High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure

Table 1 Comparisons of deceased and surviving patients

Parameter	All patients (n = 412)	Surviving patients (n = 335)	Deceased patients (n = 77)	P value
Age (yr)	44.6 ± 10.6	43.9 ± 10.6	47.6 ± 10.2	0.007
Male, n (%)	346 (84.0)	279 (83.3)	67 (87.0)	0.421
Albumin (g/L)	30.8 ± 12.3	30.5 ± 5.1	32.2 ± 6.7	0.587
Globulin (g/L)	29.6 ± 9.0	29.7 ± 8.9	29.2 ± 9.4	0.624
Bilirubin (mg/dL)	19.6 ± 7.9	19.0 ± 7.7	22.4 ± 8.1	0.001
ALT (U/L)	145 (63-360)	151 (63-353)	183 (74-458)	0.255
AST (U/L)	153 (86-299)	143 (85-285)	189 (110-363)	0.100
GGT (U/L)	67 (40-101)	69 (40-102)	57 (39-94)	0.226
Creatinine (μmol/L)	74.2 ± 26.8	71.6 ± 21.7	85.1 ± 40.8	0.006
INR	2.3 ± 0.6	2.7 ± 0.7	2.7 ± 0.7	< 0.001
WBC (× 109/L)	7.3 ± 3.3	7.0 ± 3.0	8.3 ± 4.1	0.015
Hemoglobin (g/L)	115 ± 23	117 ± 21	111 ± 29	0.095
Platelet count (× 109/L)	89 ± 45	90 ± 43	85 ± 53	0.367
HBV DNA (log10 IU/mL)	3.1 ± 2.3	3.0 ± 2.3	3.3 ± 2.4	0.467
MELD	24.4 ± 4.5	23.6 ± 4.2	27.8 ± 4.5	< 0.001
HE, n (%)	57 (13.9)	37 (11.1)	20 (26.7)	< 0.001
UGB, n (%)	11 (2.7)	5 (1.5)	6 (7.8)	0.002
SBP, n (%)	151 (37.0)	125 (37.7)	26 (34.2)	0.575
Infection excluding SBP, n (%)1	84 (20.5)	65 (19.5)	19 (25.0)	0.286
Hyponatremia, n (%)	178 (43.8)	138 (41.9)	40 (51.9)	0.151
Renal disfunction, n (%)2	15 (3.7)	6 (1.8)	9 (11.8)	< 0.001
IL-6 (pg/mL)	11.8 (5.4-25.9)	10.4 (4.7-22.3)	17.9 (7.3-57.6)	0.011

¹Including respiratory, urinary, and digestive infections, as well as sepsis.

²Serum creatinine level ranging from 1.5 to 1.9 mg/dL[7]. P values shown in bold indicate statistical significance. ALT: Alanine transaminase; AST: Aspartate transaminase; GGT: γ-glutamyl transferase; INR: International normalized ratio; WBC: White blood cell count; HBV DNA: Hepatitis B virus deoxyribonucleic acid; MELD: Model for end-stage liver disease; HE: Hepatic encephalopathy; UGB: Upper gastrointestinal bleeding; SBP: Spontaneous bacterial peritonitis; IL-6: Interleukin-6.

Table 2 Comparisons of characteristics between patients with different levels of interleukin-6

Parameter	High IL-6 level (n = 207)	Low IL-6 level (n = 205)	P value
Age (yr)	44.8 ± 10.7	44.5 ± 10.5	0.777
Male, n (%)	172 (83.1)	174 (84.9)	0.621
Albumin (g/L)	29.6 ± 4.7	32.1 ± 16.8	0.039
Globulin (g/L)	29.8 ± 9.3	29.5 ± 8.7	0.795
Bilirubin (mg/dL)	20.0 ± 8.0	19.3 ± 7.8	0.362
ALT (U/L)	119 (63, 333)	178 (64, 433)	0.070
AST (U/L)	148 (84, 277)	167 (92, 361)	0.132
GGT (U/L)	61 (38, 95)	74 (42, 117)	0.018
Creatinine (μmol/L)	75.8 ± 28.8	72.5 ± 24.7	0.222
INR	2.3 ± 0.6	2.3 ± 0.6	0.924
WBC (× 109/L)	7.5 ± 3.6	7.0 ± 2.9	0.149
Hemoglobin (g/L)	113 ± 23	118 ± 23	0.036
Platelet count (× 109/L)	89 ± 49	90 ± 42	0.815
HBVDNA (log10 IU/mL)	3.1 ± 2.4	3.1 ± 2.2	0.825
MELD	24.7 ± 4.6	24.2 ± 4.4	0.241
HE, n (%)	33 (16.1)	24 (11.8)	0.206
UGB, n (%)	7 (3.4)	4 (2.0)	0.368
SBP, n (%)	73 (35.8)	78 (38.2)	0.608
Infection excluding SBP, n (%)1	43 (21.0)	41 (20.1)	0.826
Hyponatremia, n (%)	94 (43.8)	90 (42.5)	0.266
Renal disfunction, n (%)2	9 (4.4)	6 (2.9)	0.441
Mortality, n (%)	50 (24.2)	27 (13.2)	0.004

¹Including respiratory, urinary, and digestive infections, as well as sepsis.

²Serum creatinine level ranging from 1.5 to 1.9 mg/dL[7]. P values shown in bold indicate statistical significance. ALT: Alanine transaminase; AST: Aspartate transaminase; GGT: γ-glutamyl transferase; INR: International normalized ratio; WBC: White blood cell count; MELD: Model for End-stage Liver Disease; HE: Hepatic encephalopathy; UGB: Upper gastrointestinal bleeding; SBP: Spontaneous bacterial peritonitis; IL-6: Interleukin-6.

Table 3 Risk factors associated with prognosis in hepatitis B virus-associated acute-on-chronic liver failure patients

Parameter	First step			Last step
	OR	95%CI	P value	OR	95%CI	P value
Age, per yr	1.03	1.01-1.06	0.008	1.04	1.01-1.07	0.009
Bilirubin, per 1 mg/dL	1.05	1.02-1.09	0.001	1.04	1.002-1.08	0.037
Albumin, per 1 g/L	1.01	0.99-1.03	0.339	-	-	-
Creatinine, per 1 μmol/L	1.02	1.01-1.03	< 0.001	1.02	1.01-1.03	0.001
INR, per 1 unit	3.46	2.27-5.28	< 0.001	3.54	2.19-5.72	< 0.001
ALT, per 1 U/L	1.00	1.00-1.00	0.197	-	-	-
AST, per 1 U/L	1.00	1.00-1.00	0.093	-	-	-
GGT, per 1 U/L	1.00	0.99-1.00	0.132	-	-	-
Hemoglobin, per 1 g/L	0.99	0.98-1.00	0.042	-	-	-
HE (yes vs no1)	2.92	1.58-5.40	0.001	2.47	1.15-5.32	0.021
UGB (yes vs no1)	5.54	1.65-18.67	0.006	4.73	1.02-21.98	0.047
Hyponatremia (yes vs no1)	1.37	0.99-1.90	0.057	-	-	-
Renal disfunction (yes vs no1)2	7.34	2.53-21.32	< 0.001	-	-	-
IL-6, pg/ml (> 11.8 vs ≤ 11.81)	2.10	1.26-3.51	0.005	2.11	1.15-3.90	0.017

¹Reference value.

²Serum creatinine level ranging from 1.5 to 1.9 mg/dL[7]. P values shown in bold indicate statistical significance. OR: Odds ratio; CI: Confidence interval; INR: International normalized ratio; ALT: Alanine transaminase; AST: Aspartate transaminase; GGT: γ-glutamyl transferase; HE: Hepatic encephalopathy; UGB: Upper gastrointestinal bleeding; IL-6: Interleukin-6.

Table 4 Mortality between weeks 5 to 8 according to interleukin 6 levels at 4 wk

	Mortality	P value	HR (95%CI)	P value
With low levels of IL-6 (n = 166)	11 (6.6%)	0.035	1
With high levels of IL-6 (n = 80)	12 (15.0%)		2.39 (1.05-5.41)	0.037

P values shown in bold indicate statistical significance. HR: Hazard ratio; CI: Confidence interval; IL-6: Interleukin-6.

Table 5 Mortality according to the dynamic changes in interleukin-6 within 4 wk

	Mortality	HR (95%CI)	P value	P value for trend
Group A (n = 60)	3 (5.0%)	1		0.023
Group B (n = 106)	8 (7.5%)	1.53 (0.41-5.78)	0.528
Group C (n = 26)	3 (11.5%)	2.41 (0.49-12.0)	0.281
Group D (n = 54)	9 (16.7%)	2.80 (0.72-10.83)	0.136

P values shown in bold indicate statistical significance. A: Patients with high interleukin 6 (IL-6) levels at baseline and low IL-6 levels at 4 wk; B: Patients with low IL-6 levels both at baseline and at 4 wk; C: Patients with low IL-6 levels at baseline and high IL-6 levels at 4 wk; D: Patients with high IL-6 levels both at baseline and at 4 wk. HR: Hazard ratio; CI: Confidence interval.