1. Acute On Chronic Liver Failure- Evolution of Concept 23 October 2015

4. 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

5. Definitions in past

6. 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

7. 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

8. Differences compared to APASL

9. 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.

10. 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

12. Organ Failure predicts mortality

13. Act before its too late

14. Pathophysiology

15. Acute injury in ACLF

17. 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

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

21. NASCELD Study(2012)

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

23. Comparison between survivors and non survivors

25. CANONIC Study(2013)

27. CLIF- SOFA Score

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

29. Diagnostic criteria for ACLF Acute decompensation( Inclusion criteria) Organ failure( defined by CLIF-SOFA) High 28 day mortality( predefined threshold of 15%)

30. Mortality at 28 days 14.6 % with one organ failure 32% with two organs failure 78.6% with three organs failure

31. Type of organ failure dictating mortality?

32. 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

33. 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

34. 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

35. 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

36. 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 In total, 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.

37. 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.

38. 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.

39. Mortality: different stages

40. SOFA in era of CTP/MELD

41. CTP/MELD better for stable cirrhotics Organ failure scores better in predicting outcome in ACLF

42. Jalan et al. Journal of Hepatology 2014

43. 31 children ACLF defined by APASL Etiology : Chronic disease : AIH 41%, Wilson 41%, HAV most common precipitating event Hepatology International 2011

44. 100 patients ACLF defined by APASL Etiology Alcohol 72%, HBV/HCV 5%, NASH 8% AIH 4% J Dig Dis 2013

45. 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

47. Decompensated Cirrhosis not included in APASL

48. 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

49. Need to include decompensated cirrhosis: Unifying concept Jalan R et al. Gastroenterology 2014

50. 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

51. 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).

52. 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

53. 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

54. 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.

55. Etiologies of acute hepatic insult and underlying chronic liver disease

56. Baseline clinical characteristics, laboratory parameters, and survival rates in ACLF due to different acute hepatic insults VariableHEV(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 mm 3 10600(4900- 18900) 10100(2000- 46400) 14050(4500- 62000) 12100(2600- 42100).020 CLIF-SOFA6(1-13)6.5(2-17)8(1-33)8(3-20).009 APACHE15(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 CLD27(69.3%)25(59.5%)28(39.4%)21(47.7%).010 Overt CLD12(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 stay15(2-40)7.5(3-30)7.5(1-21)10(1-63).032

57. Comparison of variables between survivors and non survivors

58. Multivariate analysis of factors influencing mortality

59. Number of organ failures and mortality

60. ACLF in India- INASL Consortium Experience

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

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

63. 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%)

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

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

66. Evolution in management strategies MARS Role of liver transplantation

67. Banares R, et al. Hepatology 2013

69. Liver Transplantation Chan C et al. Heoptology Int 2009.

73. 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

74. Thank you