1) Acute-on-chronic liver failure (ACLF) is a condition where an acute hepatic insult further decompensates an underlying chronic liver disease, leading to liver failure within 4 weeks. 2) The acute insult can be due to infections like hepatitis viruses, drugs, alcohol use, or other causes, while the underlying chronic liver disease can be due to conditions like hepatitis, alcohol, or non-alcoholic fatty liver disease. 3) Prognostic scores like MELD, CLIF-SOFA, and AARC are used to determine disease severity and predict outcomes in ACLF, with higher scores indicating poorer prognosis. Management involves treating the acute insult, supporting failing organs, and consideration

1. ACUTE ON CHRONIC LIVER
FAILURE
MODERATOR : DR. BS RANA

2. • The ACLF is a clinical syndrome
manifesting as acute and severe
hepatic derangements resulting from
varied insults.
• It is a condition in which two insults to
liver are operating simultaneously, one
of them being ongoing and chronic,
and the other acute
INTRODUCTION

3. Degree of acute and chronic insult in acute-on-chronic liver failure (ACLF): Two scenarios. The
first artwork shows a patient with mild chronic liver disease but severe acute liver insult leading
to ACLF.
The second artwork shows a patient with moderate chronic liver disease and less severe acute
insult. The resulting severity of ACLF is same in these two situations

4. • Acute hepatic insult manifesting as
jaundice, and coagulopathy
• Complicated within 4 weeks by ascites
and or encephalopathy
• In a patient with previously diagnosed
or undiagnosed chronic liver disease.
ACLF – 3 components

5. DEFINITION
ACLF is an acute hepatic insult manifesting as
jaundice ( serum bilirubin >= 5 mg/dl ) and
coagulopathy ( INR >= 1.5 ) complicated with in 4
weeks by clinical ascitis and / or encephalopathy in
a patient with previously diagnosed or undiagnosed
chronic liver disease or cirrhosis and is associated
with a high 28 day mortality.
APASL 2019

6. ACLF IS DISTINCT FROM ACUTE
DECOMPENSATION
 AD – presentation is either
hepatic ( jaundice, ascitis, HE) or
extrahepatic ( variceal bleed , acute kidney injury or sepsis)
 ACLF – hepatic decompensation ( jaundice, coagulopathy, ascitis
and/or HE) where the insult is only hepatic and leads to liver failure
in a period of 4 weeks.
 Development of ascitis represents a state of acute portal
hypertension in ACLF patients.
APASL 2019

7. ACLF vs Acute Decompensation
PARAMETERS ACLF AD
PRESENTATION Hepatic insult
index
Hepatic or non hepatic
Can be index or subsequent
Jaundice and coagulopathy
followed by development of
ascites and/or HE
Jaundice, ascites, HE, variceal
bleed, coagulopathy
jaundice ± ascites, HE ±ascites
±jaundice, HE± variceal bleed,
variceal bleed± ascites etc
IDENTIFIABLE PRECIPITANT Upto 95% cases Upto 70% cases
TIME FROM INSULT TO
PRESENTATION
Within 4 weeks Upto 12 weeks
UNDERLYING CIRRHOSIS May or may not be present Always present
PRIOR DECOMPENSATION No With or without prior
decompensation
MORTALITY AT 1 AND 3 MONTHS 33-51% 23-29%
REVERSAL OR RECOVERY In half of cases Uncommon APASL 2019

8. ACUTE EVENTS IN ACLF
• INFECTIOUS ETIOLOGY
1) Hepatotropic viruses HAV, HEV
2) Reactivation of hepatitis B or hepatitis C
3) Other infectious agents afflicting the liver
Bacterial , parastic , fungal
• NON INFECTIOUS ETIOLOGY
1) Alcohol: active drinking within the last 4 weeks
2) ACLF-D : Heaptotoxic drugs
3) ACLF-AIH
4) Acute variceal bleeding
5)Vascular liver diseases :PVT, HVOTO
APASL 2019

9. Acute events
1.Infections
Hepatotropic infections.
 Hepatotropic viral infections: reactivation of Hepatitis B virus
infection and super-infection with hepatitis virus HAV ,HEV.
 Hepatotropic non-viral infections: bacterial, parasitic, and fungal
infections
2.Drug-induced ACLF (ACLF-D)
antitubercular drugs,
Complimentary and alternative medications,
antiretroviral drugs and Methotrexate.
APASL 2019

10. 3.ACLF –AIH
• present as seronegative for autoantibodies or normal IgG levels
• requires liver biopsy ( transjuglar route preferred)
• suspicion is high if there are extrahepatic features of autoimmunity ,
family history of autoimmunity or autoimmune diseases like vitligo,
thyroiditis.
4.Acute variceal bleed
• AVB in compensated cirrhosis leads to development of ACLF in less than
5%.
5.Vascular liver diseases (PVT , HVOTO)
• Development of acute occlusive portal vein thrombosis (PVT) may
precipitate ACLF
• no evidence currently to suggest that NCPF or EHPVO may present as
ACLF APASL 2019

11. Acute Insult in ACLF
HAV (%) HEV (%) HAV+HEV (%)
Pant 2004 ( n = 10 ) 100
SGPGI 2004 ( n = 32) 100
Vallore 2004 ( n = 9 ) 100
AIIMS 2007 ( n = 42) 50
SGPGI 2009 (n=121) 27.2 61.1 6.1
Radha Krishna et al. Liver International (2009)
Rajnish Monga IGJ 2004, 23; 50-52
Arvind kumar IGJ 2004, 23; 59-62
Jeyamani Ramachandran JGH 2004,19, 134–138
Acharya SK J Hepatol 2007;46:387–394

12. 1.Cirrhotic and non-cirrhotic chronic liver diseases qualify as chronic liver diseases
chronic liver diseases include alcohol, hepatitis B, hepatitis C, NAFLD related chronic liver disease or cirrhosis of
the liver
2.Chronic hepatitis and/or significant fibrosis without cirrhosis should be taken as a chronic liver disease,
if such a patient presents as ACLF .
3.NAFLD-related chronic hepatic injury, NASH, if associated with significant fibrosis, should be taken
as a chronic liver disease in ACLF .
4.Patients with known previous decompensation with jaundice, HE, and ascites should be excluded .
Diagnosis of chronic liver disease and cirrhosis in the setting of ACLF is made by history, physical
examination, laboratory, endoscopic or radiological investigations .
A liver biopsy through the trans jugular route may be helpful when the presence of underlying chronic
liver disease and/or the cause of chronic liver disease and/or the acute insult is not clear.
Defining underlying CLD
APASL 2019

13. 1. Compensated Cirrhosis of any etiology
2. Chronic liver disease with / without significant fibrosis
1. Alcohol
2. Hepatitis B, Hepatitis C
3. NAFLD related chronic liver disease or cirrhosis of the liver
3. NASH with significant fibrosis, simple steatosis does not qualifies for CLD for ACLF
4. Cholestatic liver disease
5. Metabolic liver disease
CHRONIC LIVER DISEASE IN ACLF
APASL 2019

14. Changing trends for the etiology of acute
insult and chronic injury
• Alcohal is now the commenest etiology.
• DILI and Autoimmune etiologies have shown increasing trend.
• HBV infection – reactivation of hepatitis B induced ACLF as well as acute
HAV / HEV induced ACLF shows a decreasing trend.
• Alcohal ,herbs , drugs and suppliments (HDS ) induced ACLF shows an
increasing trend.
APASL 2019

15. PATHOGENISIS
1) SYSTEMIC INFLAMATION
2) IMMUNOSUPRESSION
JHEP REPORTS

16. JHEP REPORTS

17. IMMUNOSUPRESSION
• Secondary infections are common complications of ACLF
• Defective responses to PAMPs have been shown in macrophages
• Decreased frequencies of other myeloid mononuclear cells
(conventional and plasmacytoid dendritic cells) in patients with ACLF
• Neutrophils in patients with ACLF have a marked defect in both the
production of antimicrobial superoxide anion and bactericidal activity
JHEP REPORTS

18. PROGNOSTIC MODELS AND DISEASE SEVERITY
SCORES
• MELD
• SOFA
• APACHE II
• CLIF-SOFA
• CLIF-C OF
• CLIF-C ACLFs
• AARC -SCORE

19. AARC SCORE
POINTS Total
bilirubin(mgdl)
HE grade PT-INR Lactate(mmol/l) Creatinine(mg/dl)
1 <15 0 <1.8 <1.5 <0.7
2 15-25 I-II 1.8-2.5 1.5-2.5 0.7-1.5
3 >25 I-IV >2.5 >2.5 >1.5
Minimum 5 and
Maximum 15
AARC-ACLF GRADE 28 day Mortality
GRADE SCORE
1 5-7 12.7%
2 8-10 44.5%
3 11-15 85.9%
PROGNOSTIC MODELS AND DISEASE SEVERITY SCORES
APASL 2019

20. • Superior to MELD/MELD Na , CLIF-SOFA and SOFA scores for patients with ACLF.
• Trend of AARC score with in first week can predict the need of liver transplant.
score of less than 10 at presentation or decrease in score below 10 by
the end of first week is associated with higher chance of survival.
• AARC score greater than 10 should be listed for LT.
• AARC-ACLF score should also be estimated on Day 4 and Day 7 to predict the
course of illness and prognosis.
APASL 2019

22. CLIF-SOFA Score
ORGAN/SYSTEM 0 1 2 3 4
LIVER(Bilirubin
mg/dl )
<1.2 >=1.2 to<=2.0 >=2.0 to <6.0 >=6.0 to <12.0 >=12.0
KIDNEY(Creatini
ne mg/dl)
<1.2 >=1.2 to<=2.0 >=2.0 to <3.5 >=3.5 to <5.0 >5.0
Coagulation
(INR)
<1.1 >1.1 to <1.25 >=1.25 to <1.5 >=1.5 to <2.5 >=2.5
CIRCULATION
(MAP)
>=70 <70 dopamine<=5 or
Dobutamine or
terlipressin
Dopamine>5 or
E <=0.1 or
NE <=0.1
Dopamine >15
or E >0.1 or
NE >0.1
LUNGS
PaO2/FiO2
SpO2/FiO2
>400
>512
>300 to <=400
>357 to<=512
>200 to <=300
>214 to<=357
>100 to <=200
>89 to <=214
<=100
<=89
CEREBRAL (HE
GRADE)
NO HE 1 2 3 4

23. CHRONIC LIVER FAILURE-CONSORTIUM
ORGAN FAILURE SCALE
ORGAN SYSTEM VARIABLE 1 POINT 2 POINTS 3 POINTS
LIVER Bilirubin (mg/dl) <6.0 >=6.0 to <12.0 >=12
KIDNEY Creatinine (mg/dl) >1.5 to <2.0 >=2.0 to <3.5 >=3.5 or use of RRT
CEREBRAL HE GRADE (West
Haven Criteria)
0 1-2 3-4 or endotracheal
intubation for HE
COAGULATION INR <2.0 >=2.0 to <2.5 >=2.5
CIRCULATION MAP(mmhg) >= 70 <70 Use of vasopressors
RESPIRATION PaO2/fiO2
spO2/FiO2
>300
>357
>200 to <=300
>214 to <=357
<=200
<=214
Or use of
mechanical
ventilation

24. CLIF - C ACLF Score
= 10 [0.3 x CLIF-C OF Score + 0.04 x age + 0.63 x Ln (WBC count) – 2 ]
28 and 90 days mortality
CLIF-C ACLFs of 40 or lower
90% negative predictive value and 97% sensitivity
CLIF-C ACLFs of 60 or higher
82% positive predictive value and 94% specificity

25. APASL 2019

26. MANAGEMENT

27. ACLF- Management
• Management of precipitating event
• Anti virals
• Anti cytokines
• Steroids
• Anti-inflammatory agents
• Supporting end organs
• Management of Liver failure
• ECLAD
• Liver transplantation
• Hepatocyte transplantation

29.  Complete workup at diagnosis of ACLF to rule out infections
 High dose broad spectrum antibiotics at diagnosis.
 Daily reassessment of antibiotic therapy
 Do not delay in administration of antibiotics to the
obtention of cultures
 Empirical antifungal therapy only of respective for invasive
fungal infections
INFECTIONS
JHEP REPORTS

30.  Assessment of AKI Severity using modified KDIGO Criteria
 (0.5 mg/hour ) 20 %albumin (1gm/kg for 48 hours ) in patients
with AKI stage 2 or 3
 In type 1 HRS: 20% Albumin( 1 gm /kg for 48 hours then 20-40
g/day) +Terlipressin(2mg/24 hours) or norepinephrine
 RRT- Define goal bridging to LT
 Avoid nephrotoxic drugs(NSAIDS)
 Avoid early initiation of RRT
KIDNEY
JHEP REPORTS

31.  Early goal directed therapy within first 6 hours
 Maintain MAP > 65 mm of hg
 Fluid Challenges until no further hemodynamic response
 Prefer crystalloids and 5% ALBUMIN as resuscitation fluid
 Strong indications of Albumin- SBP
Large volume parascentesis
AKI
 Norepinephrine as first line vasopressor, epinephrine or
terlipressin when additional agent needed
 IV Hydrocortisone if refractory shock
 Limit saline solutions in patients with ascites or anasarca.
HEMODYNAMICS
JHEP REPORTS

32.  Fibrinogen and/or Platelets in patients with severe
hypofibrinogenemia(<1gm/) and/or
thrombocytopenia(<20000) undergoing invasive
procedures
 Prophylaxis for DVT in patients without severe
coagulopathy
 Avoid correction of INR alterations with FFP in absence of
bleeding
COAGULATION
JHEP REPORTS

33.  Lactulose and Enemas for HE.
 Use sedation protocols targeting specific
endpoints.
 Use short acting sedative agents.
 Avoid deep sedation, avoid
benzodiazepenes
 Avoid neuro muscular agents in pts with
ARDS
CNS
JHEP REPORTS

34.  ET intubation for Patients with West Heaven
grade 3 or 4 HE.
 Lung protective ventilation strategy.
 Prone positioning feasible
Parascentesis in case of tense ascites.
 Consider stress ulcer prophylaxis
 Administer early oral or antral feedings as
tolerated,goal 10-15 kcal/kg/day by day 4
LUNGS
GIT
JHEP REPORTS

35. • Presence of high HBV DNA [> 10(5) copies/ml/ or>2 × 10 (4) IU/ml] is
highly sensitive and specific for the diagnosis.
• Nucleoside analogs should be started immidiately in all HBV- infected
patients at presentation while waiting for confirmation by HBV DNA
level
-tenofovir
-tenofovir ,alafenamide or entecavir
• Assessment of reduction of HBV DNA level at day 15 after nucleoside
analog is encouraged.
ANTIVIRAL STRATEGIES IN ACLF HBV REACTIVATION
APASL 2019

36. Steroids in Severe Alcoholic Hepatitis with ACLF
77% for patients without ACLF,
52% for ACLF-1,
42% for ACLF-2
8% for ACLF-3
With the current data, no definitive recommendation on the systematic use of corticosteroids in sAH with
ACLF (in particular high grades of ACLF)
Also ACLF is not an absolute Contraindication to steroids use
T Gustot et al Journal of Hepatology 2019 :70 ; 319–327

37. APASL Algorithm for management of ACLF
APASL 2019

38. LIVER TRANSPLANTATION
• LT should be offered early in the course of ACLF.
• Organ failure per se should not be a contraindication for liver transplantation, except if
cardiac or pulmonary support is needed or there is rapidly progressive organ failure at
day 4 or 7.
• Patients with HBV reactivation with intermediate MELD should be assessed for early
transplant if cirrhosis, bilirubin>10 mg/dL, PT<40% and platelet<100 × 109/L .
• Steroid ineligible patients with severe alcoholic hepatitis should be listed on priority for
liver transplant.
• Liver transplantation should be reserved for severe alcoholic hepatitis patients.
APASL 2019

39. Liver Dialysis
• Hepatocellular injury in ACLF is driven by a “cytokine burst”
• with elevated levels of multitude of cytokines
• small molecular weight toxins
• vasoactive substances which accumulate secondary to the failing liver
• Injury due to endotoxin and metabolites released from gut bacteria.
• Toxins potentiate
• hepatic injury due to systemic inflammation
• loss of adaptive and innate immunity
• cause vital organ dysfunction, which affects all the major organs
These toxins also deprive the liver of an environment, which is conducive for
regeneration
APASL 2019

40. • Extracorporeal liver support therapies are used to bridge the liver
until recovery or liver transplantation
• Various randomized controlled trials in patients with ACLF have
shown improvement in HE, hepatorenal syndrome, circulatory
dysfunction and immune dysfunction without improvement in
transplant-free survival
• RELIEF trial (for MARS)
• HELIOS (for Prometheus)
APASL 2019

41. Novel Therapies for ACLF
• G-CSF
• Faecal Microbiota transplant
• Bovine colostrum
• Anti –IL1- anakinra
• IL22- Liver regeneration
• Selonsertib – anti-inflammatory

42. COMPARISONS OF EXISTING DEFINITIONS
APASL EASL/CLIF
Acute hepatic insult manifesting as
jaundice (s.bilirubin >= 5mg/dl )
and coagulopathy (INR >= 1.5)
complicated with in 4 weeks by
clinical ascitis and / or
enecephalopathy in a patient with
previously diagnosed or
undiagnosed
CLD/cirrhosis and is associated
with high 28 day mortality.
An acute detrioration of
preexisting CLD usually
related to a precipitating
event and associated with
increased mortality at 3
months due to multiorgan
failure.

43. APASL EASL/CLIF
INCLUSION 1. Compensated cirrhosis
( dx or undx)
2. CLD but not cirrhosis
3. Acute insult directed to
liver
4. Presentation with liver
failure
1. Cirrhosis only
2. Compensated or
decompensated
3. Renal failure is
mandatory
4. Presentation not
necessarily be liver
failure
EXCLUSION Prior decompensation
HCC
HCC

44. APASL EASL/CLIF
Time frame 4 weeks 4- 12 weeks
Acute insullt Hepatic Hepatic or extrahepatic
Sepsis Consequence
/complication
Cause/precipitant
Organ failure Liver is primary to start
with then others
subsiquently
Systemic inflammation
leading to kidney failure
as the primary with or
without other organ
failure
Disease severity score AARC Score CLIF-SOFA
Golden window Well defined for therapy
i.e by 7 days SIRS or
Sepsis as well as for
decision regarding liver
transplant
no such

45. APASL 2019

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