Korean Multicenter Cohort Study of Acute-on- Chronic Liver Failure : Korean Acute-on-Chronic Liver Failure Study (KACLiF)

Transcription

1 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

2 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)

3 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

4 Korean Acute-on- Chronic Liver Failure Study From January 2013 to December university hospitals KACLiF study

5 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

6 Patients 200 patients 274 patients

7 Prevalence AARC definition (N=200, 13.6%) At admission : 155 patients 15.2% - 155/ % - 155/1470 After admission : 45 patients 4.4% - 45/ % - 45/ % - 45/200 EASL CLIF-C definition (N=274, 18.6%) At admission : 197 patients 14.6% - 197/ % - 197/1470 After admission : 77 patients 5.7% - 77/ % - 77/ % - 77/274 Both definitions 1) or 380 patients (25.9%) 2) and - 94 patients

8 Patients diagram A : Total enrolled patients (N=1470)

9 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)

10 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)

11 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)

12 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 ± ± ± 8 < ± ± Male sex 1092 (74.3) 976 (74.2) 116 (74.8) (73.7) 154 (78.2) Previous decompensation * 449 (30.5) 449 (34.1) 0 (0.0) < (28.8) 82 (41.6) <0.001 Presence of Cirrhosis 1352 (92.0) 1206 (91.7) 146 (94.2) (90.7) 197 (100.0) <0.001 Etiology of CLD < 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) < < < (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) < <0.001 < < (3.2) 44 (3.3) 3 (1.9) (3.0) 9 (4.6) SIRS 355 (24.1) 311 (23.7) 44 (28.4) (22.5) 68 (34.5) Mean Blood Pressure 87 ± ± ± ± ± (mmhg)

13 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 ± ± ± ± ± Laboratory findings WBC (x10 9 /L) 8.09 ± ± ± 5.38 < ± ± 6.07 <0.001 ANC (x10 9 /L) 5.79 ± ± ±4.98 < ± ± 5.49 <0.001 Hemoglobin (g/dl) 10.2 ± ± ± ± ± 2.7 <0.001 Platelet count (x10 9 /L) 106 ± ± ± ± ± Albumin (g/dl) 2.9 ± ± ± 0.5 < ± ± 0.6 <0.001 Bilirubin (mg/dl) 5.2 ± ± ± 8.2 < ± ± 9.6 <0.001 ALT (U/L) 105 ± ± ± ± ± AST (U/L) 185 ± ± ± ± ± GGT (U/L) 255 ± ± ± ± ± 274 <0.001 INR 1.53 ± ± ± 0.66 < ± ± 0.93 <0.001 CRP (mg/l) 3.4 ± ± ± ± ± Creatinine (mg/dl) 1.2 ± ± ± ± ± 2.7 <0.001 Sodium (meq/l) 136 ± ± ± 6 < ± ± 7 <0.001 Clinical scores CTP score 9 ± 2 9 ± 2 11 ± 1 < ± 2 11 ± 2 <0.001 MELD score 17 ± 7 15 ± 6 26 ± 7 < ± 5 27 ± 8 <0.001 MELD-Na score 19 ± 8 18± 6 28 ± 6 < ± 7 29 ± 7 <0.001 CLIF-SOFA score 5 ± 3 5 ± 3 8 ± 3 < ± 2 10 ± 4 <0.001 Organ failure by CLIF-SOFA score Liver 176 (12.0) 100 (7.6) 76 (49.0) < (8.5) 68 (34.5) <0.001 Kidney 137 (9.3) 105 (8.0) 32 (20.6) < (1.1) 123 (62.4) <0.001 Cerebral 104 (7.1) 85 (6.5) 19 (12.3) (4.3) 49 (24.9) <0.001 Coagulation 78 (5.3) 50 (3.8) 28 (18.1) < (1.7) 56 (28.4) <0.001 Circulation 55 (3.7) 48 (3.7) 7 (4.5) (1.1) 41 (20.8) <0.001 Lungs 35 (2.4) 28 (2.1) 7 (4.5) (0.4) 30 (15.2) <0.001

14 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< P<0.001 P< day mortality day mortality day mortality day mortality AARC definition EASL-CLIF consortium definition

15 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 AARC Only EASL-CLIF Only Both No. at risk No ACLF AARC Only EASL-CLIF Only Both

16 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 ACLF at admission ACLF after admission No. at risk No ACLF ACLF at admission ACLF after admission

17 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 = P < P = P< 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

18 Previous acute decompensation Confine to first AD vs. encompass previous AD P=0.185 P<0.001

19 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 = P = No. at risk LF as a prerequisite Extra-hepatic organ failure without LF No. at risk LF as a prerequisite Extra-hepatic organ failure without LF Liver failure : jaundice (serum bilirubin 5 mg/dl) and coagulopathy (INR 1.5 or prothrombin activity 40 %) AARC definition

20 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 < Bilirubin <5 mg/dl Bilirubin 5-12 mg/dl Bilrubin 12 mg/dl P < No. at risk < 5mg/dL mg/dl mg/dL No. at risk < 5mg/dL mg/dl mg/dL Liver failure : jaundice (serum bilirubin 12 mg/dl) EASL-CLIF definition

21 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

22 CLIF-SOFA score validation

23 CLIF-SOFA score Organ/system Liver (bilirubin, mg/dl) < to < to < to < Kidney (creatinine, mg/dl) < to < to < to < or use of renal replacement therapy Cerebral (HE grade) No HE I II III IV Coagulation (INR) < to < to < to < 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 SpO 2 /FIO 2 >512 >357 to 512 >214 to 357 >89 to Moreau et al. Gastroenterology 2013; 144:

24 CLIF consortium organ failure (CLIF-C OF) score CLIF-C OF score Liver (bilirubin, mg/dl) < to < Kidney (creatinine, mg/dl) < to < or RRT Cerebral (HE grade) No HE I - II III - IV Coagulation (international normalized ratio) < to < 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 CLIF-C ACLF score = 10X[0.33 X CLIF-OF score X Age+0.63 X ln(wbc count) -2] Jalan et al. J Hepatol 2014; 61:

25 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)

26 Prediction of 28-day mortality and 90-day mortality 28-day mortality 90-day mortality

27 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 < <0.001 MELD < MELD-Na < CLIF-C OF < CLIF-C ACLF < CLIF-SOFA <0.001 Reference 90-day mortality Child-Pugh < <0.001 MELD < MELD-Na < CLIF-C OF < CLIF-C ACLF < CLIF-SOFA <0.001 Reference

28 Prediction of 28-day mortality and 90-day mortality Predictive factor 28-day mortality Cut-off point Youden's index Sensitivity (%) Specificity (%) Child-Pugh MELD MELD-Na CLIF-C OF CLIF-C ACLF CLIF-SOFA day mortality Child-Pugh MELD MELD-Na CLIF-C OF CLIF-C ACLF CLIF-SOFA Youden s index = Sensitivity + specificity -1 PPV (%) NPV (%)

29 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 % < ACLF 32.5 % < day mortality No ACLF 7.2 % < ACLF 40.3 % < Total enrolled patients No ACLF ACLF

30 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)

31 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

32 CLIF-SOFA and hyponatremia

33 Study population/ Data collection 21 hospital, 1861 pt. with acute decompensation on LC or CLD Screening at ~ (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

34 ACLF and hyponatremia 100 Hyponatremia : <130 meq/l no ACLF + no hypo-na 80 p< % 46.7% 28 days 90 days no ACLF + hypo-na ACLF + no hypo-na ACLF + hypo-na p<0.001 p=n.s % 3.9% 0 no ACLF ACLF Mortality rate Survival months

35 CLIF-SOFA 7 and hyponatremia 100 CLIF-SOFA 7+ no hypo-na 80 CLIF-SOFA 7+ hypo-na % CLIF-SOFA >7+ no hypo-na 28 days % 90 days CLIF-SOFA >7+ hypo-na % 13.3% 27.2% p< % 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

36 Hyponatremia could give more accurate information adding to CLIF-SOFA score

37 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)

38 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)

39 Prospective study