2015 KASL Single Topic Symposium Korean Multicenter Cohort Study of Acute-on- Chronic Liver Failure : Korean Acute-on-Chronic Liver Failure Study (KACLiF) Do Seon Song Department of Internal Medicine, College of Medicine, The Catholic University of Korea
ACLF definitions Differences between Eastern (AARC) and Western (EASL-CLIF) Qualification for chronic liver disease Acute insult (AARC) or precipitating event (EA SL-CLIF) - Hepatic vs. non-hepatic - Variceal bleeding - Infection or sepsis Organ failure - Kidney faliure AARC (APASL, 2014) EASL-CLIF consortium (2013) Both cirrhotic and non-cirrhotic chronic liver Only cirrhosis diseases Must be new and acute Including those with prior decompensation ( Patients with known previous decompensati on with jaundice, HE, and ascites should be e xcluded. ) Should be hepatic (the core premise of ACLF) Non-hepatotrophic insults like surgery, trau ma, and viral infections if producing hepatic i nsult could lead to ACLF. Variceal bleed per se may not qualify unless it produces jaundice and coagulopathy (need more data) Whether sepsis is a consequence of or a cau se of liver failure is not clear from the current data on ACLF. Do not incorporate organ failure in the definit ion Quite different (higher prevalence, rapid prog ression to tubular damage, and mortality), but Hepatic and non-hepatic Non-hepatic events also qualifies as precipit ants Variceal bleeding also qualifies as precipitants Bacterial infection or sepsis are major events ACLF diagnosis and grading by organ failure Kidney failure and serum creatinine level is im portant in ACLF diagnosis and grading not incorporate into diagnosis Predefined significant mortality rate >33% at 4 weeks >15% at 28-day (increased mortality at 3 mo nths, AASLD/EASL 2011)
ACLF definitions Differences between Eastern (AARC) and Western (EASL-CLIF) No data for differences of prevalence, mortality and characteristics of ACLF according to different definitions
Korean Acute-on- Chronic Liver Failure Study From January 2013 to December 2013 21 university hospitals KACLiF study
Patients Inclusion criteria Chronic liver disease patients with acute decompensation Acute decompensation (By CANONIC study definition) Ascites Hepatic encephalopathy GI bleeding Infection Liver dysfunction (bilirubin 3mg/dL) Exclusion criteria Age<18 Absence of any chronic liver disease The presence of HCC The presence of severe chronic extra-hepatic disease Admission for the control of other chronic illness Co-infection of HIV Chronic decompensation of ESLD Less than 28 days follow up Incomplete data
Patients 200 patients 274 patients
Prevalence AARC definition (N=200, 13.6%) At admission : 155 patients 15.2% - 155/1021 10.5% - 155/1470 After admission : 45 patients 4.4% - 45/1021 3.1% - 45/1470 22.5% - 45/200 EASL CLIF-C definition (N=274, 18.6%) At admission : 197 patients 14.6% - 197/1352 13.4% - 197/1470 After admission : 77 patients 5.7% - 77/1352 5.2% - 77/1470 28.1% - 77/274 Both definitions 1) or 380 patients (25.9%) 2) and - 94 patients
Patients diagram A : Total enrolled patients (N=1470)
Patients diagram A : Total enrolled patients (N=1470) B : CLD patients without prior history of decompensation (N=1021) C : ACLF development by AARC definition (N=200)
Patients diagram A : Total enrolled patients (N=1470) D : cirrhotic patients regardless of prior history of decompensation (N=1352) E : ACLF development by EASL-CLIF consortium definition (N=274)
Patients diagram A : Total enrolled patients (N=1470) D : cirrhotic patients regardless of prior history of decompensation (N=1352) B : CLD patients without prior history of decompensation (N=1021) F: Both definitions (N=94) C : ACLF development by AARC definition (N=200) E : ACLF development by EASL-CLIF consortium definition (N=274)
Baseline characteristics AARC EASL-CLIF consortium Characteristics All Patients No ACLF ACLF P value No ACLF ACLF P value (N = 1470) (N = 1315) (N = 155) (N = 1273) (N = 197) Age (y) 55 ± 12 56 ± 12 50 ± 8 <0.001 55 ± 12 55 ± 11 0.632 Male sex 1092 (74.3) 976 (74.2) 116 (74.8) 0.868 938 (73.7) 154 (78.2) 0.180 Previous decompensation * 449 (30.5) 449 (34.1) 0 (0.0) <0.001 367 (28.8) 82 (41.6) <0.001 Presence of Cirrhosis 1352 (92.0) 1206 (91.7) 146 (94.2) 0.282 1155 (90.7) 197 (100.0) <0.001 Etiology of CLD <0.001 0.068 HBV HCV HBV+HCV Alcohol HBV+alcohol HCV+alcohol Others 214 (14.6) 75 (5.1) 2 (0.1) 928 (63.1) 108 (7.3) 25 (1.7) 118 (8.0) 202 (15.4) 74 (5.6) 2 (0.2) 805 (61.2) 100 (7.6) 21 (1.6) 111 (8.4) 12 (7.7) 1 (0.6) 0 (0.0) 123 (79.4) 8 (5.2) 4 (2.6) 7 (4.5) 195 (15.3) 66 (5.2) 2 (0.2) 783 (61.5) 96 (7.5) 23 (1.8) 108 (8.5) 19 (9.6) 9 (4.6) 0 (0.0) 145 (73.6) 12 (6.1) 2 (1.5) 10 (5.1) Acute Decompensation # Ascites Hepatic encephalopathy Variceal Bleeding GI Bleeding Infection More than one event Precipitating events Bacterial infection Variceal bleeding GI bleeding Active alcoholism Toxic material Reactivation of viral infection Others 485 (33.0) 244 (16.6) 474 (32.2) 128 (8.7) 154 (10.5) 150 (10.2) 1169 (79.5) 133 (9.0) 347 (23.6) 115 (7.8) 595 (40.5) 37 (2.5) 61 (4.1) 407 (31.0) 215 (16.3) 444 (33.8) 123 (9.4) 131 (10.0) 126 (9.6) 1033 (78.6) 122 (9.3) 323 (24.6) 107 (8.1) 501 (38.1) 27 (2.1) 52 (4.0) 78 (50.3) 29 (18.7) 30 (19.4) 5 (3.2) 23 (14.8) 24 (15.5) 136 (87.7) 11 (7.1) 24 (15.5) 8 (5.2) 94 (60.6) 10 (6.5) 9 (5.8) <0.001 0.455 <0.001 0.010 0.061 0.022 0.007 0.371 0.012 0.192 <0.001 0.001 0.274 421 (33.1) 169 (13.3) 413 (32.4) 116 (9.1) 118 (9.3) 107 (8.4) 998 (78.4) 94 (7.4) 298 (23.4) 103 (8.1) 509 (40.0) 34 (2.7) 57 (4.4) 64 (32.5) 75 (38.1) 61 (31.0) 12 (6.1) 36 (18.3) 43 (21.8) 171 (86.8) 39 (19.8) 49 (24.9) 12 (6.1) 86 (43.7) 3 (1.5) 4 (2.0) 0.871 <0.001 0.679 0.162 <0.001 <0.001 0.007 <0.001 0.653 0.331 0.329 0.338 0.109 47 (3.2) 44 (3.3) 3 (1.9) 0.345 38 (3.0) 9 (4.6) 0.240 SIRS 355 (24.1) 311 (23.7) 44 (28.4) 0.192 287 (22.5) 68 (34.5) 0.001 Mean Blood Pressure 87 ± 21 87 ± 21 88 ± 17 0.373 88 ± 21 83 ± 21 0.003 (mmhg)
Baseline characteristics AARC EASL-CLIF consortium Characteristics All Patients No ACLF ACLF No ACLF ACLF P value (N = 1470) (N = 1315) (N = 155) (N = 1273) (N = 197) P value Mean Blood Pressure (mmhg) 87 ± 21 87 ± 21 88 ± 17 0.373 88 ± 21 83 ± 21 0.003 Laboratory findings WBC (x10 9 /L) 8.09 ± 4.99 7.86 ± 4.89 10.09 ± 5.38 <0.001 7.70 ± 4.68 10.63 ± 6.07 <0.001 ANC (x10 9 /L) 5.79 ± 4.49 5.56 ± 4.38 7.70 ±4.98 <0.001 5.39 ± 4.19 8.33 ± 5.49 <0.001 Hemoglobin (g/dl) 10.2 ± 2.8 10.2 ±2.8 10.2 ± 2.4 0.772 10.3 ± 2.8 9.2 ± 2.7 <0.001 Platelet count (x10 9 /L) 106 ± 63 106 ± 62 106 ± 63 0.982 108 ± 64 92 ± 53 0.001 Albumin (g/dl) 2.9 ± 0.6 2.9 ± 0.6 2.6 ± 0.5 <0.001 2.9 ± 0.6 2.5 ± 0.6 <0.001 Bilirubin (mg/dl) 5.2 ± 6.6 4.1 ± 5.5 14.4 ± 8.2 <0.001 4.5 ± 5.8 9.5 ± 9.6 <0.001 ALT (U/L) 105 ± 370 98 ± 353 168 ± 492 0.087 106 ± 382 96 ± 285 0.716 AST (U/L) 185 ± 635 159 ± 381 409 ± 1597 0.053 168 ± 393 292 ± 1418 0.226 GGT (U/L) 255 ± 368 255 ± 377 250 ± 280 0.894 267 ± 379 176 ± 274 <0.001 INR 1.53 ± 0.58 1.47 ± 0.53 2.07 ± 0.66 <0.001 1.45 ± 0.46 2.04 ± 0.93 <0.001 CRP (mg/l) 3.4 ± 9.7 3.3 ± 9.8 4.9 ± 8.9 0.046 3.0 ± 9.2 6.0 ± 12.2 0.001 Creatinine (mg/dl) 1.2 ± 1.3 1.1 ± 1.0 1.6 ± 2.4 0.001 0.9 ± 0.4 2.8 ± 2.7 <0.001 Sodium (meq/l) 136 ± 6 136 ± 6 133 ± 6 <0.001 136 ± 6 133 ± 7 <0.001 Clinical scores CTP score 9 ± 2 9 ± 2 11 ± 1 <0.001 9± 2 11 ± 2 <0.001 MELD score 17 ± 7 15 ± 6 26 ± 7 <0.001 15 ± 5 27 ± 8 <0.001 MELD-Na score 19 ± 8 18± 6 28 ± 6 <0.001 17 ± 7 29 ± 7 <0.001 CLIF-SOFA score 5 ± 3 5 ± 3 8 ± 3 <0.001 4 ± 2 10 ± 4 <0.001 Organ failure by CLIF-SOFA score Liver 176 (12.0) 100 (7.6) 76 (49.0) <0.001 108 (8.5) 68 (34.5) <0.001 Kidney 137 (9.3) 105 (8.0) 32 (20.6) <0.001 14 (1.1) 123 (62.4) <0.001 Cerebral 104 (7.1) 85 (6.5) 19 (12.3) 0.008 55 (4.3) 49 (24.9) <0.001 Coagulation 78 (5.3) 50 (3.8) 28 (18.1) <0.001 22 (1.7) 56 (28.4) <0.001 Circulation 55 (3.7) 48 (3.7) 7 (4.5) 0.591 14 (1.1) 41 (20.8) <0.001 Lungs 35 (2.4) 28 (2.1) 7 (4.5) 0.065 5 (0.4) 30 (15.2) <0.001
Mortality 28-day mortality : 7.6% (112/1470) 90-day mortality : 13.2% (173/1307) *Pre-defined 28- day mortality - AARC : 33% - EASL-CLIF : 15% (A) (B) (%) (%) 80 No ACLF ACLF 80 No ACLF ACLF 70 P<0.001 P<0.001 70 P<0.001 P<0.001 60 60 54.5 50 50 40 39.1 40 35.4 30 22.5 30 20 20 10 0 2.7 28-day mortality 4.3 90-day mortality 10 0 1 28-day mortality 3.4 90-day mortality AARC definition EASL-CLIF consortium definition
Mortality 28-day 90-day P=0.001 P<0.001 P<0.001 P=0.016 P<0.001 P=0.006 P<0.001 P<0.001 No. at risk No ACLF 1090 1087 1085 1084 1080 AARC Only 106 106 105 104 101 EASL-CLIF Only 180 149 141 133 125 Both 94 81 71 67 55 No. at risk No ACLF 1090 1077 997 942 AARC Only 106 101 91 82 EASL-CLIF Only 180 122 98 90 Both 94 54 32 21
Mortality AARC definition EASL CLIF-C definition P<0.001 P<0.001 P=0.059 P<0.001 P<0.001 P<0.001 No. at risk No ACLF 1270 1199 1095 1032 ACLF at admission 155 125 99 83 ACLF after admission 45 30 24 20 No. at risk No ACLF 1196 1178 1088 1024 ACLF at admission 197 133 107 91 ACLF after admission 77 43 23 20
Chronic liver disease Confine to liver cirrhosis only vs. encompass liver cirrhosis and non-cirrhotic chronic liver disease (%) (%) 40 AARC ACLF (-) AARC ACLF (+) 60 AARC ACLF (-) AARC ACLF (+) 35 P = 0.353 P < 0.001 50 P = 0.033 P<0.001 30 40.1 25 23.4 40 20 30 25 15 10 5 2.8 8.3 5.5 20 10 4.4 9.8 0 LC (-) LC (+) 0 LC (-) LC (+) (N=118) (N=1352) (N=103) (N=1204) 28-day mortality 90-day mortality 1 death out of 12 patients 3 death out of 12 patients
Previous acute decompensation Confine to first AD vs. encompass previous AD P=0.185 P<0.001
Organ failure Liver failure as a prerequisite vs. extra-hepatic organ failures without liver failure Liver failure as a prerequisite Extra-hepatic organ failure without liver failure Liver failure as a prerequisite Extra-hepatic organ failure without liver failure P = 0.029 P = 0.036 No. at risk LF as a prerequisite 200 187 176 171 156 Extra-hepatic organ failure without LF 180 149 141 133 125 No. at risk LF as a prerequisite 200 155 123 103 Extra-hepatic organ failure without LF 180 122 98 90 Liver failure : jaundice (serum bilirubin 5 mg/dl) and coagulopathy (INR 1.5 or prothrombin activity 40 %) AARC definition
Organ failure Liver failure as a prerequisite vs. extra-hepatic organ failures without liver failure P=0.071 P<0.001 P=0.003 P=0.223 P<0.001 Bilirubin <5 mg/dl Bilirubin 5-12 mg/dl Bilrubin 12 mg/dl P < 0.001 Bilirubin <5 mg/dl Bilirubin 5-12 mg/dl Bilrubin 12 mg/dl P < 0.001 No. at risk < 5mg/dL 101 81 80 79 78 5-12 mg/dl 116 109 106 104 101 12mg/dL 163 146 131 121 102 No. at risk < 5mg/dL 101 77 67 62 5-12 mg/dl 116 100 85 72 12mg/dL 163 100 69 59 Liver failure : jaundice (serum bilirubin 12 mg/dl) EASL-CLIF definition
AARC vs. EASL CLIF-C ACLF Frequently occur Associated with high short-term mortality rate Different prevalence and mortality according to definitions Underlying chronic liver disease Non-cirrhotic CLD : high mortality rate if met the ACLF Previous acute decompensation Significantly lower survival in the patients with AD within 1 year Organ failure Extra-hepatic organ failure is more likely to influence short-term mortality in the patients with ACLF
CLIF-SOFA score validation
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 (creatinine, mg/dl) <1.2 1.2 to <2.0 2.0 to <3.5 3.5 to <5.0 5.0 or use of renal replacement therapy Cerebral (HE grade) No HE I II III IV Coagulation (INR) <1.1 1.1 to <1.25 1.25 to <1.5 1.5 to <2.5 2.5 or platelet c ount 20 x 10 9 /L Circulation (mean arterial p ressure, mm Hg) 70 <70 Dopamine 5 or Dopamine >5 or Dopamine >15 or dobutamine or E 0.1 or E >0.1 or terlipressin NE 0.1 NE >0.1 Lungs PaO 2 /FIO 2 or >400 >300 to 400 >200 to 300 >100 to 200 100 SpO 2 /FIO 2 >512 >357 to 512 >214 to 357 >89 to 214 89 Moreau et al. Gastroenterology 2013; 144: 1426-1437
CLIF consortium organ failure (CLIF-C OF) score CLIF-C OF score 1 2 3 Liver (bilirubin, mg/dl) <6.0 6.0 to <12.0 12.0 Kidney (creatinine, mg/dl) <2.0 2.0 to <3.5 3.5 or RRT Cerebral (HE grade) No HE I - II III - IV Coagulation (international normalized ratio) <2.0 2.0 to <2.5 2.5 Circulation (mean arterial Use of vasopressor 70 <70 pressure, mmhg) s Lungs PaO/FiO2 or >300 or 300 and >200 or 200 or SpO2/FiO2 >357 >214 and 357 214 CLIF-C ACLF score = 10X[0.33 X CLIF-OF score + 0.04 X Age+0.63 X ln(wbc count) -2] Jalan et al. J Hepatol 2014; 61: 1038-1047
Patients diagram A : Total enrolled patients (N=1470) D : cirrhotic patients regardless of prior history of decompensation (N=1352) B : CLD patients without prior history CLIF-SOFA score of decompensation (N=1021) F: Both definitions (N=94) CLIF-C OF score CLIF-C ACLF score C : ACLF development by AARC definition (N=200) E : ACLF development by EASL-CLIF consortium definition (N=274)
Prediction of 28-day mortality and 90-day mortality 28-day mortality 90-day mortality
Prediction of 28-day mortality and 90-day mortality Pairwise comparison of AUROCs for prediction of 28- and 90-day mortality Variable AUROC 95% CI P-value 28-day mortality AUROC Difference 95% CI P-value Child-Pugh 0.774 0.750-0.796 <0.001 0.092 0.055-0.129 <0.001 MELD 0.842 0.821-0.861 <0.001 0.024-0.002-0.050 0.073 MELD-Na 0.843 0.822-0.862 <0.001 0.023-0.006-0.052 0.123 CLIF-C OF 0.847 0.827-0.866 <0.001 0.018-0.003-0.039 0.100 CLIF-C ACLF 0.846 0.826-0.865 <0.001 0.019-0.013-0.051 0.254 CLIF-SOFA 0.865 0.846-0.883 <0.001 Reference 90-day mortality Child-Pugh 0.780 0.757-0.802 <0.001 0.064 0.032-0.095 <0.001 MELD 0.822 0.801-0.842 <0.001 0.022-0.001-0.044 0.055 MELD-Na 0.834 0.813-0.853 <0.001 0.010-0.014-0.035 0.410 CLIF-C OF 0.821 0.799-0.841 <0.001 0.023 0.004-0.043 0.020 CLIF-C ACLF 0.824 0.802-0.844 <0.001 0.020-0.010-0.050 0.190 CLIF-SOFA 0.844 0.823-0.863 <0.001 Reference
Prediction of 28-day mortality and 90-day mortality Predictive factor 28-day mortality Cut-off point Youden's index Sensitivity (%) Specificity (%) Child-Pugh 10 0.4 66 74 97 16 MELD 22 0.54 85 69 97 28 MELD-Na 22 0.54 71 83 98 20 CLIF-C OF 8 0.545 77 78 98 23 CLIF-C ACLF 44 0.552 83 72 97 27 CLIF-SOFA 7 0.59 79 80 98 25 90-day mortality Child-Pugh 10 0.42 68 74 95 24 MELD 21 0.48 82 66 95 34 MELD-Na 22 0.54 73 81 96 30 CLIF-C OF 8 0.516 79 73 95 32 CLIF-C ACLF 44 0.47 84 63 94 36 CLIF-SOFA 7 0.56 82 74 96 36 Youden s index = Sensitivity + specificity -1 PPV (%) NPV (%)
Prediction of 28-day mortality and 90-day mortality Performance of CLIF-SOFA score by the presence of ACLF Mortality rate AUROC 95% CI P-value Optimal cut-off value 28-day mortality No ACLF 3.6 % 0.730 0.653-0.806 <0.001 6 ACLF 32.5 % 0.877 0.827-0.927 <0.001 12 90-day mortality No ACLF 7.2 % 0.753 0.698-0.807 <0.001 6 ACLF 40.3 % 0.853 0.801-0.904 <0.001 10 Total enrolled patients No ACLF ACLF
Prediction of 28-day mortality and 90-day mortality CLIF-SOFA scores of ACLF grade employed in the previous study (Lee M et al. Liver Int. 2015; 35(1) : 46-57)
CLIF-SOFA score validation CLIF-SOFA score was an independent predictor of shortterm mortality in Korean cirrhotic patients with AD CLIF-SOFA score provide accurate prognostic information on patients admitted because of AD, especially those with ACLF Further study CLIF-C AD score Subgroup analysis
CLIF-SOFA and hyponatremia
Study population/ Data collection 21 hospital, 1861 pt. with acute decompensation on LC or CLD Screening at 2013.1~2013.12 (retrospective cohort) Exclusion criteria : 206 pts 34 pts.: absence of LC or CLD 42 pts.: presence of HCC 35 pts.: extrahepatic complications 130 pts.: the control of chronic illness Missing data 144 pts: short-term follow-up <28 days 4 pts.: death < 24hrs 48 pts: incomplete data 21 hospital, 1459 pts were enrolled in this study 197 pts ACLF at enrollment 1273 Pts No ACLF at enrollment
ACLF and hyponatremia 100 Hyponatremia : <130 meq/l no ACLF + no hypo-na 80 p<0.001 60 40 32.1% 46.7% 28 days 90 days no ACLF + hypo-na ACLF + no hypo-na ACLF + hypo-na p<0.001 p=n.s. 20 8.2% 3.9% 0 no ACLF ACLF Mortality rate Survival months
CLIF-SOFA 7 and hyponatremia 100 CLIF-SOFA 7+ no hypo-na 80 CLIF-SOFA 7+ hypo-na 60 53.1% CLIF-SOFA >7+ no hypo-na 28 days 40 33.5% 90 days CLIF-SOFA >7+ hypo-na 20 22.4% 13.3% 27.2% p<0.001 3.5% 6.2% 0 1.7% CLIF-SOFA CLIF-SOFA CLIF-SOFA CLIF-SOFA 7 + no hypo-na 7 + hypo- Na >7 + no hypo-na >7 + hypo- Na Survival months Mortality rate
Hyponatremia could give more accurate information adding to CLIF-SOFA score
KACLiF Study Dong Joon Kim (Hallym University College of Medicine) Tae Yeob Kim (Hanyang University Guri Hospital) Do Seon Song (College of Medicine, The Catholic University of Korea) Hee Yeon Kim (College of Medicine, The Catholic University of Korea) Dong Hyun Sinn (Samsung Medical Center) Eileen L. Yoon (Inje University Sanggye Paik Hospital) Chang Wook Kim (College of Medicine, The Catholic University of Korea) Young Kul Jung (Korea University Ansan Hospital) Ki Tae Suk (Hallym University College of Medicine) Sang Soo Lee (Gyeongsang National University Hospital) Chang Hyeong Lee (Catholic University of Daegu School of Medicine) Tae Hun Kim (Ewha Womans University School of Medicine) Jeong Han Kim (Konkuk University School of Medicine) Sung Eun Kim (Hallym University Sacred Heart Hospital)
KACLiF Study Soon Koo Baik (Yonsei University Wonju College of Medicine) Byung Seok Lee (Chungnam National University School of Medicine) Jae Young Jang (Soonchunhyang University College of Medicine) Jeong Ill Suh (Dongguk University Gyeongju Hospital) Hyoung Su Kim (Hallym University Kangdong Sacred Heart Hospital) Seong Woo Nam (National Medical Center, Seoul) Hyeok Choon Kwon (National Medical Center, Seoul) Young Seok Kim (Soonchunhyang University Bucheon Hospital) Jin Mo Yang (College of Medicine, The Catholic University of Korea) Joo Hyun Sohn (Hanyang University Guri Hospital, Guri) Heon Ju Lee (Yeungnam University College of Medicine) Seung Ha Park (Inje University Haeundae Paik-Hospital) Byung Hoon Han (Kosin University College of Medicine)
Prospective study