Prognostic value of dynamic changes in C-reactive protein to albumin ratio in patients with acute-on-chronic liver failure

Table 1 Baseline characteristics of patients stratified by 28-day survival status, n (%)

Characteristic	All patients (n = 126)	Survivors (n = 91)	Non-survivors (n = 35)	P value
Demographics
Age, years	51.8 ± 12.7	49.2 ± 13.0	54.2 ± 11.9	0.023
Male	95 (75.4)	69 (75.8)	26 (74.3)	0.682
Etiology of chronic liver disease				0.398
HBV infection	85 (67.5)	63 (69.2)	22 (62.9)
Alcohol	24 (19.0)	15 (16.5)	9 (25.7)
HCV infection	8 (6.3)	6 (6.6)	2 (5.7)
Autoimmune	6 (4.8)	5 (5.5)	1 (2.9)
Others	3 (2.4)	2 (2.2)	1 (2.9)
Precipitating events				0.176
HBV reactivation	49 (38.9)	35 (38.5)	14 (40.0)
Alcohol	32 (25.4)	22 (23.8)	10 (28.6)
Bacterial infection	23 (18.3)	16 (17.6)	7 (20.0)
Indeterminate	22 (17.5)	15 (16.5)	7 (20.0)
Complications
Ascites	82 (64.9)	52 (57.1)	30 (85.7)	0.002
Acute variceal bleeding	41 (32.5)	26 (28.6)	15 (42.9)	0.083
Hepatic encephalopathy	29 (23.0)	14 (15.4)	15 (42.9)	< 0.001
Grade 1-2	22 (17.5)	12 (13.2)	10 (28.6)	0.037
Grade 3-4	7 (5.6)	2 (2.2)	5 (14.3)	0.009
Organ failures
Liver	105 (83.7)	72 (79.1)	33 (94.3)	0.020
Coagulation	36 (28.6)	18 (19.8)	18 (51.4)	0.034
Circulation	22 (17.8)	9 (9.9)	13 (37.1)	0.027
Renal	13 (10.3)	5 (5.5)	8 (22.9)	0.004
Cerebral	7 (5.6)	2 (2.2)	5 (14.3)	0.008
Respiration	4 (3.4)	1 (1.1)	3 (8.6)	0.032
Laboratory parameters
Total bilirubin (mg/dL)	26.0 ± 9.0	22.1 ± 7.2	29.5 ± 9.3	< 0.001
Albumin (g/dL)	2.8 ± 0.5	3.0 ± 0.5	2.6 ± 0.4	0.023
ALT (U/L)	275 (139-657)	293 (157-678)	258 (124-642)	0.217
AST (U/L)	243 (149-528)	251 (158-541)	239 (137-516)	0.386
INR	2.26 ± 0.67	1.98 ± 0.47	2.51 ± 0.72	0.029
Creatinine (mg/dL)	1.41 ± 0.75	1.18 ± 0.53	1.62 ± 0.87	0.014
Sodium (mEq/L)	134.2 ± 5.8	135.9 ± 5.0	132.6 ± 6.1	0.006
Neutrophil count (109/L)	7.8 (5.2-11.8)	6.5 (4.6-9.2)	9.2 (6.7-13.5)	0.073
Lymphocyte count (109/L)	0.87 (0.58-1.31)	1.04 (0.72-1.47)	0.76 (0.52-1.12)	0.134
Platelet count (109/L)	79 (54-115)	86 (60-126)	73 (51-107)	0.213
Inflammatory indices
White blood cell count (109/L)	9.8 (6.9-14.2)	8.7 (6.3-11.8)	11.3 (8.2-16.1)	0.041
CRP (mg/L)	25.8 (14.6-42.9)	18.2 (11.4-29.5)	35.7 (22.1-51.9)	0.028
NLR	9.0 (8.8-9.2)	6.1 (4.1-9.4)	11.5 (7.8-17.2)	0.039
CAR	2.03 (1.52-3.27)	1.42 (0.95-2.31)	2.68 (1.82-4.23)	0.031
Prognostic scores
MELD	28.6 (23.9-33.4)	25.2 ± 5.5	31.8 ± 6.2	< 0.001
MELD-Na	30.7 (25.8-35.3)	27.6 ± 5.1	33.6 ± 5.8	< 0.001
CTP	11.3 ± 1.8	10.5 ± 1.6	12.0 ± 1.7	0.019
COSSH-ACLF	7.3 (6.1-8.7)	6.4 ± 1.2	8.2 ± 1.5	< 0.001
Mortality				< 0.001
ACLF 1 (n = 74)	10 (13.5)	64 (86.5)	10 (28.6)
ACLF 2 (n = 38)	15 (39.5)	23 (60.5)	15 (42.9)
ACLF 3 (n = 14)	10 (71.4)	4 (28.6)	10 (28.6)

Values are expressed as mean ± SD, median (interquartile range), or number (percentage). HBV: Hepatitis B virus; HCV: Hepatitis C virus; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; INR: International normalized ratio; CAR: C-reactive protein to albumin ratio; CRP: C-reactive protein; CTP: Child-Turcotte-Pugh; NLR: Neutrophil-to-lymphocyte ratio; MELD: Model for End-stage Liver Disease; COSSH-ACLF: Chinese Group on the Study of Severe Hepatitis B-Acute-on-Chronic Liver Failure; MELD-Na: Model for end-stage liver disease-sodium.

Table 2 Predictive performance of inflammatory markers for mortality

Inflammatory marker	28-day mortality, AUC (95%CI)	90-day mortality, AUC (95%CI)	28-day, P value vs baseline CAR	90-day, P value vs baseline CAR
Baseline inflammatory markers
C-reactive protein	0.652 (0.560-0.744)a	0.624 (0.534-0.714)a	0.032a	0.041a
White blood cell count	0.635 (0.542-0.728)a	0.617 (0.527-0.707)a	0.025a	0.035a
Neutrophil-lymphocyte ratio	0.645 (0.552-0.738)a	0.619 (0.529-0.709)a	0.028a	0.038a
Baseline CAR	0.698 (0.610-0.786)	0.662 (0.575-0.749)	Reference	Reference
Dynamic changes in CAR
ΔCAR-4	0.706 (0.618-0.794)	0.687 (0.602-0.772)	0.068	0.072
ΔCAR-7	0.765 (0.684-0.846)	0.723 (0.641-0.805)	0.003	0.006
ΔCAR-14	0.712 (0.625-0.799)	0.695 (0.611-0.779)	0.056	0.065

^aP < 0.05 vs baseline C-reactive protein to albumin ratio.

AUC: Area under the receiver operating characteristic curve; CAR: C-reactive protein to albumin ratio.

Table 3 Cox regression analysis for 28-day mortality in patients with acute-on-chronic liver failure

Variables	Univariate analysis		Multivariate analysis
	HR (95%CI)	P value	HR (95%CI)	P value
Demographics
Age (per year)	1.03 (1.00-1.05)	0.025	1.01 (0.98-1.04)	0.472
Male sex	0.82 (0.41-1.64)	0.578	—	—
Complications
Ascites	1.65 (1.15-2.36)	0.026	1.18 (0.78-1.79)	0.431
HE grade	2.15 (1.63-2.84)	< 0.001	1.92 (1.43-2.58)	0.027
AVB	1.53 (1.09-2.15)	0.079	—	—
Laboratory parameters
White blood cell count (per × 109/L)	1.07 (1.06-1.09)	< 0.001	1.02 (0.99-1.05)	0.214
Hemoglobin (per g/L)	0.99 (0.98-1.00)	0.035	1.00 (0.99-1.01)	0.837
Platelet count (per × 109/L)	0.997 (0.994-1.000)	0.127	—	—
NLR	1.05 (1.02-1.08)	0.023	1.02 (0.98-1.06)	0.106
C-reactive protein (per mg/L)	1.015 (1.011-1.020)	0.031	1.004 (0.998-1.010)	0.183
Serum albumin (per g/dL)	0.35 (0.18-0.67)	0.043	0.78 (0.37-1.65)	0.518
ALT (per U/L)	1.000 (1.000-1.001)	0.652	—	—
Serum potassium (per mmol/L)	1.54 (1.32-1.81)	0.036	1.14 (0.93-1.39)	0.213
Serum sodium (per mmol/L)	0.96 (0.94-0.98)	0.012	0.99 (0.96-1.02)	0.038
Total bilirubin (per mg/dL)	1.09 (1.05-1.13)	0.019	1.03 (0.98-1.08)	0.024
Creatinine (per mg/dL)	1.68 (1.32-2.14)	0.025	1.22 (0.91-1.63)	0.031
INR (per unit)	2.41 (1.72-3.38)	0.032	1.31 (0.87-1.97)	0.039
CAR parameters
Baseline CAR	1.24 (1.12-1.37)	0.037	1.12 (0.94-1.33)	0.203
ΔCAR-4	1.38 (1.21-1.58)	0.025	1.17 (0.98-1.39)	0.079
ΔCAR-7	1.67 (1.43-1.95)	0.004	1.53 (1.29-1.82)	0.036
ΔCAR-14	1.45 (1.26-1.67)	0.085	—	—
Prognostic scores
CTP	1.12 (1.07-1.17)	0.037	1.02 (0.95-1.06)	0.146
MELD	1.12 (1.07-1.17)	< 0.001	1.03 (0.97-1.09)	0.031
MELD-Na	1.15 (1.09-1.21)	< 0.001	1.08 (1.04-1.12)	0.022
COSSH-ACLF	1.89 (1.54-2.32)	< 0.001	1.24 (0.95-1.62)	0.019

Hepatic encephalopathy grade is scored as 0 (none), 1 (grade 1-2), or 2 (grade 3-4). —: Indicates no statistical difference in univariate analysis. AVB: Acute variceal bleeding; CAR: C-reactive protein to albumin ratio; ΔCAR-4, ΔCAR-7, ΔCAR-14: Change in CAR from baseline to day 4, 7, and 14, respectively; CTP: Child-Turcotte-Pugh; COSSH-ACLF: Chinese Group on Study of Severe Hepatitis B-Acute-on-Chronic Liver Failure; HE: Hepatic encephalopathy; MELD: Model for end-stage liver disease; MELD-Na: Model for end-stage liver disease-sodium; INR: International normalized ratio; NLR: Neutrophil-to-lymphocyte ratio; ALT: Alanine aminotransferase.

Table 4 Predictive performance of Chinese Group on the Study of Severe Hepatitis B- C-reactive protein to albumin ratio

Prognostic model	28-day mortality original AUC (95%CI)	28-day mortality bootstrap corrected AUC (95%CI)	90-day mortality original AUC (95%CI)	90-day mortality bootstrap corrected AUC (95%CI)	P value Original	P value Bootstrap
COSSH-CAR	0.832 (0.756-0.895)	0.821 (0.793-0.849)	0.811 (0.732-0.874)	0.798 (0.767-0.829)	Reference	Reference
MELD	0.743 (0.658-0.818)	0.731 (0.698-0.764)	0.725 (0.640-0.800)	0.712 (0.679-0.745)	0.008	0.005
MELD-Na	0.768 (0.685-0.840)	0.752 (0.721-0.783)	0.751 (0.667-0.825)	0.736 (0.703-0.769)	0.015	0.012
CTP	0.721 (0.635-0.798)	0.709 (0.675-0.743)	0.708 (0.622-0.785)	0.693 (0.658-0.728)	0.002	< 0.001
COSSH-ACLF	0.786 (0.704-0.856)	0.769 (0.737-0.801)	0.772 (0.690-0.842)	0.758 (0.726-0.790)	0.027	0.023

P values for comparison with Chinese Group on the Study of Severe Hepatitis B-C-reactive protein to albumin ratio using the DeLong test for paired receiver operating characteristic curves. Bootstrap resampling performed with 1000 iterations using bias-corrected and accelerated method. AUC: Area under the receiver operating characteristic curve; CTP: Child-Turcotte-Pugh; MELD: Model for end-stage liver disease; CAR: C-reactive protein to albumin ratio; COSSH-ACLF: Chinese Group on Study of Severe Hepatitis B-Acute-on-Chronic Liver Failure.