Acute On Chronic Liver Failure- Evolution of Concept

23 October 2015

First Case

• In 1995, a case report published• Ohnishi H et al. [Acute-on-chronic liver

failure]. Ryoikibetsu Shokogun Shirizu. 1995;(7):217-9.

• Idea gained momentum that treating acute event by supporting liver function e.g MARS will improve survival/buy time to transplantation

Definitions in past

• First consensus on ACLF (2009)• Acute hepatic insult manifesting as jaundice

andcoagulopathy complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed liver disease

• Jaundice : Bil > 5 mg/dL• Coagulopathy: INR > 1.5 mandatory for

definition of ACLF

AASLD-EASL

• Acute deterioration of pre-existing chronic liver disease usually related to a precipitating event and associated with increased mortality at 3 months due to multi system organ failure

• Jalan R, et al. Journal of Hepatology 2012

Differences compared to APASL

Organ failure

• Central component of the syndrome• Hypothesis: Organs may behave differently to

chronic decompensated liver disease• Organ failure is defined as need for support • Single organ failure is reversible in 50% of

cases.

Importance of organ failure

• Scoring systems addressing severity of liver disease like Child-Pugh score and MELD perform less well than the systems addressing organ dysfunction like SOFA and APACHE

• It is the degree of end organ failure that determines the outcome

Organ Failure predicts mortality

Act before its too late

Pathophysiology

Acute injury in ACLF

Acute injury in ACLF

Infections

• 40-50% of hospital admissions in cirrhotics is due to infections

• 20% will further develop nosocomial infections• In hospital mortality of cirrhotics with infection-

15%• Mortality in septic shock – 60-100%• Can precipitate hepatic encephalopathy, renal

failure and rebleeding

Patients who fail to resolve CARS- becomes infected and have highest mortality

NASCELD Study(2012)

Percentage of infections( first and second) according to body site

Comparison between survivors and non survivors

Comparison between survivors and non survivors

CANONIC Study(2013)

CLIF- SOFA Score

CLIF- SOFA Score

CLIF – SOFA is different from SOFA score with inclusion of INR, hepatic encephalopathy and exclusion of Glasgow score, urine output criteria and thrombocytopenia

Diagnostic criteria for ACLF

• Acute decompensation( Inclusion criteria)• Organ failure( defined by CLIF-SOFA)• High 28 day mortality( predefined threshold of

15%)

Mortality at 28 days

• 14.6 % with one organ failure• 32% with two organs failure• 78.6% with three organs failure

Type of organ failure dictating mortality?

Risk factors for mortality

(1) the presence of 2 organ failures or more(2) the presence of one organ failure when the

organ that failed was the kidney(3) the coexistence of a single “non kidney”

organ failure with kidney dysfunction (ie, serum creatinine level ranging from 1.5 to 1.9 mg/dL) and/or mild to moderate hepatic encephalopathy

Grades of ACLF

• No ACLF. This group comprises 3 subgroups: (1) patients with no organ failure (2) patients with a single “non-kidney” organ

failure (ie, single failure of the liver, coagulation, circulation, or respiration) who had a serum creatinine level < 1.5 mg/dL and no hepatic encephalopathy,

(3) patients with single cerebral failure who had a serum creatinine level <1.5 mg/dL

Grades of ACLF

• No ACLF. This group comprises 3 subgroups: (1) patients with no organ failure (2) patients with a single “non-kidney” organ

failure (ie, single failure of the liver, coagulation, circulation, or respiration) who had a serum creatinine level < 1.5 mg/dL and no hepatic encephalopathy,

(3) patients with single cerebral failure who had a serum creatinine level <1.5 mg/dL

In total, 1040 of the 1343 enrolled patients(77.4%) had no ACLF at enrollment. The 28-day and

90-day mortality rates were 4.7% and 14%, respectively

• ACLF grade 1. This group includes 3 subgroups: (1) patients with single kidney failure (2) patients with single failure of the liver,

coagulation, circulation, or respiration who had a serum creatinine level ranging from 1.5 to 1.9 mg/dL and/or mild to moderate hepatic encephalopathy,

(3) patients with single cerebral failure who had a serum creatinine level ranging from 1.5 and 1.9 mg/dL

• ACLF grade 1. This group includes 3 subgroups: (1) patients with single kidney failure (2) patients with single failure of the liver,

coagulation, circulation, or respiration who had a serum creatinine level ranging from 1.5 to 1.9 mg/dL and/or mild to moderate hepatic encephalopathy,

(3) patients with single cerebral failure who had a serum creatinine level ranging from 1.5 and 1.9 mg/dL

Intotal, 148 patients (11.0%) had ACLF grade 1 at enrollment.

The 28-day and 90-day mortality rates were 22.1%and 40.7%, respectively.

• ACLF grade 2• This group includes patients with 2 organ

failures• 108 patients (8.0%) had ACLF grade 2 at

enrollment. • The 28-day and 90-day mortality rates were

32.0% and 52.3%, respectively.

• ACLF grade 3.• This group includes patients with 3 organ

failures or more• 47 patients (3.5%) had ACLF grade 3 at

enrollment. • The 28-day and 90-day mortality rates were

76.7% and 79.1%, respectively.

Mortality: different stages

SOFA in era of CTP/MELD

SOFA in era of CTP/MELD

CTP/MELD better for stable cirrhoticsOrgan failure scores better in predicting outcome in ACLF

Jalan et al. Journal of Hepatology 2014

• 31 children• ACLF defined by APASL• Etiology : Chronic disease : AIH 41%, Wilson

41%, HAV most common precipitating event

Hepatology International 2011

• 100 patients• ACLF defined by APASL• Etiology Alcohol 72%, HBV/HCV 5%, NASH 8% AIH

4%

J Dig Dis 2013

• 1700 patient records were analysed against 200 in 2009 APASL guidelines

• Acute hepatic insult manifesting as jaundice and• coagulopathy complicated within 4 weeks by

clinical ascites and/or encephalopathy in a patient with previously diagnosed or undiagnosed chronic liver disease

• associated with a high 28-day mortality

Decompensated Cirrhosis not included in APASL

Golden window

• Short period of about 1 week before onset of about 1 week before onset of sepsis and development of extra hepatic organ failure in a patient with ACLF.

APASL 2014

Need to include decompensated cirrhosis: Unifying concept

Jalan R et al. Gastroenterology 2014

Unifying Concept

• ACLF:• Syndrome in patients with CLD with or without

previously diagnosed cirrhosis• Which is characterised by acute hepatic decompensation

resulting in liver failure (jaundice and prolongation of the INR [International Normalized Ratio])

• And one or more extra-hepatic organ failures that is associated with increased mortality

• Within a period of 28 days and up to 3 months from onset

Jalan et al, Gastroenterology, 2014

• 50 patients, 38 had ACLF (CLIF SOFA) and 19 had ACLF( as per ACLF)• The 28-d mortality in no ACLF and ACLF groups was 8.3% and 47.4% (P

= 0.018) as per CLIF-SOFA and 39% and 37% (P = 0.895) as per APASL criteria

• On multivariate analysis of these scores, CLIF-SOFA was the only significant independent predictor of mortality with an odds ratio 1.538 (95%CI: 1.078-2.194).

AIIMS Data

• Acute on Chronic Liver Failure due to Acute Hepatic Insults: Etiologies, Course, Extrahepatic Organ Failure and Predictors of Mortality

Shalimar et al. JGH, 2015

• ACLF patients according to APASL included between Jan 2011 to Feb 2014• Patients with overt CLD were also included• Hepatic decompensation due to variceal

bleed, bacterial infections or HCC excluded

Primary Objectives

1) etiology of ACLF other than variceal bleed/ sepsis, and influence of etiology on the

outcome, 2) the course of ACLF patients with overt and

silent CLD 3) type and number of OF and their influence

on mortality 4) the predictors of mortality.

Etiologies of acute hepatic insult and underlying chronic liver disease

Baseline clinical characteristics, laboratory parameters, and survival rates in ACLF due to different acute hepatic insults

Variable HEV(n=39) HBV(n=42) Alc(n=71) Cryptogenic(n=44)

P value

Males,n(%) 32(82%) 26(61.9%) 71(100%) 25(56.8%) .0001

Ventilation,n(%)

2(5.1%) 7(16.6%) 18(25.4%) 11(25.0%) .031

TLC(per mm3

10600(4900-18900)

10100(2000-46400)

14050(4500-62000)

12100(2600-42100)

.020

CLIF-SOFA 6(1-13) 6.5(2-17) 8(1-33) 8(3-20) .009

APACHE 15(3-26) 12.5(2-31) 15(2-33) 18(6-38) .047

Creatinine(mg/dl)

0.9(0.3-8.5) 1(0.2-3.9) 1.6(0.4-9.3) 1.6(0.2-9.4) .001

Silent CLD 27(69.3%) 25(59.5%) 28(39.4%) 21(47.7%) .010

Overt CLD 12(30.7%) 17(40.5%) 43(61.5%) 23(53.5%) .010

In hospital mortality

5(12.8%) 14(33.3%) 39(54.9%) 24(54.5%) <.001

Hospital stay 15(2-40) 7.5(3-30) 7.5(1-21) 10(1-63) .032

Comparison of variables between survivors and non survivors

Multivariate analysis of factors influencing mortality

Number of organ failures and mortality

ACLF in India- INASL Consortium Experience

Etiology of acute hepatic and extrahepatic precipitating events in patients with ACLF (n=1049)

224; 21%

374; 36%60; 6%

174; 17%

88; 8%

104; 10%

25; 2%

Viral Superinfection/ Flare (HEV,HAV and HBV)Continuous alcohol consumptionDrugs (including antituberculosis drugs)SepsisVariceal bleedingCryptogenicOthers (AIH fare and Surgery)

Etiology of chronic liver disease in ACLF patients (n=1049)

167; 16%

595; 57%

51; 5%

10; 1%

204; 19%

5; 0% 17; 2%

Viral (HBV and HCV)AlcoholAutoimmuneWilsonsCryptogenicHVOTOViral and Alcohol

Frequency of various organ failures in ACLF patients (n = 381)

• Type of Organ failure• Liver failure-259 (68%)• Renal failure-121 (31.8%)• Coagulation failure-120 (31.5%)• Respiratory failure-86 (22.6%)• Circulatory failure-57 (15%)• Cerebral failure-55 (14.4%)

In hospital mortality as per the number of organ failures (n=381)

In hospital mortality as per the grade of ACLF (n=381)

Evolution in management strategies

• MARS• Role of liver transplantation

Banares R, et al. Hepatology 2013

Banares R, et al. Hepatology 2013

Liver Transplantation

Chan C et al. Heoptology Int 2009.

Take Home Message

• ACLF has evolved into area of Excellency from waters of mediocrity in last two decades

• More focus on extrahepatic organ failure • CLIF-SOFA is backbone of ACLF• Which patient of ACLF will benefit from LT-

area of research

Thank you