Diagnosis and management of ACLF

2.  ACLF is a clinical syndrome manifesting as acute and
severe hepatic dysfunction resulting from varied insults.
 An acute severe hepatic insult in a healthy liver can lead
to ALF.
 with aggressive critical care, a non-transplantation
survival of up to 60% can be achieved in ALF.
 In the presence of CLD, an acute insult can lead to
rapid and progressive liver failure, with a high short-term
mortality.

4. The concept of the hepatic reserve and ACLF

7.  Development and progression of ACLF
broadly depends :
 the nature and severity of the acute insult,
 the stage of underlying CLD or cirrhosis,
 the rapidity and degree of liver failure.

8.  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 aetiology.

9.  Hepatitis E virus (HEV) infection is a leading
cause of ALF in Asia and Africa, with a median
incidence of 21%.
 HEV infection is associated with a more
severe form of ACLF with higher mortality than
with HAV.
 Super-infection with hepatitis A virus and HEV
lead to the development of ACLF.

10.  The dose and duration of alcohol consumption
determines the stage of CLD.
 Recent alcohol intake and/or binge drinking
behaviour is what contributes to rapid liver
failure.
 The presence of obesity and/or diabetes
mellitus increases disease severity.

11.  Most data relates to drug-induced ALF and information
on ACLF is limited.
 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.
 Antibiotics and anti-epileptic drugs account for >60% of
patients with DILI in the West.

12.  Liver failure in patients with acute variceal
bleeding is mainly due to:
 hepatic ischaemia,
 increased bacterial translocation from the gut.
 was considered a precipitating event in
13.8% of patients in the CANONIC study.

13.  Bacterial infections are more frequent in patients with cirrhosis than in
the general population.
 Cirrhosis-associated immune deficiency syndrome, an emerging
concept, relates to a relative inefficiency of the innate and adaptive
immune system.
 Whether sepsis is a consequence or a cause of liver failure is not clear
from the current data.
 One viewpoint considers sepsis as a common extrahepatic precipitant
of ACLF (I-ACLF).
 The other school of thought supports the concept that sepsis is a result
of liver failure(concept of golden window)

14.  In a patient with Child–Pugh stage B or C
cirrhosis and HCC, acute deterioration
leading to ACLF can develop after TACE or
RFA.

15.  Is difficult unless previously confirmed or when
overt signs of cirrhosis are present.
 History,
 Signs of portal hypertension
 Laboratory test results
 Endoscopic or radiological investigations are
required to confirm the diagnosis.
 If these parameters are not conclusive, a
histopathological evaluation, often by transjugular
biopsy, is recommended.

16.  The earlier definition of ACLF from EASL and
the American Association for the Study of
Liver Disease (AASLD) in 2011 included only
patients with cirrhosis.
 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)
type-C(patients with ACLF, cirrhosis and prior hepatic
decompensation)

17.  Liver failure in ACLF is multifactorial and self-perpetuating.
 The acute insult or pathogen (inducer), directly or indirectly
activates different cell types (sensors) and inflammatory
cytokine pathways (mediators).
 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
mechanisms.

19. Organ system score:1 Score:2 Score:3
Liver
(Bilirubin)
<6mg/dl ≥6 and <12mg/dl ≥12mg/dl
Kidney
(creatinine)
<2md/dl ≥2 and 3.5 mg/dl ≥3.5 mg/dl
Brain
(Encephalopathy)
0 1-2 3-4
Coagulation INR < 2.0 INR ≥ 2 and <2.5 ≥2.5
Respiratory
(PaO2/FiO2)
>300 ≤300 and >200 ≤200
SpO2/FiO2 >357 >214 and ≤357 ≤214
Circulatory MAP ≥ 70mmhg MAP < 70mmhg use of vasopressosrs

20. Grade of ACLF Organ failure 28 day mortality 90 day mortality
1 Single kidney failure
Single ‘non-kidney
failure’
22.1% 40.7%
2 Presence of 2 organ
failures
32.1% 52.3%
3 Presence of ≥3 76.7% 79.1%

21. Nutrition
 Anorexia adds to nutritional compromise
and poor outcomes.
 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 survival

22.  Patients with ACLF need close monitoring
to detect the development of SIRS,
hypotension and shock.
 Use of prophylactic antibiotics might help
in prevention of infection if given at the
onset of SIRS.

23.  Patients with ACLF and septic shock are
extremely ill with mortality exceeding 80%.
 Septic shock is fluid responsive in only ~12%
and vasopressor responsive in 50% of
patients
 Terlipressin alone or in combination with
noradrenaline helps reverse septic
shock,reduce the risk of variceal bleeding and
SBP.

24.  The use of albumin is suggested to improve
intravascular volume, and prevent and manage acute
kidney injury (AKI) and infections.
 PGE2 is one of the main drivers for immunosuppression
in patients with acute decompensation 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 infections.

25.  About 40% of patients with ACLF develop hepatic encephalopathy and require
intensive care.
 Although little evidence exists at present for targeted ammonia reduction
therapies, such as lactulose and rifaximin, they can be given empirically.
 Renal impairment occurs in about one-quarter of patients.
 Use of terlipressin with albumin is effective at treating AKI in only 35% patients
and the responders do have a survival advantage.
 Nonresponders to terlipressin treatment might require renal replacement
therapy in the form of intermittent haemodialysis, slow low-efficient dialysis or
continuous renal replacement therapy.

26.  N-acetyl cysteine, modulation of gut
flora,anti-TNF agents and faecal microbial
transplantation are emerging therapeutic

27.  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 Prometheus
System® (Fresenius Medical Care, Germany).
 RELIEF study 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 benefits.
 The FPSA (Prometheus System®) device used in the HELIOS study (n = 145) reported a
notable reduction in serum bilirubin levels.
 The survival benefit was limited to patients with type I HRS and a MELD score of >30

29.  G-CSF therapy substantially enhances the mobilization of bone marrow HSCs
with homing of these cells in the hepatic parenchyma .
 Is associated with a reduction of Child–Pugh, MELD and SOFA scores,
reduced sepsis, hepatorenal syndrome and hepatic encephalopathy, and
improved survival .
 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 presence of
AKI, ongoing sepsis, significant haemolysis or macrophage activation
syndrome