Role of ammonia in predicting the outcome of patients with acute-on-chronic liver failure

Table 1 General cohort characteristics

Variable	Value
Age, median (IQR)	59 (50-65)
Male sex, n (%)	256 (57.4)
Etiology of liver disease, n (%)
Alcohol	351 (78.7)
Hepatitis C virus	50 (11.2)
Hepatitis B virus	28 (6.1)
Alcohol + hepatitis B virus	8 (1.8)
Alcohol + hepatitis C virus	6 (1.3)
Hepatitis B and C virus	3 (0.7%)
Albumin (g/dL), mean ± SD	2.38 ± 0.59
Bilirubin (mg/dL), median (IQR)	2.53 (1.41-4.82)
INR, median (IQR)	1.47 (1.29-1.74)
Platelets (× 109/L), median (IQR)	128 (90-178)
WBC (× 109/L), median (IQR)	7.41 (5.45-10.36)
CRP (mg/dL), median (IQR)	1.51 (0.82-3.1)
Venous ammonia (μmol/L), median (IQR)	103 (78-148)
Sodium (mmol/L), median (IQR)	134 (130-137)
Creatinine (mg/dL), median (IQR)	0.815 (0.63-1.27)
Lactate (mmol/L), median (IQR)	1.7 (1.2-2.1)
Child-Pugh score, median (IQR)	11 (10-12)
Child-Pugh class, n (%)
A	3 (0.7)
B	84 (19.2)
C	350 (80.1)
MELD, mean ± SD	19.13 ± 6.79
AARC score, median (IQR)	7 (6-8)
ACLF, n (%)
Grade I	296 (66.4)
Grade II	139 (31.2)
Grade III	11(2.5)
Ascites, n (%)	408 (91.5)
Grade I	37(9.1)
Grade II	112 (27.5)
Grade III	259 (63.5)
HE, n (%)	374 (83.9)
Grade I	127 (34)
Grade II	139 (37.2)
Grade III	88(23.5)
Grade IV	20(5.3)
Precipitating factors, n (%)
Alcohol	146 (32.7)
Upper GI bleeding	89 (19.9)
Infections	94 (21)
Hepatitis B virus activation	7 (1.5)
Unknown	110 (24.6)
Upper GI bleeding, n (%)	89 (20)
SBP, n (%)	24 (5.4)
Other infections, n (%)	70 (15.7)
UTI	28 (38.4)
Pneumonia	7 (9.6)
CDI	20 (27.4)
Sepsis	5 (6.8)
Cutaneous	11 (15.1)
Oral candidiasis	2 (2.7)
AKI, n (%)	52 (11.7)
HCC, n (%)	11 (2.5)
Hospital stay (d), median (IQR)	8 (5-11)
In-hospital death rate, n (%)	35 (7.8)

IQR: Interquartile range; SD: Standard deviation; INR: International normalized ratio; WBC: White blood cells; CRP: C-reactive protein; MELD: Model for end-stage liver disease; AARC score: APASL ACLF Research Consortium score; HE: Hepatic encephalopathy; GI: Gastrointestinal; UTI: Urinary tract infection; CDI: Clostridium Difficile infection; AKI: Acute kidney injury; SBP: Spontaneous bacterial peritonitis; HCC: Hepatocellular carcinoma.

Table 2 Mortality analysis

Variable	Survivors, n (%) 411 (92.2)	Non-survivors, n (%) 35 (7.8)	P value
Age, median (IQR)	59 (50-65)	60 (49-66)	0.956
Male sex, n (%)	239 (58.2)	17 (48.6)	0.271
Albumin (g/dL), mean ± SD	2.4 ± 0.59	2.16 ± 0.5	0.022
Bilirubin (mg/dL), median (IQR)	2.33 (1.37-4.67)	3.52 (1.93-6.49)	0.013
INR, median (IQR)	1.45 (1.27-1.68)	1.81 (1.5-2.6)	0.005
Creatinine (mg/dL), median (IQR)	0.82 (0.63-1.26)	0.77 (0.62-1.32)	0.397
Platelets (× 109/L), median (IQR)	132 (92-180)	123 (82-173)	0.481
WBC (× 109/L), median (IQR)	7.24 (5.37-9.89)	11.04 (6.79-13.45)	0.014
CRP (mg/dL), median (IQR)	1.36 (0.8-2.98)	3.15 (1.7-4.67)	0.001
Venous ammonia (μmol/L), median (IQR)	100 (75-139)	198 (125-345)	< 0.001
Venous ammonia > 152.5 μmol/L, n (%)	75 (19)	24 (70.6)	< 0.001
Sodium (mmol/L), median (IQR)	134 (130-137)	133 (130-137)	0.215
Child-Pugh score, median (IQR)	11 (10-12)	13 (11-15)	< 0.001
Child-Pugh score ≥ 12.5	58 (14.4)	19 (57.6)	< 0.001
Child-Pugh class, n (%)
A	3 (0.7)	0
B	84 (20.8)	0
C	317 (78.5)	33 (100)
MELD score, mean ± SD	18.43 ± 6.26	27.31 ± 7.37	< 0.001
MELD score ≥ 22.5	119 (29)	27 (77.1)	< 0.001
AARC score, median (IQR)	7 (6-8)	9 (9-11)	< 0.001
AARC score ≥ 8.5	42 (10.2)	26 (74.3)	< 0.001
ACLF, n (%)
Grade I	291 (70.8)	5(14.3)
Grade II	117 (28.5)	22 (62.9)
Grade III	3 (0.7)	8(22.9)
Ascites, n (%)	376 (91.5)	32 (91.4)	0.991
HE, n (%)	341 (83)	33 (94.3)	0.081
Grade I	126 (37)	1 (3)
Grade II	135 (39.6)	4 (12.1)
Grade III	76 (22.3)	12 (36.4)
Grade IV	4 (1.2)	16 (48.5)
Grade I or II HE, n (%)	261 (76.5)	5 (15.2)	< 0.001
Grade III or IV HE, n (%)	80 (23.5)	84.8 (28)
Upper GI bleeding, n (%)	82 (20)	7 (21.2)	0.862
SBP, n (%)	22 (5.4)	2 (5.9)	0.705
Other infections, n (%)	63 (15.3)	7 (20)	0.466
AKI, n (%)	39 (9.5)	13 (38.1)	< 0.001
HCC, n (%)	9 (2.2)	2 (5.7)	0.211
Hospital stay (d), median (IQR)	8 (6-11)	5 (3-10)	0.160

IQR: Interquartile range; SD: Standard deviation; INR: International normalized ratio; WBC: White blood cells; CRP: C-reactive protein; MELD: Model for end-stage liver disease; AARC score: APASL ACLF Research Consortium score; HE: Hepatic encephalopathy; GI: Gastrointestinal; AKI: Acute kidney injury; SBP: Spontaneous bacterial peritonitis; HCC: Hepatocellular carcinoma.

Table 3 Multivariate analysis of the predictive factors for in-hospital mortality

	Variables in the equation
Step 11	B	SE	Wald	df	Sig	Exp (B)	95%CI for EXP (B)
							Lower	Upper
AKI	0.593	0.577	1.055	1	0.304	1.809	0.584	5.607
MELD score ≥ 22.5	0.815	0.610	1.787	1	0.181	2.259	0.684	7.463
Child-Pugh score ≥ 12.5	0.366	0.568	0.415	1	0.520	1.442	0.473	4.394
AARC score ≥ 8.5	1.849	0.642	8.305	1	0.004	6.354	1.807	22.349
HE grade III or IV	1.154	0.628	3.383	1	0.066	3.172	0.927	10.853
Venous ammonia ≥ 152 μmol/L	-1.813	0.508	12.763	1	0.000	0.163	0.060	0.441
Constant	-2.795	1.368	4.172	1	0.041	0.061

¹Variable(s) entered on step 1: AKI, MELD score ≥ 22.5, Child-Pugh score ≥ 12.5, AARC score ≥ 8.5, HE grade III or IV, Venous ammonia ≥ 152 μmol/L.AKI: Acute kidney injury; MELD: Model for end-stage liver disease; AARC score: APASL ACLF Research Consortium score; HE: Hepatic encephalopathy; Sig: Significant; SE: Standard error; CI: Confidence interval.

Table 4 Comparison of patient characteristics based on the presence of hepatic encephalopathy

Variable	HE, n (%) 374 (83.9)	No. HE, n (%) 72 (16.1)	P value
Age, median (IQR)	60 (50-65)	56 (47-65)	0.413
Male sex, n (%)	211 (56.4)	45 (62.5)	0.339
Albumin (g/dL), mean ± SD	2.33 ± 0.55	2.60 ± 0.74	< 0.001
Bilirubin (mg/dL), median (IQR)	2.62 (1.54-5.11)	1.72 (0.73-3.30)	0.015
INR, median (IQR)	1.49 (1.31-1.75)	1.34 (1.14-1.57)	0.054
Creatinine (mg/dL), median (IQR)	0.82 (0.63-1.26)	0.77 (0.62-1.32)	0.520
Platelets (× 109/L), median (IQR)	127 (90-173)	154 (93-193.5)	0.054
WBC (×109/L), median (IQR)	7.5 (5.41-10.45)	7.12 (5.76-9.09)	0.898
CRP (mg/dL), median (IQR)	1.53 (0.83-3.15)	1.29 (0.72-2.24)	0.795
Venous ammonia (μmol/L), median (IQR)	111 (86-158)	74 (60-93)	< 0.001
Venous ammonia > 152.5 μmol/L, n (%)	96 (26.6)	3 (4.5)	< 0.001
Sodium (mmol/L), median (IQR)	134 (129-137)	135 (131-138)	0.883
Child-Pugh score, median (IQR)	11 (10-12)	9 (8-11)	< 0.001
Child-Pugh class, n (%)
A	1 (0.3)	2 (3)
B	47 (12.7)	37 (55.2)
C	322 (87)	28 (41.8)
MELD, mean ± SD	19.74 ± 6.88	15.97 ± 5.24	< 0.001
AARC score, median (IQR)	7 (6-8)	9 (9-11)	< 0.001
ACLF, n (%)
Grade I	224 (59.9)	72(100)
Grade II	139 (37.2)	0
Grade III	11 (2.9)	0
Ascites, n (%)	337 (90.1)	71 (98.6)	0.018
Upper GI bleeding, n (%)	71 (19)	18 (25)	0.247
SBP, n (%)	23 (6.1)	1 (1.4)	0.150
Other infections, n (%)	64 (17.1)	6 (8.3)	0.061
AKI, n (%)	51 (13.6)	1 (1.4)	0.003
HCC, n (%)	10 (2.7)	1 (1.4)	0.520
Hospital stay (d), median (IQR)	8 (6-11)	5 (3-10)	0.061
In-hospital death rate, n (%)	33 (8.8)	2 (2.8)	0.081

IQR: Interquartile range; SD: Standard deviation; INR: International normalized ratio; WBC: White blood cells; CRP: C-reactive protein; MELD: Model for end-stage liver disease; AARC score: APASL ACLF Research Consortium score; HE: Hepatic encephalopathy; GI: Gastrointestinal; AKI: Acute kidney injury; SBP: Spontaneous bacterial peritonitis; HCC: Hepatocellular carcinoma.

Table 5 Comparison of patient characteristics based on the presence of high venous ammonia

Variable	Venous ammonia > 152.5 μmol/L, n (%) 99 (23.1)	Venous ammonia ≤ 152.5 μmol/L, n (%) 329 (76.9)	P value
Age, median (IQR)	57 (48-65)	60 (50-65)	0.481
Male sex, n (%)	58 (58.6)	190 (57.8)	0.883
Albumin (g/dL), mean ± SD	2.33 ± 0.54	2.38 ± 0.59	0.452
Bilirubin (mg/dL), median (IQR)	2.7 (1.48-5)	2.33 (1.37-4.7)	0.230
INR, median (IQR)	1.5 (1.31-1.83)	1.46 (1.27-1.72)	0.584
Creatinine (mg/dL), median (IQR)	0.85 (0.63-1.54)	0.81 (0.63-1.18)	0.397
Platelets (× 109/L), median (IQR)	121 (73-173)	134 (93-182)	0.134
WBC (× 109/L), median (IQR)	8.39 (5.251-11.02)	7.26 (5.47-9.92)	0.359
CRP (mg/dL), median (IQR)	1.4 (0.84-4.16)	1.5 (0.8-2.98)	0.682
HE, n (%)	265 (80.5)	96 (97)	< 0.001
HE grade III or IV, n (%)	55 (20.8)	49 (51)	< 0.001
Sodium (mmol/L), median (IQR)	134 (131-137)	134 (129-137)	0.970
Child-Pugh score, median (IQR)	11 (10-12)	11 (10-12)	0.173
Child-Pugh class, n (%)
A	1 (1)	2 (0.6)
B	12 (12.4)	70 (21.4)
C	84 (86.6)	255 (78)
MELD, mean ± SD	20.76 ± 7.72	18.61 ± 6.34	0.013
AARC score, median (IQR)	7 (6-8)	9 (9-11)	< 0.001
ACLF, n (%)
Grade I	47 (47.5)	238 (72.3)
Grade II	46 (46.5)	87 (26.4)
Grade III	6 (6.1)	4 (1.2)
Ascites, n (%)	82 (82.8)	308 (93.6)	0.001
Upper GI bleeding, n (%)	22 (22.4)	57 (17.3)	0.252
SBP, n (%)	4 (4)	20 (6.1)	0.440
Other infections, n (%)	16 (16.2)	49 (14.9)	0.758
AKI, n (%)	16 (16.2)	32 (9.7)	0.075
HCC, n (%)	5 (5.1)	6 (1.8)	0.137
Hospital stay (d), median (IQR)	8 (6-11)	5 (3-10)	0.969
In-hospital death rate, n (%)	24 (24.2)	10 (3)	< 0.001

IQR: Interquartile range; SD: Standard deviation; INR: International normalized ratio; WBC: White blood cells; CRP: C-reactive protein; MELD: Model for end-stage liver disease; AARC score: APASL ACLF Research Consortium score; HE: Hepatic encephalopathy; GI: Gastrointestinal; AKI: Acute kidney injury; SBP: Spontaneous bacterial peritonitis; HCC: Hepatocelular carcinoma.