IL‑6 are perturbed in patients with ACLF because of increased myofibroblast-
driven tissue scarring, which inhibits hepatocyte self-replication. However, restoration of lost hepatic mass is achieved
by the rapid activation and differentiation of HPCs and ductular proliferation. Furthermore, endogenous mobilization of
bone marrow derived HSCs, MSCs and possibly EPCs in response to injury, and therapeutic supplementation by
exogenous G‑CSF or darbopoetin‑α, potentiates the recruitment of bone-marrow-derived stem cells to the injured liver.
The dotted lines and ‘?’ depict mechanism(s) that are not established or lack direct evidence to date. ACLF,
acute‑on‑chronic liver disease; EPCs, endothelial progenitor cells; G‑CSF, granulocyte colony-stimulating factor; Hh,
hedgehog; HPC, hepatic progenitor cell; HSCs, haematopoietic stem cells; IH, intermediate hepatocyte;
MSCs, mesenchymal stem cells.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 13

© 2016 Macmillan Publishers Limited. All rights reserved

REVIEWS
the augmentation of regeneration166. The release of
haemato­poietic stem cells (HSCs) into the systemic cir-
culation occurs in response to stress or injury and leads
to their transendothelial migration162 and homing to the
liver. Bone-marrow-derived epithelial progenitor cells
increase after partial hepatectomy as well as in cirrho-
sis156,166. They stimulate liver sinusoidal endothelial cells
for tube formation and angiogenesis, a prerequisite for
liver regeneration167,168.
The role of growth factors in hepatic regeneration
More often than not, hepatic injury in ACLF is more
aggressive than the body’s ability to restore balance
and stimulate hepatic regeneration. Also, hepatocytes
in patients with CLD are often in a state of replicative
senescence169. Supplementing hepatic regeneration with
in vivo or ex vivo approaches is therefore worthwhile.
Di Campli et al.170 showed successful dose-dependent
mobilization of bone marrow stem cells in patients
with ACLF after 3 days of G‑CSF therapy. Garg et al.171
showed that substantial regeneration goes on in the wake
Hepatocyte self replication HPC-mediated liver regeneration
a e
ALF
100× 100×
b and GF
ACLF
200× 200×
c regenerates through hepatocyte self-replication (increased
DC
200× 200×
d Bone marrow HSC mobilization by G-CSF
ACLF
200×
200× CD34+ cells
30% pretherapy 70% post-G-CSF therapy
14 | ADVANCE ONLINE PUBLICATION www.nature.com/nrgastro
© 2016 Macmillan Publishers Limited. All rights reserved
of ongoing liver failure as evidenced by the presence of
large numbers of CD34+ cells in liver tissue samples from
patients with ACLF (FIG. 6). The authors further showed
that G‑CSF therapy given over 1 month substantially
enhanced the mobilization of bone marrow HSCs in
comparison with the placebo group and showed ­homing
of these cells in the hepatic parenchyma in follow‑up
liver biopsy samples. This therapy was associated with
a reduction of Child–Pugh, MELD and SOFA scores,
reduced sepsis, hepa­torenal syndrome and hepatic
encephalopathy, and improved survival (66% versus
26%, P <0.01)171. In very ill patients with a MELD score
of >30, G‑CSF therapy should, however, be considered
only if liver transplantation is not feasible and preferably
by specialists experienced in this therapy; this approach
should not be used in patients with ACLF in the pres-
ence of AKI, ongoing sepsis, significant haemolysis
or macrophage activation syndrome. In the latter, it is
likely that levels of G-CSF and granulocyte macrophage
colony stimulating factor (GM-CSF) levels are already
too high171,172.
G-CSF
Bone marrow Liver
• ↑ Trafficking Blood
• ↑ Proliferation
of HSC and • CD34
• Neutrophils • ↑Regeneration
EPCs • ↓Fibrosis
• Monocytes
• ↑ Cytokines • MAPC • ↓Inflammation
• ↓ Apoptosis
Prevention of sepsis
Figure 6 | Histological images of liver regeneration
in patients with ACLF, ALF and decompensated
cirrhosis. a | In patients with ALF, the liver predominantly
hepatocyte Ki67 expression) and stimulation of resident
HPCs. b | By contrast, in ACLF, hepatocyte self-replication is
impaired and the liver regenerates more through activation
and hepatic maturation of HPCs. c | In decompensated
cirrhosis, both hepatocyte self-replication and HPC
activation occurs, but the extent of these processes is much
less compared with that seen in ALF and ACLF. Increased
senescence of hepatocytes and bone marrow progenitors is
likely. d | Spontaneous recruitment of bone marrow stem
cells to ongoing liver injury as in ACLF liver is limited.
e | Therapeutic mobilization of these cells using growth
factors (e.g. G‑CSF) increases their recruitment to the liver
and potentiates the regenerative response. G‑CSF also
increases the number of peripheral neutrophil migrating to
the liver as well as improving their function, which helps
to prevention development of sepsis. ACLF,
acute‑on‑chronic liver disease; ALF, acute liver failure;
DC, decompensated cirrhosis; EPCs, endothelial progenitor
cells; G‑CSF, granulocyte colony-stimulating factor;
GF, growth factor; HPCs, hepatic progenitor cells;
MAPC, multipotent adult progenitor cell.
Nature Reviews | Gastroenterology & Hepatology
 REVIEWS

On a cellular basis, G‑CSF therapy in combination
with stem cell factors was found to immunologically mod-
ulate the biliary cellular niches as well as the intrahepatic
milieu for regeneration in a rat model of partial hepatec-
tomy173. G‑CSF therapy in human beings has been shown
to recruit DCs in the liver and inhibit IFNγ‑secreting
CD8+ T cells to ameliorate hepatocellular injury57. HPC
proliferation174, CXCR4 expression, and neutrophil and
macrophage activation are all increased by G‑CSF175.
Developing therapeutic synergism by combining
G‑CSF with other growth factors is an area of intense
research. Erythropoietin (EPO) has been shown to
mobilize EPCs and enhance their in vivo regenerative
role via the PI3K–AKT pathway176. Darbopoetin‑α,
due to better bioavailability and ease of once weekly
administration, has higher potency than recombinant
human erythropoietin (rhEPO)177. Kedarisetty et al.172
in a unique human study used the combination of
G‑CSF and darbopoetin‑α, which improved hepatic
regeneration compared with placebo. This observation
was assessed indirectly in relation to clinical param­
eters: 1‑year survival increased (68.6% versus 26.9%;
P = 0.003), Child–Pugh score reduced (48.6% versus
39.1%; P = 0.001); MELD scores reduced (40.4% ver-
sus 33%; P = 0.03) and lower incidence of septic shock
(6.9% versus 38.5%; P = 0.005). Other cytokines such
as augmentor of liver regeneration, hepatocyte growth
factor, vascular endothelial growth factor and bone
­marrow cell-mobilizing factors, such as plerixafor, are
under evaluation (FIG. 6)178,179.
In vivo or ex vivo hepatic regeneration?
Conventionally, bone-marrow-derived HSCs or mesen­
chymal stem cells are externally modulated ex vivo
under the influence of growth factors 180. However,
this technique requires good manufacturing practice
facilities and expertise in isolation, in vitro culture and
­reinfusion in to the patient through the hepatic artery or
portal vein. By contrast, in vivo autologus bone marrow
HSC ­mobilization, by giving subcutaneous injections
of G‑CSF, is a novel approach and can be used easily
by an experienced physician. After the initial study by
Garg et al.171, survival benefits with in vivo G‑CSF
therapy have been reaffirmed in patients with ACLF
related to HBV infection181 as well as in patients with
severe alcoholic hepatitis178, with a notable increase
in circulating CD34+ bone marrow HSCs182. Variable
results with respect to regeneration and survival benefit
have been found by several investigators using mesen­
chymal stem cell therapy in patients with cirrhosis183,184.
The only study in patients with ACLF using cell ther-
apy by Shi et al.185 has shown a substantial reduction of

ACLF

Acute insult Chronic liver disease Liver failure

Identify Compensated cirrhosis Grade and/or severity score
No cirrhosis
MELD score at admission

<30 ≥30
Specific therapy Standard care
Ethanol — abstinence, steroid D4–D7
HBV —nucleoside analogue New onset OF No or single OF 2 or more OF
AIH — steroid
DILI — stop drug, liver dialysis Yes No
Wilson disease — plasmapheresis, Organ support Regenerative therapy Organ support and/or
D-pencillamine and/or Bridging therapy bridging therapy
Sepsis — antibiotic bridging therapy
D4–D7
Monitor for
OF recovery
deterioration
Yes No

Standard care
Liver transplant
Poor prognosis

Figure 7 | Management algorithm for patients with ACLF. Management of patients

Nature Reviews with ACLF includes identification
| Gastroenterology & Hepatology
of the acute hepatic insult and the specific therapy (if possible) that should be offered to ameliorate liver injury.
Chronic liver disease includes patients without cirrhosis and with stable cirrhosis. Diagnosing cirrhosis often requires
transjugular liver biopsy, but is not mandatory. The management strategy for those in liver failure, is primarily based upon
the baseline MELD score and presence (or absence) and number of organ failures. Standard medical care (that is, nutrition,
diuretics, antibiotics and intravenous albumin) is given upon hospital admission and is continued with assessments on
day 4–7 (during the first week). Development or increase in the number of organ failures needs early or emergency liver
transplantation. Organ support and bridging therapy (such as artificial liver support system, plasmapheresis) and
regenerative therapy can be considered in selective cases with careful monitoring and a back‑up liver transplantation
plan. ACLF, acute‑on‑chronic liver disease; AIH, autoimmune hepatitis; DILI, drug-induced liver injury; MELD, model
of end-stage liver disease; OF, organ failure. *Denotes a therapy that is not currently established as a standard treatment.

NATURE REVIEWS | GASTROENTEROLOGY & HEPATOLOGY ADVANCE ONLINE PUBLICATION | 15

© 2016 Macmillan Publishers Limited. All rights reserved

REVIEWS

MELD score, increase in serum albumin, cholinesterase Conclusions

and prothrombin activity after mesenchymal stem cell
infusion and increased survival during 48 weeks and
72 weeks of follow‑up compared with the placebo group.
Can ACLF be prevented?
Patient education, anticipation and early identification
of the acute insult and early detection of CLD, would be
immensely helpful. Universal HBV screening before ini-
tiation of immunosuppressive therapy is recommended
in hepatitis B surface antigen positive, and hepatitis B
surface antigen negative and HBcAg-positive patients186.
Nucleotide analogues, such as teno­fovir and enteca-
vir, should be pre-emptively used in those with HBV
infection187. Modulation of gut flora with pro­biotics
does ameliorate ethanol-induced liver injury as well as
progression of NASH to cirrhosis188, but their role in
prevent­ing the development of ACLF is u ­ nexplored.
The best way for prevention of DILI is to educate
patients, monitor ALT levels during drug therapy189
and stratify high-risk patients such as the elderly, and
those with ­obesity, diabetes, alcoholisn, co‑infected with
HIV, or using known hepatotoxic drugs. We present a
­management algorithm for patients with ACLF in FIG. 7.
ACLF is a serious and often progressive liver disease.
Despite no universally accepted definition, the common
approach for better patient outcomes includes, identifi­
cation of the acute precipitant causing hepatic failure,
controlling the deregulated inflammatory response,
and the prevention and early detection of organ failure.
Early detection and prevention of sepsis, support for
organ failure, augmentation of liver regeneration, and
the use of bridging therapy with artificial liver support
systems in addition to specific treatment of the acute
insult improve the outcomes of patients who do not
undergo liver transplantation. Liver transplantation
remains the definitive therapy and in patients with a
high MELD score, priority listing for deceased donor
liver tissue or work‑up for ­living donor transplant tissue
should be done. Furthermore, identification of risk fac-
tors, the hepatic reserve and potential acute insults could
prevent the occurrence of ACLF. This Review provides
common ground for understanding the concept, natural
history and management options of ACLF, by bringing
the approaches used in the West and the East together,
and opens new vistas and targets for liver support and
­regeneration during ongoing liver failure.

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Acknowledgements
Authors are grateful to N. Trehanpati, A. Kumar, A. Rastogi,
R. K. Gulati, S Baweja and A. Khanam for their intellectual
inputs in the preparation of the figures.
Author contributions
A.C. prepared the draft manuscript and designed the sections;
S.K.S. conceived, edited, revised and prepared the final draft.
Competing interests statement
The authors declare no competing interests.