Acute-on-chronic liver failure is independently associated with higher mortality for cirrhotic patients with acute esophageal variceal hemorrhage: Retrospective cohort study

Table 1 Demographic, clinical and laboratory findings of the study population for Acute decompensation and Acute-on-chronic liver failure

Variable	Study population (n = 97)	AD (n = 57)	ACLF (n = 40)	ACLF grade 1 (n = 14)	ACLF grade 2 (n = 20)	ACLF grade 3 (n = 6)
Age (yr)1	56 (9)	58 (10)	54 (8.7)	52 (9.8)	55 (8.0)	53 (92.0)
Male sex2	75 (77.3)	40 (70.2)	35 (87.5)	14 (100)	17 (85)	4 (66.6)
Etiology of cirrhosis2
Alcohol	60 (61.8)	32 (56.1)	28 (70)	10 (71.4)	14 (70)	4 (66.6)
Hepatitis C	15 (15.4)	10 (17.5)	5 (12.5)	2 (14.3)	2 (10)	1 (16.6)
Alcohol and hepatitis C	13 (13.4)	9 (15.8)	4 (10)	1 (7.1)	2 (10)	2 (33.3)
Other	9 (9.2)	6 (10.5)	3 (7.5)	1 (7.1)	2 (10)	0
Active alcoholism2	45 (46.3)	24 (42)	21 (52.5)	7 (50)	11 (55)	3 (50)
Previous use of medications2
PPI	28 (28.8)	20 (35.1)	8 (20)	4 (28.6)	3 (15)	1 (16.6)
Spironolactone	16 (16.4)	5 (8.8)	11 (27.5)	3 (21.4)	6 (30)	2 (33.3)
Furosemide	16 (16.4)	4 (7)	12 (30)	4 (28.6)	6 (30)	2 (33.3)
NSBB	23 (23.7)	15 (26.3)	8 (20)	3 (21.4)	5 (25)	0
Renal replacement therapy2	2 (2)	1 (1.8)	1 (2.5)	1 (7.1)	0	0
Portal vein thrombosis2	3 (3.1)	3 (5.3)	0	0	0	0
Hepatocellular carcinoma2	9 (9.2)	6 (10.5)	3 (7.5)	1 (7.1)	1 (5)	1 (16.6)
Hepatorenal syndrome2	19 (19.5)	3 (5.3)	16 (40)	6 (14.9)	7 (35)	3 (50)
Ascites2	47 (48.4)	31 (54.4)	26 (65)	10 (71.4)	12 (60)	4 (66.6)
Hepatic encephalopathy2
Absent	72 (74.3)	46 (80.7)	26 (65)	9 (64.3)	13 (35)	4 (66.6)
Grade 1	6 (6.2)	2 (3.5)	4 (10)	3 (21.4)	1 (5)	0
Grade 2	7 (7.2)	3 (5.3)	4 (10)	2 (14.3)	2 (10)	0
Grade 3	8 (8.2)	4 (7.0)	4 (10)	0	3 (15)	1 (16.6)
Grade 4	4 (4.1)	2 (3.5)	2 (5)	0	1 (5)	1 (16.6)
Esophageal varices2
Small caliber	14 (14.5)	12 (21)	2 (5)	2 (14.2)	0	0
Medium caliber	28 (28.8)	16 (28.1)	12 (30)	6 (42.9)	6 (30)	0
Large caliber	55 (56.7)	29 (50.9)	26 (65)	6 (42.9)	14 (70)	6 (100)
Infection2
Absent	67 (69)	43 (75.4)	24 (60)	8 (57.1)	14 (70)	2 (33.3)
SBP	5 (5.1)	3 (5.3)	2 (5)	2 (14.3)	0	0
RTI	9 (9.2)	6 (10.5)	3 (7.5)	1 (7.1)	1 (5)	1 (16.6)
UTI	5 (5.1)	3 (5.3)	2 (5.0)	0	2 (10)	0
Sepsis with undefined source of infection	8 (8.2)	0	8 (20)	3 (21.4)	2 (10)	3 (50)
Other	3 (3.1)	2 (3.5)	1 (2.5)	0	1 (5)	0
Index endoscopy
Red marks2	36 (37.1)	24 (42.1)	12 (30)	4 (28.6)	5 (25)	3 (50)
Rupture point2	28 (28.8)	14 (24.6)	14 (35)	6 (42.9)	7 (35)	1 (16.6)
Active bleeding2	12 (12.3)	5 (8.8)	7 (17.5)	3 (21.4)	3 (15)	1 (16.6)
Variceal banding2	40 (41.2)	21 (36.8)	19 (47.5)	10 (71.4)	7 (35)	2 (33.3)
Esclerotherapy2	7 (7.2)	4 (7)	3 (7.5)	0	2 (10)	1 (16.6)
Door to endoscopy time (hours)1	31.2 (35.9)	29.4 (35)	35 (37)	32 (36)	39 (43)	33 (12)
Laboratory – in admission1
Hemoglobin (g/dL)	8.4 (2.4)	8.5 (2.6)	8.4 (2.8)	9.7 (2.5)	7.4 (2.0)	8.9 (4.3)
Hematocrit (%)	26.4 (19.4)	28.4 (24.9)	24.4 (7.6)	26.9 (8.0)	22.2 (5.3)	26 (11.7)
Leukocyte (/mm³)	12038 (5565)	7974 (5211)	9850 (4026)	9887 (6202)	12870 (5695)	9635 (5069)
Platelets (10³/mm³)	102 (63)	90 (55)	115 (72)	115 (76)	120 (67)	98 (88)
Total bilirubin (mg/dL)	3.2 (3.9)	2.2 (2.0)	4.7 (5.3)	2.8 (2.1)	4.2 (5.0)	10.0 (7.9)
INR	1.6 (0.6)	1.3 (0.3)	1.9 (0.8)	1.5 (0.3)	2.1 (0.9)	2.0 (0.9)
AST (U/L)	174 (303)	138 (257)	211 (351)	141 (136)	281 (473)	139 (160)
ALT (U/L)	78 (128)	70 (136)	85 (118)	84 (118)	99 (136)	42 (26)
GGT (U/L)	238 (333)	305 (366)	161 (284)	138 (101)	198 (374)	86 (68)
Creatinine (mg/dL)	1.3 (1.1)	0.8 (0.3)	1.9 (1.4)	1.3 (0.5)	2.1 (1.4)	2.8 (2.3)
Sodium (mg/dL)	136 (14)	135 (18)	138 (5)	137 (4)	139 (5)	135 (6)
Potassium (mg/dL)	5.7 (1.7)	6.7 (1.8)	4.5 (1.0)	4.3 (0.8)	4.7 (1.1)	4.2 (0.8)
Albumin (mg/dL)	2.6 (0.5)	2.7 (0.5)	2.5 (0.5)	2.4 (0.5)	2.5 (0.5)	2.7 (0.6)
CRP (mg/L)	27 (29)	23 (25)	31 (32)	3 (1)	35 (26)	47 (63)
Blood products1
Packed red blood cells (units)	5.4 (5.7)	6.1 (6.4)	4.4 (4.5)	3.8 (3.1)	4.7 (4.7)	4.8 (6.8)
Packed red blood cells (mL)	1427 (976)	1607 (1746)	1171 (1092)	1026 (823)	1212 (983)	1372 (1936)
Fresh frozen plasma (units)	4.1 (6.2)	3.4 (5.8)	5.2 (6.7)	3.4 (5.3)	6.2 (7.1)	6.5 (8.4)
Fresh frozen plasma (mL)	744 (1121)	626 (1100)	912 (1114)	621 (928)	1069 (1051)	1066 (1287)
Platelets (units)	2.7 (7.7)	2 (4.7)	4 (10.5)	4.6 (12.8)	1.6 (3.8)	9.8 (18.0)
Platelets (mL)	196 (535)	142 (349)	273 (721)	314 (816)	116 (267)	703 (1,315)
Liver-specific scores1
CTP	9 (2)	8 (2)	10 (2)	9 (2)	9 (2)	11 (2)
MELD	16 (7)	12 (5)	21 (7)	17 (4)	23 (6)	27 (10)
MELD-Na	17 (7)	13 (5)	22 (7)	18 (5)	24 (6)	27 (11)
CLIF-SOFA	8.8 (1.5)	8 (0.9)	10 (1.5)	8 (0.9)	10 (0.8)	12 (1.3)
CLIF-C AD or ACLF	49 (9.9)	17 (10.3)	50 (9.2)	46 (7)	52 (10)	56 (6)
Time to death (days)1	94 (203)	144 (243)	71 (183)	99 (156)	66 (234)	25 (51)
Treatment failure1	7 (7.2)	5 (8.8)	2 (5)	1 (7.1)	0	1 (16.6)
All-cause mortality2
30-day	35 (36)	8 (14)	27 (67.5)	8 (57.1)	14 (70)	5 (83.3)
90-day	39 (40.2)	12 (21.1)	27 (67.5)	8 (57.1)	14 (70)	5 (83.3)
365-day	48 (49.4)	17 (29.8)	31 (77.5)	12 (85)	14 (70)	6 (100)

¹mean (SD).

²Frequency (%).

AD: Acute decompensation; ACLF: Acute-on-chronic liver failure; PPI: Proton pump inhibitor; NSBB: Non-selective beta-blockers; SBP: Spontaneous bacterial peritonitis; RTI: Respiratory tract infection; UTI: Urinary tract infection; INR: International normalized ratio; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl transferase; CRP: C-reactive protein; CTP: Child-turcotte-pugh score; MELD: Model for end-stage liver disease; MELD-Na: Modified model including sodium; CLIF-SOFA: Chronic liver failure sequential organ failure assessment; CLIF-C AD or ACLF: CLIF Consortium acute decompensation or acute-on-chronic liver failure.

Table 2 Univariate analysis for 30- and 90-day mortality

Variable	Hazard ratio (95%CI)
	30-day mortality	90-day mortality
Age (yr)1	0.98 (0.95-1.02), P = 0.42	0.98 (0.95-1.01), P = 0.36
Male sex	1.04 (0.47-2.29), P = 0.90	1.05 (0.50-2.20), P = 0.88
Etiology of cirrhosis	0.48 (0.22-1.01), P =0.055	0.51 (0.25-1.02), P = 0.06
Active alcoholism	1.39 (0.73-2.66), P = 0.31	1.19 (0.65-2.19), P = 0.55
Previous use of medications
PPI	0.44 (0.18-1.07), P = 0.072	0.53 (0.24-1.15), P = 0.10
Spironolactone	1.18 (0.51-2.69), P = 0.69	1.22 (0.56-2.64), P = 0.60
Furosemide	1.21 (0.53-2.76), P = 0.64	1.05 (0.46-2.37), P = 0.89
NSBB	0.33 (0.12-0.95), P = 0.04	0.45 (0.19-1.07), P = 0.07
Renal replacement therapy	1.21 (0.16-8.87), P = 0.84	1.10 (0.15-8.03), P = 0.92
Portal vein thrombosis	0.04 (0.001-39.9), P = 0.37	0.99 (0.24-4.11), P = 0.99
Hepatocellular carcinoma	1.15 (0.41-3.27), P = 0.78	1.29 (0.50-3.29), P = 0.59
Hepatic encephalopathy	2.03 (1.04-3.96), P = 0.03	1.73 (0.91-3.30), P = 0.09
Treatment failure	1.05 (0.24-4.51), P = 0.94	0.84 (0.19-3.55), P = 0.81
Index endoscopy
Red marks	0.44 (0.17-1.15), P = 0.09	0.39 (0.16-0.94), P = 0.03
Rupture point	1.75 (0.74-4.12), P = 0.20	1.68 (0.78-3.65), P = 0.18
Active bleeding	2.65 (1.02-6.84), P = 0.043	2.08 (0.83-5.19), P = 0.11
Variceal banding or sclerotherapy	0.28 (0.09-0.84), P = 0.02	0.43 (0.18-1.03), P = 0.06
Esophageal varices caliber	1.14 (0.48-2.70), P = 0.75	0.93 (0.43-2.04), P = 0.87
Infection
SBP	0.97 (0.13-7.26), P = 0.98	1.19 (0.168.78), P = 0.86
RTI	0.01 (0.001-1.70), P = 0.97	0.01 (0.001-1.30), P = 0.97
UTI	1.64 (0.19-14.04), P = 0.65	1.72 (0.20-14.80), P = 0.61
Sepsis with undefined source of infection	0.55 (0.03-8.89), P = 0.67	0.54 (0.03-8.74), P = 0.67
Other	6.49 (0.79-85.86), P = 0.08	7.62 (0.93-62.41), P = 0.05
Laboratory
Hemoglobin < 9 g/dL	1.25 (0.65-2.39), P = 0.49	1.23 (0.67-2.26), P = 0.50
Leukocyte > 10000/mm3	0.50 (0.26-0.97), P = 0.04	0.50 (0.27-0.93), P = 0.03
Total bilirubin > 2 mg/dL	0.37 (0.18-0.75), P = 0.005	0.40 (0.21-0.78), P = 0.008
INR > 1.31	0.31 (0.13-0.72), P = 0.006	0.35 (0.21-0.78), P = 0.006
AST > 40 U/L	0.66 (0.27-1.60), P = 0.35	0.59 (0.24-1.42), P = 0.24
ALT > 40 U/L	67 (0.34-1.34), P = 0.26	0.72 (0.37-1.39), P = 0.33
GGT > 60 U/L	1.04 (0.43-2.49), P = 0.91	0.99 (0.44-2.23), P = 0.99
Creatinine > 2 mg/dL	0.50 (0.25-0.98), P = 0.046	0.52 (0.27-1.00), P = 0.05
Sodium > 135 mg/dL	0.64 (0.30-1.33), P = 0.23	0.51 (0.26-1.00), P = 0.052
Potassium > 3.5 mg/dL	1.61 (0.38-6.7), P = 0.50	1.88 (0.45-7.82), P = 0.38
Albumin > 3.5 mg/dL	0.40 (0.16-0.99), P = 0.048	0.39 (0.17-0.89), P = 0.02
Terlipressin – total dose (mg)	1.04 (0.94-1.15), P = 0.43	1.05 (0.95-1.15), P = 0.30
Blood products (used versus not used)
Packed red blood cells	0.61 (0.28-1.3), P = 0.22	0.61 (0.29-1.29), P = 0.20
Fresh frozen plasma	2.9 (1.33-6.39), P = 0.007	3.07 (1.46-6.44), P = 0.003
Platelets	0.94 (0.43-2.06), P = 0.88	0.93 (0.44-1.96), P = 0.86
Liver-specific scores1
CTP	1.35 (1.17-1.56), P < 0.001	1.35 (1.18-1.55), P < 0.001
MELD	1.10 (1.06-1.15), P < 0.001	1.11 (1.07-1.15), P < 0.001
MELD-Na	1.10 (1.06-1.15), P < 0.001	1.11 (1.07-1.15), P < 0.001
CLIF-SOFA	1.51 (1.29-1.76), P < 0.001	1.49 (1.27-1.73), P < 0.001
CLIF-C AD or ACLF	1.04 (1.01-1.07), P = 0.007	1.03 (1.004-1.06), P = 0.02
ACLF2	1.13 (1.60-3.0), P < 0.001	1.19 (1.09-1.39), P < 0.001

¹Hazard ratio per unit.

²Hazard ratio per grade.

CI: Confidence interval; PPI: Proton pump inhibitor; NSBB: Non-selective beta-blockers; SBP: Spontaneous bacterial peritonitis; RTI: Respiratory tract infection; UTI: Urinary tract infection; INR: International normalized ratio; AST: Aspartate transaminase; ALT: Alanine transaminase; GGT: Gamma-glutamyl transferase; CTP: Child-Turcotte-Pugh score; MELD: Model for end-stage liver disease; MELD-Na: Modified model including sodium; CLIF-SOFA: Chronic liver failure sequential organ failure assessment; CLIF-C AD or ACLF: CLIF consortium acute decompensation or acute-on-chronic liver failure.

Table 3 Multivariate analysis for 30- and 90-day mortality

Variable	Hazard ratio (95%CI)
	30-day mortality	90-day mortality
Previous use of NSBB	0.29 (0.1-0.91), P = 0.08	0.35 (0.13 -0.94), P = 0.08
MELD1	1.05 (1.01-1.11), P = 0.01	1.06 (1.01-1.12), P = 0.02
CTP1	-	1.56 (0.73-3.35), P = 0.1
ACLF2	4.9 (2.0-11.9), P < 0.001	3.73 (1.64-8.51), P = 0.006

¹Hazard ratio per unit.

²Hazard ratio per grade.

CI: Confidence interval; NSBB: Non-selective beta-blockers; MELD: Model for end-stage liver disease; CTP: Child-Turcotte-Pugh score; ACLF: Acute-on-chronic liver failure.