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Reviews: Acute On Chronic Liver Failure: Terminology, Mechanisms and Management
Reviews: Acute On Chronic Liver Failure: Terminology, Mechanisms and Management
Liver failure is a frequent and often fatal medical emer- hepatic regeneration. This Review discusses the concept,
gency. The incidence is rising with the increasing use mechanisms, management and prevention of ACLF
of alcohol, overuse of drugs and the growing epidemic of and highlights the controversies and future directions
obesity and diabetes mellitus1. Liver failure can present of the field.
as acute liver failure (ALF; in the absence of any pre-
existing liver disease), acute‑on‑chronic liver failure The concept of ACLF and critical mass
(ACLF; in the presence of chronic liver disease (CLD) ACLF is a clinical syndrome manifesting as acute and
or cirrhosis), or an acute worsening of decompensated severe hepatic dysfunction resulting from varied insults2.
cirrhosis. The former and the latter are well-defined The term was coined in 1995 to describe a condition in
disease entities. However, owing to overlap of termin which an acute and a chronic hepatic insult are operating
ologies, more than a dozen definitions have emerged simultaneously4 (FIG. 1). An acute severe hepatic insult
to describe ACLF. The two most widely accepted ones in a healthy liver can lead to ALF, and with aggressive
are from the Asian Pacific Association for the Study critical care, a non-transplantation survival of up to
of the Liver (APASL)2 and the European Association 60% can be achieved5. In the presence of CLD, an acute
for the Study of the Liver (EASL) Chronic Liver insult can lead to rapid and progressive liver failure,
Failure (EASL-CLIF) consortium3. Terms such as late- with a high short-term mortality as the liver’s functional
onset liver failure, sub-acute hepatic failure, impaired reserve is limited4. However, potential for reversing pro-
Department of Hepatology, regeneration syndrome, acute‑on‑chronic liver disease, gressive liver failure exists in a c rucial ‘golden window’
Institute of Liver and Biliary sub-fulminant hepatic failure and so on have become period, by ameliorating the acute insult, preventing
Sciences, D-1, Vasant Kunj,
New Delhi 110070, India.
less relevant and are not often used. ACLF is one of development of sepsis and extrahepatic organ failure
Correspondence to S.K.S. the most challenging fields in hepatology today, with and supporting hepatic regeneration (FIG. 2). The prime
sksarin@ilbs.in intense research underway to decipher the mechanisms drivers of patient outcome at different time points are a
doi:10.1038/nrgastro.2015.219 of progressive liver failure and to develop therapeutic combination of the critical functional hepatic reserve,
Published online 3 Feb 2016 strategies to suppress ongoing injury and supplement and the nature and severity of the acute insult2.
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 cells (TH1; IFNγ, IL‑2 and TNF) and type 2 T helper cells
programmed cell death protein 1 (PD‑1; also known (TH2; IL‑10)31,32. An increase in the median percentage
as PDCD1) after HBV reactivation24. PD‑1 upregula- of CD4+CD25+Foxp3+ regulatory T (TREG) cells and
tion might efficiently mitigate pathogenic CD8+ T‑cell CD4+CD25−Foxp3+ effector TREG cells occurs along
responses and liver damage leading to recovery25. with increased IL‑10 levels, suggesting a role for TREG
cells in liver injury and recovery33. Acute hepatitis due
Acute viral hepatitis to new HEV infection can contribute up to 20% of acute
Hepatitis E virus (HEV) infection is a leading cause exacerbations of chronic hepatitis B34.
of ALF in Asia and Africa, where it is endemic, with a Super-infection with hepatitis A virus (HAV)35 and
median incidence of 21% (range 4–72%)26. Although HEV36 lead to the development of ACLF. HEV infection
large studies from India report a high mortality in is associated with a more severe form of ACLF with
patients with HEV-related ACLF and ALF26,27, the higher mortality than those infected with HAV. The poly
contribution of HEV in precipitating ACLF in the West morphisms in the gene encoding the receptor for HAV,
is not known as these patients are not routinely tested HAVCR1 (also known as TIM1) predispose the host to
for HEV and the prevalence of HEV infection is gen- severe hepatitis37. During HAV infection the size of the
erally sporadic28. In the general population, the sero- TREG pool is contracted owing to apoptosis of TREG cells
prevalence of HEV has been reported as 5–52.5% and induced by a Fas-mediated mechanism38. A decrease in
6–26% in Europe and the US, respectively29. A French TREG-cell numbers leads to reduced suppressive activity
study considering 343 patients with cirrhosis showed the and consequently results in severe liver injury38.
incidence of HEV to be 3.2% (11 of 343) in patients with
decompensated cirrhosis, without any substantial effect Alcohol
on liver failure and mortality30. HEV infection causes The dose and duration of alcohol consumption
cell-mediated immune injury and hepatocyte damage, determines the stage of CLD; however, recent alco-
with high cytokine levels produced by type 1 T helper hol intake and/or binge drinking behaviour is what
contributes to rapid liver failure2. The presence of obesity predictors of mortality and early consideration for trans-
and/or diabetes mellitus increases disease severity39. plantation51. Patients with cirrhosis are more vulnerable
Liver injury occurs because of ethanol hepatotoxicity; and less likely to recover from DILI due to reduced
enhanced apoptosis, activation of innate and adaptive hepatic drug clearance, aberrant metabolism, altered
immunity and impaired hepatic regeneration40. Ethanol- excretion and/or impaired adaptive responses and high
mediated gut dysbiosis and increased intestinal perme- free-circulating drug levels due to low albumin50.
ability leads to increased release of endotoxins to the
liver. Ethanol metabolism leads to accumulation of Acute variceal bleeding
reactive oxygen species (ROS) and subsequent mito- Liver failure in patients with acute variceal bleeding is
chondrial endoplasmic reticulum stress leading to mainly due to hepatic ischaemia, increased b acterial
hepatocyte apoptosis41. Apoptosis is due to inhibition translocation from the gut and subsequent bac
of survival genes (Met) and induction of proapoptotic terial infections52. Whether to consider acute variceal
signalling molecules (TNF and tumour necrosis factor bleeding as an acute event of ACLF or a form of decom-
ligand superfamily member 6 (FASLG; also known as pensation of underlying CLD is debatable. Acute variceal
FasL))40. Release of danger-associated molecular pat- bleeding was considered a precipitating event in 13.8%
terns (DAMPs) after cellular necrosis cause macrophage of patients in the CANONIC study3 and 28% of cases in
and neutrophil activation42 and mammaglobin‑A and another study53. In fact, if the acute variceal bleed results
microRNA‑122 mediated cell death. Complement C3 in hepatic ischaemia, ischaemic hepatitis and jaundice,
and C5 activation, increased neutrophilic infiltration and fulfils the criteria of liver failure in the given time
(upregulated by IL‑8, CXCL1 and IL‑1), activation frame, it could then be included as a precipitating event
of Toll-like receptor (TLR)-2 and TLR‑6 (recognize for ACLF2.
bacter ial lipopeptides), TLR‑9 (recognize bacterial
DNA-containing unmethylated CpG motifs), lead to Sepsis and ACLF
an increase in the proinflammatory cascade mediated Bacterial infections are more frequent in patients with
mainly by Kupffer cells43. Ethanol induced injury leads cirrhosis than in the general population54. Cirrhosis-
to an increase in pro-inflammatory drivers (TNF, IL‑1, associated immune deficiency syndrome, an emerging
IL‑6, IL‑17) and a decrease in anti-inflammatory driv- concept, relates to a relative inefficiency of the innate
ers (mainly adiponectin and adenosine)44. TNF and and adaptive immune system in patients with cirrhosis
tumour necrosis factor receptor superfamily member to prevent or clear infectious agents in comparison with
1B (TNFRSF1B) closely correlate with disease severity, those without cirrhosis55. In this context, an acute insult
hepatocyte apoptosis, endotoxaemia and mortality44. and ongoing hepatocellular injury, as seen in ACLF,
Ethanol causes impaired liver regeneration by limit- would lead to an aberrant host inflammatory response,
ing DNA synthesis and normal microRNA signalling in SIRS and infection (FIG. 3).
mature hepatocytes45. At a cellular level, chronic alcohol Reduced expression of HLA‑DR in monocytes and an
consumption induces senescent replication of hepato- inability to produce TNF increases the risk of infection
cytes and impaired proliferation of liver progenitors46. and its severity, and correlates with survival in patients
This effect has been indirectly evidenced from patients with ACLF56. A substantial reduction in numbers of both
with severe alcoholic hepatitis who do not respond to plasmacytoid dendritic cells (pDCs) and myeloid DCs
medical treatment as they have low hepatic expression (mDCs) in addition to increased IFNγ-producing CD8+
of TNF and IL‑6 with an aberrant regeneration process47. T cells in patients with ACLF, further increases the risk
of sepsis and death57. In alcoholic hepatitis, neutrophil
Hepatotoxic drugs activation, indicated by increased resting respiratory
The liver is the main organ for biotransformation of burst and reduced phagocytic function, was predictive
drugs and metabolites, which involves cytochrome P450 of subsequent infection, organ failure and mortality58.
(CYP; phase 1), conjugation (phase 2) and transport Genetic predisposition for increased risk of infections in
ation (phase 3). Drugs are, therefore, one of the common cirrhosis has been seen with the TLR2 GT microsatellite
precipitants of liver failure. However, most data relates polymorphism (16934 (rs4696480)) and NOD2 vari-
to drug-induced ALF and information on ACLF is lim- ants particularly for spontaneous bacterial peritonitis
ited. Devarbhavi et al.48 reported high mortality (17.1%) (OR 11.3; P = 0.00002)59.
in a cohort of patients with severe drug-induced liver Whether sepsis is a consequence or a cause of liver
injury (DILI), having ascites and encephalopathy, which failure is not clear from the current data on ACLF.
is akin to ACLF. In a multinational Asian study of 660 Large cohort studies including patients with ACLF and
patients, DILI contributed as an acute insult in 9.1% infection at baseline and comparing them with those
of patients and in 53.3% of these patients the acute insult who develop infection subsequently could address
was attributed to anti-tubercular drugs followed by com- this issue. One viewpoint considers sepsis as a com-
plementary alternative medications49. Antibiotics and mon extrahepatic precipitant of ACLF60 and as such
anti-epileptic drugs account for >60% of patients with ACLF has been subclassified as infection-related ACLF
DILI in the West50. The baseline model for end-stage (I‑ACLF)11. However, liver failure is a late event in this
liver disease (MELD) score (29 in survivors versus 34 group of patients with cirrhosis often concomitant
in non-survivors; P <0.006) and hepatic encephalopathy with other organ failures and has a different clinical
(23% grade 3 versus 96% grade 4; P <0.01) were strong course11. So the I‑ACLF term adds to confusion and
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
• Inflammation
• Hepatocyte death
SIRS, CARS
Systemic circulation
Organ failure
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.
reserve and predict development of ACLF. A model non-parenchymal cells69. Tissue damage as a result of
using risk factors such as portal vein thrombosis, high infection is caused by three factors: first, direct action
levels of aspartate transaminase and bilirubin, raised of virulence factors that induce marked alterations in
α‑fetoprotein levels, and low serum albumin and sodium tissue homeostasis; second, an excessive host immune
levels can reliably predict post‑TACE liver failure64. response; and third, failed host immune-mediated
tolerance mechanisms70.
Aetiology and diagnosis of CLD Pathogens, such as bacterial products and toxins,
As with the acute insult, the aetiology of CLD and reach the liver mainly by translocation from the gut into
cirrhosis varies in different parts of the world. The the portal circulation60. This inducer-sensor-mediator
functional hepatocyte mass is difficult to quantify and tissue damage sequence and immune deregulation
the current methods are rather primitive, especially to cause continued inflammatory injury. The range and
evaluate the percentage of parenchymal loss when an sequence of events, that is, the acute insult, inflamma-
acute insult precipitates ACLF. CLD includes patients tory injury, immune deregulation, SIRS, compensatory
with moderate to severe hepatic fibrosis and cirrho- anti-inflammatory response syndrome (CARS) and the
sis. Quite often CLD is detected for the first time after regenerative response, lead to either recovery of liver
the development of ACLF. The earlier definition of failure or progression with sequential involvement of
ACLF from EASL and the American Association for extrahepatic organs71,72.
the Study of Liver Disease (AASLD) in 2011 included
only patients with cirrhosis65, but now it is proposed Bacterial translocation and immune response
to include patients with or without cirrhosis in three Bacterial translocation is responsible for life-threaten-
categories; type‑A (patients with ACLF but without ing infections, such as spontaneous bacterial peritoni-
cirrhosis), type‑B (patients with cirrhosis and ACLF) tis. Gut flora release endotoxins and lipopolysaccharide
and type‑C (patients with ACLF, cirrhosis and prior (LPS), which contribute to high levels of IL‑6 and TNF
hepatic decompensation; TABLE 1)7,12. This proposal is in portal blood as well as in the liver73. Increased intes-
a way forward to achieve a common ground between tinal permeability is due to venous congestion of the gut
the APASL and EASL-CLIF definitions (type A and B due to portal hypertension, altered gut flora, the direct
ACLF from EASL-CLIF are same as in the existing effects of alcohol (in severe alcoholic hepatitis) and
definition of APASL) as proponents of both groups ROS-mediated damage to the gut barrier. Studies show
agree that CLD and cirrhosis will result in a poorer a linear increase in bacterial translocation with worse
outcome than that which results from acute insult on Child–Pugh score, (3.4%, 8.1% and 30.8%, respectively,
a healthy liver. in Child–Pugh A, B and C74). Portal hypertension also
Diagnosis of CLD in the setting of ACLF is difficult aggravates bacterial translocation75. Bacterial trans
unless previously confirmed or when overt signs of location induces and perpetuates the activated state of
cirrhosis are present. A detailed history, signs of portal the innate immune system leading to ongoing hepatic
hypertension such as an enlarged spleen, laboratory injury. Bacterial translocation has special relevance in
test results (low platelet levels, evidence of synthetic ACLF, in which both CLD and portal hypertension
dysfunction and altered aspartate aminotransferase coexist accompanied by severe hepatic failure and intes-
(AST): alanine transaminase (ALT) ratio) and endo- tinal dysbiosis. Chen et al.73 outlined the influence of gut
scopic or radiological investigations are required to dysbiosis on ACLF and showed that the abundance of
confirm the diagnosis66. If these parameters are not Pasteurellaceae species was an independent predictor
conclusive, a histopathological evaluation, often by of mortality. Altered innate immune functions, that is,
transjugular biopsy, is recommended67. reduced phagocytic activity of intestinal macrophages
The aetiology of underlying CLD and cirrhosis is for translocated microorganisms, and gut-derived
nearly similar in most parts of the world, except in the bacterial products lead to unregulated inflammation
Far East where HBV dominates16. Only hepatosteatosis as a major contributing factor in ACLF76. A negative
is not considered as a CLD as no or minimal fibrosis correlation of Ruminococcaceae and Lachnospiraceae
exists. On the other hand, NASH is an important cause species with TNF and IL‑6 levels indicates a protective
of CLD and patients >45 years of age, with diabetes, role of these bacterial families and provides a rationale
obesity and dyslipidaemia do have a high chance of for modulation of gut flora as a preventive strategy in
having stage ≥2 fibrosis68. The APASL ACLF Research liver diseases73.
Consortium data using liver biopsy studies has shown
that a proportion of patients presenting with ACLF Immunopathology of liver failure in ACLF
have advanced fibrosis without cirrhosis2. The immunopathology of ACLF is a multimodal
immunological response involving alterations in both
Mechanisms from acute injury to ACLF the innate and adaptive immunity. In ACLF, the innate
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
of increased intestinal permeability, Kupffer cells are the subsequent increase in mDCs in liver. This increase
activated through the LPS and TLR4, or complement in mDCs correlates with recovery as seen in studies con-
C3 and C5 receptor signalling pathways. The activation sidering use of granulocyte-colony stimulating factor
of M1 Kupffer cells occurs via TLRs and DAMPs in (G-CSF)57 and methylprednisolone88.
response to LPS stimulation77. The subsequent assem- Tyrosine-protein kinase Mer (MERTK) is a trans-
bly of the TLR4–CD14–Lymphoctye antigen 96 (Ly‑96 membrane protein expressed on immune cells and is a
also known as MD2) receptor complex and recruitment negative regulator of the immune system (innate immu-
of the adaptor molecules, myeloid-differentiation fac- nity in particular). MERTK-positive monocytes are
tor 88 (MYD88) and TIR domain-containing adaptor unable to mount a response on exposure to pathogen89.
molecule 1 (TRIF), and the downstream signalling cas- MERTK inhibition in ACLF monocytes in vitro leads
cades, lead to continued inflammatory response78. TNF to upregulation of HLA‑DR, and enhanced response to
and IL‑6 have dual actions of inducing hepatocyte death microbial challenge; a key mechanism to the monocyte
as well as stimulating hepatocyte proliferation79. TNF and/or macrophage dysregulation and immuneparesis89.
is the first cytokine to be released and net production MERTK expression is increased in patients with ACLF
increases (despite decreased production by monocytes), and positively correlates with development of SIRS and
and levels correlate with liver injury and development increased predisposition to infection and development
of SIRS80. Simultaneously, M2 Kupffer cells are activated of sepsis 89,90. Immune suppression in ACLF is also
by an alternative pathway in response to IL‑4 and IL‑10 mediated by increased population of TGFβ‑secreting
released from TH2 cells77. The M2 phenotype has anti- TREG cells81. TREG cells also exhibit substantial inhibi-
inflammatory effects via cytokines such as transform- tion of IFNγ production, which directly or indirectly
ing growth factor-β (TGFβ) and favours progression to deactivates monocytes and macrophages89. The pool
CARS81. Kupffer cells modulate the transformation of of TGFβ and IL‑6 secreted from monocytes helps in
quiescent hepatic stellate cells to activated myofibro- generating IL‑17A-secreting CD4+ T cells known as
blasts, thereby linking immune activation to hepatic type 17 T helper (TH17) cells. The ratio of TH17 to TREG
microcirculatory dysfunction82. Hepatic stellate cells, cells is inversely associated with survival in patients
upon activation by LPS, release endothelin‑1 (ET‑1), with ACLF91.
thromboxane A2, nitric oxide, and prostaglandins, In brief, a severely dysregulated immune system
which leads to hepatic microcirculatory dysfunction exists in patients with ACLF, from antigen processing
and an increase in portal pressure. Nitric oxide released to effector cell functions and cytokine release. The
by hepatic stellate cells causes inflammatory cell death activated immune cells seem to be dysfunctional, para
of hepatocytes via necrosis or apoptosis83,84. lysed and energy-depleted. This situation results in an
Neutrophils are increased in the liver of those with exaggerated SIRS, defective CARS and ultimately to
ACLF; however, these are predominantly dysfunctional an increased susceptibility to infections81. Moreover,
neutrophils with an increased resting respiratory burst, even in the absence of overt infection, patients with
but reduced phagocytic function58. This process pre ACLF display sepsis-like characteristics such as reduced
disposes patients to infections58, and also correlates with ex vivo TNF secretion, monocyte HLA‑DR expression
the severity of liver failure85. Monocytes and DCs are and increased IL‑6 production81.
central mediators that present antigens bound to MHC
class II molecules to T cells, leading to T‑cell activation From SIRS to organ failure in ACLF
and proliferation. With exposure to LPS, monocytes Occurrence and persistence of SIRS is associated with
secrete IL‑1 and TNF, which function in an autocrine a hyperdynamic circulation, low mean arterial pres-
and paracrine fashion86. In patients with ACLF and sure, microcirculatory disturbances owing to capillary
monocytes that have a reduced ability to produce TNF leak and tissue hypoperfusion66,92. This situation leads
an early reduction in HLA‑DR expression is observed, to organ dysfunction in up to 40% of patients with
which might represent a physiological downregulation ACLF even in the absence of any overt infection65,66,72.
of monocyte function. The persistent or long-term sup- SIRS is associated with more severe encephalopathy,
pression of HLA‑DR is associated with a poor overall an increased incidence of bacterial infections, renal
outcome in terms of increased sepsis, organ failure and failure and poor survival than those without it. In a
death86. A subsequent rebound increase in expression of large study, the persistence of SIRS for up to 7 days
HLA‑DR correlates with clinical recovery86. or new-onset SIRS within the first week of hospital-
DCs are potent antigen-presenting cells and pDCs ization, correlated with progressive liver failure and
are particularly tolerogenic and immunosuppressive87. high mortality (82% with SIRS versus 48.7% without
DCs migrate from the blood to the liver, modulate CD8+ SIRS; P <0.05)61.
T cells and reduce IFNγ production, which in turn
reduces hepatocellular damage87,88. The low numbers Liver histology in management of ACLF
of mDCs at baseline are associated with high mortal- Performing liver biopsy in the presence of coagulo
ity. Survivors exhibit an initial rapid decline in mDCs pathy and ascites in patients with ACLF is challenging
numbers followed by an increase in the circulating as and should be undertaken cautiously on an individual
well as intrahepatic number of mDCs57,88. The altered basis. Transjugular biopsy in patients with ACLF is quite
hepatic microenvironment, recruitment of mDCs or safe. In addition, the transjugular approach enables the
mDC generation in the bone marrow does account for measurement of the hepatic venous pressure gradient93.
Histopathology helps to establish the aetiology of Intensive care. Patients with ACLF need close monitor-
both acute and chronic causes, particularly Wilson ing to detect the development of components of SIRS,
disease, autoimmune hepatitis or DILI. Rastogi et al.67 hypotension and shock. Use of prophylactic antibiotics
have proposed two patterns to predict patient outcome might help in prevention of infection if given at the onset
comparing those who survived to those who died of SIRS, as it is difficult to differentiate SIRS from early
(BOX 1; FIG. 4); pattern I, which is associated with high sepsis. However, to date, no prospective or randomized
mortality and pattern II, which is associated with better control trial has been conducted on use of prophylactic
survival, irrespective of the aetiology67. Histology has antibiotics in ACLF and in fact, most other studies did
also been found to predict poor outcome and early not assess the use of antibiotics. Louvet et al.98 showed
need for transplantation67,94. Submassive hepatic necro- that nonresponders to steroid treatment have poor
sis characterized by extensive and confluent necrosis, survival and an increased risk of infection. Mookarjee
cholestasis and ductular bilirubinostasis are predictive et al.97 showed that even though infection cannot be
of poor outcome in patients with HBV-related ACLF95. detected in the majority of patients, the presence of SIRS
In those with severe alcoholic hepatitis, fibrosis stage, is associated with high mortality. This data strongly sug-
polymorphonuclear infiltration and bilirubinostasis gests that SIRS could be a manifestation of occult sepsis.
indicate unfavourable course96. Whereas bilirubino The choice of antibiotics depends on the type, severity
stasis correlates with the development of bacterial infec- and origin of infection (community acquired or noso-
tions (OR 1.57, 95%CI: 1.00–2.47; P = 0.04), advanced comial), and local epidemiological data about antibiotic
fibrosis predicts poor regeneration capabilities in any resistance2. Patients with ACLF and septic shock are
aetiology of ACLF96. In patients with alcoholic steato extremely ill with mortality exceeding 80%61,106. Septic
hepatitis on biopsy, the presence of SIRS further shock is fluid responsive in only ~12% and vasopressor
increases the mortality (P <0.01)97. High portal pressure responsive in 50% of patients106. Terlipressin alone or
correlates with the presence of alcoholic steatohepatitis in combination with noradrenaline helps reverse septic
and mortality98. Liver biopsy can also help in selec- shock, improve microcirculation and reduce the risk of
tion of patients for steroid therapy, as the response is variceal bleeding and nosocomial spontaneous bacterial
better in those with severe alcoholic hepatitis96. So early peritonitis (SBP). However, one needs to closely monitor
liver biopsy can identify the patients with ASH, with for adverse effects of terlipressin, which can be seen in
bilirubinostasis and indirectly might help to s tratify up to one-third of treated patients106.
steroid non-responders99,100. Despite the data being limited, the use of albumin
is suggested by the authors to improve intravascular
Management of ACLF volume, and prevent and manage acute kidney injury
Multiple strategies exist in the management of ACLF. (AKI) and infections. Cyclooxygenase (COX)-derived
These strategies include general measures, specific prostaglandin E2 (PGE2) is one of the main drivers
therapies, bridging and definitive treatments and for immunosuppression in patients with acute decom-
emerging therapies. pensation of cirrhosis and its level increased in ACLF.
Albumin binds to PGE2 and reduces its bioavailability,
General measures which in turn increases circulating TNF levels, reduces
Nutrition. Although the majority of patients with cir- monocyte anergy and reduces the risk of infections107.
rhosis have moderate to severe malnutrition, many with The beneficial effects of albumin could also be due to
ACLF have fairly well-preserved nutritional status101,102. its ROS-scavenging activities, protection of endothelial
In fact, obesity is one of the risk factors for ACLF102. integrity and binding of toxic molecules. Albumin
However, if such patients become acutely and severely administration in patients with ACLF could be help-
ill, their nutritional reserves do not last long to support ful in managing complications such as SBP, hepato-
the crisis and the regenerating liver. Optimal nutritional renal syndrome (HRS), hepatic encephalopathy and
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 Box 1 | Histological patterns associated with prognosis
satiety, high bilirubin and cholestasis, altered hepatic bile Pattern 1
composition and synthesis, and high catabolic demands, • Marked ductular proliferation
add to nutritional compromise and poor outcomes101,103.
• Coarse inspissated ductular bile plugs
Enteral tube feeding and the use of nutrient dense for-
• Eosinophilic degeneration of hepatocytes
mulas (1.5–2.0 kcal/ml) help ill patients who are unable
to meet their nutrient needs independently. A target • Foci of confluent or bridging necrosis
of 1.5–2.0 g protein/kg per day and 39 kcal/kg per day • Higher apoptosis
has been shown to improve hepatic encephalopathy • Pericellular fibrosis
and overall survival104,105. Carbohydrate-predominant • Mallory’s hyaline
late evening snack has been shown to be helpful in a • Higher stage of fibrosis
few studies103,104. Limited data exists on the composi-
Pattern II
tion101 and utility of parenteral nutrition in patients
• Prominent hepatocyte ballooning
with ACLF and should be used carefully in those with
• Less fibrosis and necrosis than in pattern I
intestinal ileus.
e f g h
autoimmune hepatitis, with 60% requiring transplan- options for the treatment of ACLF. Despite their poten-
tation121. Use of steroids is controversial: a UK study tial, probiotics137, thalidomide138 and plasma exchange
showed a benefit122, and a US ALF study reported bene- are only considered as experimental therapies owing to
fit in a selective cohort, that is, those with lower MELD the lack of data at this time.
scores (20 versus 26, P = 0.02) and UK‑MELD score (57
versus 59, P = 0.01)123. Patients with a high MELD score Artificial liver support
have greater treatment failure rates than those with The rationale behind artificial liver support is to remove
low scores122, and lack of large studies on use of tacroli- possible toxins and prevent further aggravation of liver
mus124 or mycophenolate125 leaves limited options for failure, stimulate liver regeneration and support hepatic
intervention except early transplantation. functions139. Liver failure in patients with ACLF leads
to the accumulation of toxic concentrations of biliru-
Corticosteroids. Steroid therapy is known to suppress bin, bile acids, ammonia, protein breakdown products
inflammatory and immune-mediated hepatocyte (aromatic amino acids, phenol and mercaptans), lactate,
injury. The benefit of steroid therapy in patients with glutamine, various mediators of oxidative stress, free
alcohol-related ACLF has not been studied and its role in fatty acids, endogenous benzodiazepines, iron metabo-
severe alcoholic hepatitis has been somewhat controver- lites and inflammatory cytokines both in blood and tis-
sial in presence of ascites, risk of sepsis, high mortality sues140. An artificial liver support system (ALSS) using
upon failure of steroid therapy and ineligibility for liver albumin dialysis, leads to removal of these vasoactive
transplantation with uncontrolled sepsis that devel- substances, improves systemic and splanchnic circula-
ops after the start of steroid treatment. Approximately tion141, liver regeneration142,143 and serves as a bridge to
60% of patients with severe alcoholic hepatitis showed liver transplantation139,140.
improved short-term survival with steroids126, however, At present, there are two main devices providing
6‑month mortality remained at ~40%127. Antibiotic ALSS; the Molecular Adsorbent Recirculating System
coverage is suggested by most of the studies as infection (MARS® (Gambro, Sweden)) and the Fractionated
is seen in 25% patients at admission and another 25% plasma separation and adsorption (FPSA; the Prome
get infected during corticosteroid treatment98. Sensitivity theus System® (Fresenius Medical Care, Germany)).
to corticosteroids improves as liver function recovers128. Studies on the use of ALSS in patients with ACLF as
per the current APASL or EASL definition are limited
Pentoxyfiline. A weak inhibitor of TNF synthesis, pen- (TABLE 2). The published RELIEF study144 using MARS®
toxyfiline, has antioxidant properties129. In patients reported a decrease in serum creatinine and bilirubin
with severe alcoholic hepatitis, pentoxyfiline improved levels with improvement of hepatic encephalopathy on
6‑month survival compared with placebo in some130,131, the fourth day of treatment, but without survival bene
but not in other studies132,133. In the STOPAH trial, con- fits. The FPSA (Prometheus System®) device used in
sisting of 1,103 patients, pentoxyfiline was comparable the HELIOS study (n = 145) reported a notable reduc-
to placebo. The corticosteroid therapy showed survival tion in serum bilirubin levels145. The survival benefit
benefit only at 28 days, but not at 90 days or 1 year134. was limited to patients with type I HRS and a MELD
score of >30 (REF. 145) . A meta-analysis showed a
Experimental therapies. Therapy with N-acetyl cysteine, decrease in mortality in those with ACLF when treated
modulation of gut flora75,76 anti-TNF agents135 and fae- with ALSS (RR 0.80; 95% CI 0.66–0.96; P = 0.018)146.
cal microbial transplantation136 are emerging therapeutic Decreasing the MELD score to <30 with ALSS before
liver transplantation, leads to reduced overall mortal- Pamecha et al.149 proposed serial assessment of disease
ity147. ALSS therefore remains a useful tool in a selected severity with CLIF‑C score of patients with ACLF in the
group of patients with ACLF to improve their clinical first week of hospitalization for prioritization for liver
and biochemical status before transplantation. transplantation. In general, patients with a MELD score
of >30, discovery of HBV reactivation with cirrhosis on
Liver transplantation in ACLF biopsy and serum bilirubin levels of ≥170 μmol/L, pro-
Patients with ACLF are relatively sick in comparison thrombin index >40%, a platelet count of <1 × 105/L and
to those with decompensated cirrhosis or patients presence of encephalopathy should be listed for early
with acute hepatitis, and often have sepsis and multi transplantation150–153. Although, many prediction mod-
organ failure leading to a 4‑week mortality close to els of early transplantation listing exist, none reliably
50%2. Liver transplantation is a potentially curative predicts chances of reversibility of ACLF.
treatment option, with a good outcome irrespective of In one series from Germany, 101 of 111 (91%)
aetiology (TABLE 3). Priority transplantation is required patients with ACLF (as defined by APASL) who could
for the ACLF patient population as SIRS and sepsis not undergo liver transplantation died owing to being
generally develop within 7 days of hospitalization61. too ill, whereas 28 of 33 (85%) who underwent trans-
Transplantation is only feasible in ~25% of patients plantation survived for a median of 29 months148. Chan
with ACLF on the deceased donor liver transplant et al.153 in a series of 149 patients with ACLF defined by
ation waiting list, owing to progressive liver failure the APASL criteria who received either deceased or liv-
and onset of multiorgan failure14,148. Disease severity ing donor transplants, showed a 5‑year survival of 90%.
scores such as MELD have been considered to deter- In a series from China, patients with ACLF as defined
mine organ allocation to those who need the organs by APASL definition, the 1‑year, 3‑year and 5‑year sur-
most in a scenario of increased demands for organs; vival rates were 76.8%, 75.6% and 74.1%, respectively152.
however, it is a solution that is far from perfect. Disease Overall, the results of transplantation in patients with
severity scores do not take into account cerebral, cir- ACLF are encouraging (TABLE 3). However, the min
culatory and respiratory failures, giving no priority imum duration of abstinence to prevent recidivism in
for patients with ACLF 14,149. Using the EASL-CLIF patients with severe alcoholic hepatitis is undecided. Of
definition, liver failure (bilirubin ≥204 μmol/L) and a note, early liver transplantation does improve survival
high CLIF‑C score at baseline, have been shown to be in those with alcohol-related ACLF that is unrespon
associated with a transplantation-free survival of only sive to steroids154. Although early transplantation in
12.8%. Early liver transplantation upon diagnosis of carefully selected patients with alcohol-related ACLF
ACLF, that is, within a median of 11 (1–28) days led improves clinical outcomes, an ethical dilemma remains
to a 75% 1‑year survival14. However, the presence of if the patient has been drinking until the last 6 months
≥4 organ failures at admission, or CLIF‑C ACLF score from index presentation. The decision becomes
of >64 at 3–7 days, in the absence of liver transplant even more challenging in a related living donor liver
ation, is associated with a 100% mortality by 28 days14. transplantation scenario155.
The emergence of regenerative therapy activate WNT3 signalling, which promotes differenti
Some special concerns related to improving hepatic ation of HPC into hepatocytes by inhibition of Notch–
regeneration as a therapeutic approach in those with Hedgehog signalling160. Lineage tracing experiments in
ACLF are: the status of liver regeneration during o
ngoing various mouse models of liver injury have shown both
liver injury; the role of growth factors in augmenting hepatic and nonhepatic cellular origins of HPCs in adult
hepatic regeneration; and the development of in vivo or liver regeneration depending on the extent of hepatic
ex vivo approaches to modulate hepatic regeneration. injury161,162. Hepatic nonparenchymal cells might also
actively participate to repopulate the liver, as suggested
Liver regeneration in a failing liver by an increase in the proportion of activated hepatic stel-
Liver regeneration is a complex process and it depends late cells per 1,000 cells in patients with ACLF (231 ± 91)
upon the extent and type of parenchymal injury156. than those with cirrhosis (73 ± 35) and healthy individ-
In ALF, regeneration occurs by self-replication of uals (25 ± 10; P <0.0001)163. The number of HPCs also
quiescent differentiated hepatocytes and cholangio- positively correlates with patient survival163,164. However,
cytes156. In ACLF, it occurs by activation and differen- whether the expanded number of activated stellate
tiation of hepatic progenitor cells (HPCs; FIG. 5)156,157. cells dedifferentiate into HPCs164 or provide paracrine
The tumour necrosis factor ligand superfamily mem- support for liver regeneration needs to be defined (FIG. 5).
ber 12 (TNFSF12, also known as TWEAK) and tumour After the hepatocytes, HPCs and hepatic stellate
necrosis factor receptor superfamily member 12A cells, the bone marrow is the third tier of regenerative
(TNFRSF12A, also known as FN14) pathway, stimulated response and has a synergistic effect on intrahepatic
by macrophages, T cells and M2 Kupffer cells is associ- regeneration165. In response to hepatic injury, stromal
ated with the differentiation of HPCs into hepatocytes in cell-derived factor‑1 increases in bone marrow and in
ACLF158,159. Dying hepatocytes engulfed by macrophages the repopulated liver along with its ligand CXCR4 for
Myofibroblast
HPC
Macrophage
Hh IH
? Phagocytosis
of dying NOTCH
hepatocytes ? ?
TWEAK Bone
WNT marrow
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.
the augmentation of regeneration166. The release of of ongoing liver failure as evidenced by the presence of
haematopoietic stem cells (HSCs) into the systemic cir- large numbers of CD34+ cells in liver tissue samples from
culation occurs in response to stress or injury and leads patients with ACLF (FIG. 6). The authors further showed
to their transendothelial migration162 and homing to the that G‑CSF therapy given over 1 month substantially
liver. Bone-marrow-derived epithelial progenitor cells enhanced the mobilization of bone marrow HSCs in
increase after partial hepatectomy as well as in cirrho- comparison with the placebo group and showed homing
sis156,166. They stimulate liver sinusoidal endothelial cells of these cells in the hepatic parenchyma in follow‑up
for tube formation and angiogenesis, a prerequisite for liver biopsy samples. This therapy was associated with
liver regeneration167,168. a reduction of Child–Pugh, MELD and SOFA scores,
reduced sepsis, hepatorenal syndrome and hepatic
The role of growth factors in hepatic regeneration encephalopathy, and improved survival (66% versus
More often than not, hepatic injury in ACLF is more 26%, P <0.01)171. In very ill patients with a MELD score
aggressive than the body’s ability to restore balance of >30, G‑CSF therapy should, however, be considered
and stimulate hepatic regeneration. Also, hepatocytes only if liver transplantation is not feasible and preferably
in patients with CLD are often in a state of replicative by specialists experienced in this therapy; this approach
senescence169. Supplementing hepatic regeneration with should not be used in patients with ACLF in the pres-
in vivo or ex vivo approaches is therefore worthwhile. ence of AKI, ongoing sepsis, significant haemolysis
Di Campli et al.170 showed successful dose-dependent or macrophage activation syndrome. In the latter, it is
mobilization of bone marrow stem cells in patients likely that levels of G-CSF and granulocyte macrophage
with ACLF after 3 days of G‑CSF therapy. Garg et al.171 colony stimulating factor (GM-CSF) levels are already
showed that substantial regeneration goes on in the wake too high171,172.
ALF
• ↑ Trafficking Blood
• ↑ Proliferation
of HSC and • CD34
• Neutrophils • ↑Regeneration
EPCs • ↓Fibrosis
100× 100× • Monocytes
• ↑ Cytokines • MAPC • ↓Inflammation
b and GF
• ↓ Apoptosis
On a cellular basis, G‑CSF therapy in combination as augmentor of liver regeneration, hepatocyte growth
with stem cell factors was found to immunologically mod- factor, vascular endothelial growth factor and bone
ulate the biliary cellular niches as well as the intrahepatic marrow cell-mobilizing factors, such as plerixafor, are
milieu for regeneration in a rat model of partial hepatec- under evaluation (FIG. 6)178,179.
tomy173. G‑CSF therapy in human beings has been shown
to recruit DCs in the liver and inhibit IFNγ‑secreting In vivo or ex vivo hepatic regeneration?
CD8+ T cells to ameliorate hepatocellular injury57. HPC Conventionally, bone-marrow-derived HSCs or mesen
proliferation174, CXCR4 expression, and neutrophil and chymal stem cells are externally modulated ex vivo
macrophage activation are all increased by G‑CSF175. under the influence of growth factors 180. However,
Developing therapeutic synergism by combining this technique requires good manufacturing practice
G‑CSF with other growth factors is an area of intense facilities and expertise in isolation, in vitro culture and
research. Erythropoietin (EPO) has been shown to reinfusion in to the patient through the hepatic artery or
mobilize EPCs and enhance their in vivo regenerative portal vein. By contrast, in vivo autologus bone marrow
role via the PI3K–AKT pathway176. Darbopoetin‑α, HSC mobilization, by giving subcutaneous injections
due to better bioavailability and ease of once weekly of G‑CSF, is a novel approach and can be used easily
administration, has higher potency than recombinant by an experienced physician. After the initial study by
human erythropoietin (rhEPO)177. Kedarisetty et al.172 Garg et al.171, survival benefits with in vivo G‑CSF
in a unique human study used the combination of therapy have been reaffirmed in patients with ACLF
G‑CSF and darbopoetin‑α, which improved hepatic related to HBV infection181 as well as in patients with
regeneration compared with placebo. This observation severe alcoholic hepatitis178, with a notable increase
was assessed indirectly in relation to clinical param in circulating CD34+ bone marrow HSCs182. Variable
eters: 1‑year survival increased (68.6% versus 26.9%; results with respect to regeneration and survival benefit
P = 0.003), Child–Pugh score reduced (48.6% versus have been found by several investigators using mesen
39.1%; P = 0.001); MELD scores reduced (40.4% ver- chymal stem cell therapy in patients with cirrhosis183,184.
sus 33%; P = 0.03) and lower incidence of septic shock The only study in patients with ACLF using cell ther-
(6.9% versus 38.5%; P = 0.005). Other cytokines such apy by Shi et al.185 has shown a substantial reduction of
ACLF
<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
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mesenchymal stem cell transfusion is safe and adsorbent recirculating system and Prometheus Authors are grateful to N. Trehanpati, A. Kumar, A. Rastogi,
improves liver function in acute‑on‑chronic liver failure devices on systemic haemodynamics and R. K. Gulati, S Baweja and A. Khanam for their intellectual
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with hepatitis B who require immunosuppressive (2006). Author contributions
therapy. Nat. Rev. Gastroenterol. Hepatol. 11, 193. Lin, K.‑H. et al. Impacts of pretransplant infections A.C. prepared the draft manuscript and designed the sections;
209–219 (2014). on clinical outcomes of patients with S.K.S. conceived, edited, revised and prepared the final draft.
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severe hepatitis B virus reactivation. Liver Int. donor liver transplantation. PLoS ONE 8, e72893 Competing interests statement
31 (Suppl. 1), 104–110 (2011). (2013). The authors declare no competing interests.