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

doi:10.3748/wjg.v26.i30.4479

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World Journal of Gastroenterology

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1007-9327

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

Retrospective Study

World J Gastroenterol. Aug 14, 2020; 26(30): 4479-4488
Published online Aug 14, 2020. doi: 10.3748/wjg.v26.i30.4479

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
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
Parameter	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%)	0.035	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.

Citation: Zhou C, Zhang N, He TT, Wang Y, Wang LF, Sun YQ, Jing J, Zhang JJ, Fu SN, Wang X, Liang XX, Li X, Gong M, Li J. High levels of serum interleukin-6 increase mortality of hepatitis B virus-associated acute-on-chronic liver failure. World J Gastroenterol 2020; 26(30): 4479-4488
URL: https://www.wjgnet.com/1007-9327/full/v26/i30/4479.htm
DOI: https://dx.doi.org/10.3748/wjg.v26.i30.4479