Changes in cellular proliferation and plasma products are associated with liver failure

doi:10.4254/wjh.v8.i32.1370

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World Journal of Hepatology

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World J Hepatol. Nov 18, 2016; 8(32): 1370-1383
Published online Nov 18, 2016. doi: 10.4254/wjh.v8.i32.1370

Table 1 Clinical characteristics of the studied population n (%)

	Acute liver failure (n = 16)	Acute hepatitis (n = 46)	Healthy control (n = 22)
Age (yr)
Mean ± SD	24.88 ± 21.52	21.21 ± 10.32	24.64 ± 8.79
25%, 75%	9.25, 49	9.1, 29.75	15.2, 47
Gender
Male	6 (37.50)	25 (54.34)	9 (40.9)
Diagnosis
Hepatitis A	11 (68.75)	38 (82.60)	0
Drug toxicity	2 (12.50)	2 (4.34)	0
Indeterminate	3 (18.75)	6 (13.04)	0
Liver enzymes
AST (UI/L)	1095.5 ± 1460	344.5 ± 444.9	21.68 ± 4.87
ALT (UI/L)	806.12 ± 639.11	517.90 ± 884.30	14.36 ± 4.50
Total bilirubin (mg/dL)	21.47 ± 10.48	10.01 ± 6.88	0.85 ± 0.09
Coma grade
0-I	3 (18.75)	0	0
II-IV	13 (81.25)	0	0
Coagulopathy
INR (mean ± SD)	4.88 ± 0.99	1.16 ± 0.04	0.98 ± 0.06
Outcome
Survived	6 (46.15)	46 (100.00)	22 (100)
Died	10 (53.84)	0	0

INR: International normalized ratio; SD: Standard deviation; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase.

Table 2 Systemic inflammatory products in the plasma samples from patients with acute hepatitis or acute liver failure and healthy subjects

Plasma variables	HC (n = 22)	AH (n = 49)	ALF (n = 13)	HC vs AH^a	HC vs ALF	AH vs ALF
IL-6 (pg/mL)	15.07 ± 25.92 (3.58-26.57)¹	68.93 ± 109.7 (38.39-99.46)	509.30 ± 678.70 (147.6-870.9)	0.0009	< 0.0001	< 0.0001
IL-8 (pg/mL)²	ND	10.50 ± 20.05 (4.92-16.09)	144.70 ± 437.6 (-88.45-377.9)	< 0.001	< 0.0001	ns
IL-10 (pg/mL)	1.81 ± 5.58 (-0.66-4.28)	17.28 ± 51.97 (2.81-31.75)	249.60 ± 379.60 (47.35-451.9)	0.0006	< 0.0001	< 0.0001
IFNγ (pg/mL)	4.80 ± 18.00 (-3.18-12.79)	113.0 ± 265.33 (39.1-186.8)	229.70 ± 342.20 (47.37-412.1)	0.0075	< 0.0001	0.0016
TNFα (pg/mL)	1.08 ± 2.38 (0.02-2.13)	27.25 ± 64.05 (9.42-45.08)	179.40 ± 161.40 (93.42-265.4)	ns	< 0.0001	< 0.0001
mtDNA (ng/100 μL plasma)	81.79 ± 121.6 (27.88-135.7)	159.6 ± 202.2 (64.99-254.3)	4228.00 ± 4286.0 (1944-6512)	0.0131	< 0.0001	0.0008

¹Mean ± standard deviation (95%CI);

²IL-8 levels in the plasma samples were evaluated only by the Kruskal-Wallis test.

^aP < 0.05. The differences between the acute liver failure patients, the self-limited acute hepatitis patients and the healthy controls were evaluated by intergroup comparisons using the Mann-Whitney U-test. IL: Interleukin; IFNγ: Interferon gamma; TNFα: Tumor necrosis factor alpha; mtDNA: Total mitochondrial DNA; ND: Not detectable; ns: Not significant; HC: Healthy control; AH: Acute hepatitis (viral plus non-viral etiologies); ALF: Acute liver failure (viral plus non-viral etiologies).

Table 3 Potential clinical and inflammatory parameters as indicators of acute liver failure syndrome and death

	Cut-off	Adjusted OR	95%CI	P value
Plasma variables¹
IL-6 (pg/mL)	> 197.6	1.36	0.04-40.27	0.856
IL-10 (pg/mL)	> 55.77	18.86	1.38-257.94	0.028
TNFα (pg/mL)	> 122.6	4.42	0.185-105.93	0.359
mtDNA (ng/100 μL plasma)	> 174	320.54	14.42-7123.33	0.000
Plasma variables²
IL-6 (pg/mL)	> 473.2	2.27	0.19-26.92	0.515
IL-8 (pg/mL)	> 66.30	10.42	1.54-70.45	0.016
IL-10 (pg/mL)	> 95.71	8.01	1.26-50.97	0.027
TNFα (pg/mL)	> 313.7	0.27	0.03-2.17	0.220
mtDNA (ng/100 μL plasma)	> 405.3	12.11	2.57-57.07	0.002
INR	> 2.12	29.88	5.44-164.19	0.000

¹Multivariate analysis from clinical and inflammatory parameters associated with ALF;

²Multivariate analysis from clinical and inflammatory parameters associated with death. OR: Odds ratio; IL: Interleukin; IFNγ: Interferon gamma; TNFα: Tumor necrosis factor alpha; mtDNA: Total mitochondrial DNA; ALF: Acute liver failure; INR: International normalized ratio.

Table 4 Variables from the mitogen-stimulated peripheral blood mononuclear cell phenotypes from patients with acute hepatitis A infection and healthy subjects

Phenotypes/cytokines (PHA/LPS)	HC (n = 10)	AH (n = 8)	ALF (n = 8)	HC vs AH	HC vs ALF	AH vs ALF
PI of CD3⁺	133.1 ± 71.12	44.4 ± 25.83	17.48 ± 5.94	0.0155	0.0021	0.0426
	(95.19-171.0)	(22.80-65.99)	(11.24-23.72)
CD4⁺CD25⁺FoxP3⁺ (%)	17.23 ± 9.74	17.08 ± 5.37	5.99 ± 2.80	ns	0.0009	0.0003
	(12.03-22.42)	(12.59-21.57)	(3.65-8.33)
CD4⁺CD29⁺CD44⁺ (%)	38.63 ± 18.37	20.75 ± 7.82	10.22 ± 4.74	0.0062	< 0.0001	0.0047
	(28.84-48.42)	(14.21-27.29)	(6.25-14.18)
CD8⁺CD29⁺CD44⁺ (%)	39.76 ± 19.91	37.56 ± 25.01	9.03 ± 4.59	ns	0.0002	0.0104
	(29.15-50.36)	(16.74-58.57)	(5.18-12.88)
CD3^-CD56⁺CD16^- (%)	8.31 ± 6.75	4.19 ± 2.28	0.50 ± 0.37	ns	0.0006	0.0009
	(2.07-14.56)	(2.08-6.30)	(0.15-0.84)
CD3^-CD56^lowCD16⁺ (%)	12.70 ± 8.93	8.52 ± 5.68	1.11 ± 0.66	ns	0.0012	0.0018
	(4.44-20.96)	(3.26-13.78)	(0.50-1.72)
CD3⁺CD56⁺CD16⁺ (%)	13.66 ± 3.54	7.20 ± 5.28	1.83 ± 1.06	0.0117	< 0.0001	0.0070
	(11.77-15.55)	(2.79-11.63)	(0.94-2.72)
IL-6 (pg/mL)	2625.33 ± 3320	565.7 ± 313.3	156.8 ± 173.9	0.0155	< 0.0001	0.0070
	(856.5-4394)	(303.8-827.6)	(11.40-302.2)
TNFα (pg/mL)	1675.20 ± 623.4	1405.0 ± 324.3	145.3 ± 107.9	ns	< 0.0001	0.0002
	(1343-2007)	(1134-1676)	(55.09-235.5)
IL-10 (pg/mL)	528.86 ± 755.1	269.5 ± 145.8	188.4 ± 267.1	ns	0.0454	ns
	(126.5-931.2)	(147.6-391.5)	(-16.88-393.7)
IFNγ (pg/mL)	3379.1 ± 1869	2467.0 ± 2787	1249.0 ± 2067	ns	0.0205	ns
	(2383-4375)	(137.1-4798)	(-479.2-2977)
IL-8 (pg/mL)	273.9 ± 116.3	274.2 ± 148.5	151.0 ± 156.4	ns	0.0205	0.0379
	(211.9-335.9)	(150.0-398.3)	(20.21-281.8)
IL-17 (pg/mL)	73.81 ± 107.0	31.55 ± 35.58	4.16 ± 3.20	ns	0.0029	0.0116
	(16.81-130.8)	(1.80-61.30)	(1.49-6.84)

The differences between the hepatitis A-induced acute liver failure (ALF) patients, the self-limited acute hepatitis A (AH) patients, and the healthy control (HC) subjects were evaluated by intergroup comparisons using the Mann-Whitney U-test. The significance cutoff for all statistical analyses was defined as P < 0.05. IL: Interleukin; IFNγ: Interferon gamma; TNFα: Tumor necrosis factor alpha; ns: Not significant; PI: Proliferation index.

Table 5 Variables from hepatitis A virus Ag-stimulated peripheral blood mononuclear cell phenotypes from patients with acute hepatitis A infection and healthy subjects

Phenotypes/cytokines (HAVAg)	HC (n = 10)	AH (n = 8)	ALF (n = 8)	HC vs AH	HC vs ALF	AH vs ALF
PI of CD3⁺	1.09 ± 0.85	3.15 ± 1.92	3.34 ± 2.29	0.0053	0.0044	ns
	(0.64-1.55)	(1.54-4.76)	(1.42-5.25)
CD4⁺CD25⁺FoxP3⁺ (%)	0.85 ± 0.96	1.0 ± 0.97	3.19 ± 1.49	ns	0.0011	0.0070
	(0.34-1.37)	(0.18-1.81)	(1.95-4.44)
CD4⁺CD29⁺CD44⁺ (%)	11.99 ± 6.43	27.93 ± 8.16	5.46 ± 5.92	0.0008	0.0077	0.0006
	(8.55-15.42)	(21.1-34.76)	(0.50-10.42)
CD8⁺CD29⁺CD44⁺ (%)	12.65 ± 4.31	30.13 ± 6.74	36.05 ± 10.59	0.0001	0.0001	ns
	(10.35-14.95)	(24.49-35.77)	(27.19-44.90)
CD3^-CD56⁺CD16^- (%)	0.19 ± 0.20	0.30 ± 0.19	1.33 ± 0.85	ns	0.0009	0.0005
	(0.05-0.34)	(0.13-0.46)	(0.62-2.04)
CD3^-CD56^lowCD16⁺ (%)	4.28 ± 2.22	10.09 ± 8.94	14.24 ± 11.81	ns	ns	ns
	(2.70-5.87)	(2.61-17.5)	(4.36-24.12)
CD3⁺CD56⁺CD16⁺ (%)	1.67 ± 2.71	4.25 ± 4.06	15.06 ± 7.74	0.0110	0.0003	0.0019
	(0.22-3.12)	(0.85-7.65)	(8.58-21.53)
IL-6 (pg/mL)	50.49 ± 76.14	76.41 ± 93.18	139.7 ± 165.9	ns	ns	ns
	(9.92-91.06)	(-1.46-154.3)	(0.98-278.4)
TNFα (pg/mL)	92.49 ± 133.4	23.96 ± 28.92	1.63 ± 1.01	ns	0.0089	0.0098
	(21.42-163.6)	(-0.21-48.14)	(0.78-2.48)
IL-10 (pg/mL)	10.39 ± 13.97	52.78 ± 62.06	164.3 ± 75.56	0.0297	0.0001	0.0148
	(2.94-17.84)	(0.89-104.7)	(101.1-227.5)
IFNγ (pg/mL)	0.88 ± 1.08	106.6 ± 183.9	1095 ± 1962	0.0035	0.0001	0.0499
	(0.30-1.46)	(-47.14-260.4)	(-546-2735)
IL-8 (pg/mL)	88.64 ± 45.40	148.9 ± 54.77	150.2 ± 72.19	0.0131	0.0110	ns
	(64.44-112.8)	(103.1-194.7)	(89.84-210.5)
IL-17 (pg/mL)	3.36 ± 3.75	32.61 ± 38.30	7.58 ± 5.43	0.0008	ns	0.0499
	(1.36-5.36)	(0.59-64.64)	(3.05-12.13)

The differences between the hepatitis A-induced acute liver failure (ALF) patients, the self-limited acute hepatitis A (AH) patients and the healthy control (HC) subjects were evaluated by intergroup comparisons using the Mann-Whitney U-test. The significance cutoff for all statistical analyses was defined as P < 0.05. IL: Interleukin; IFNγ: Interferon gamma; TNFα: Tumor necrosis factor alpha; ns: Not significant; PI: Proliferation index.

Table 6 Variables from mitogen-stimulated peripheral blood mononuclear cells from non-viral acute hepatitis patients and healthy control subjects

Phenotypes/cytokines (PHA/LPS)	HC (n = 10)	AH (n = 8)	ALF (n = 5)	HC vs AH	HC vs ALF	AH vs ALF
PI of CD3⁺	133.1 ± 71.12	173.3 ± 91.84	268.4 ± 101.6	ns	ns	ns
	(95.19-171.0)	(96.51-250.1)	(142.3-394.5)
CD4⁺CD25⁺FoxP3⁺ (%)	17.23 ± 9.74	15.82 ± 8.13	6.84 ± 5.12	ns	ns	ns
	(12.03-22.42)	(9.02-22.62)	(0.48-13.2)
CD4⁺CD29⁺CD44⁺ (%)	38.63 ± 18.37	21.84 ± 7.50	36.67 ± 14.54	ns	ns	ns
	(28.84-48.42)	(15.56-28.11)	(18.61-54.73)
CD8⁺CD29⁺CD44⁺(%)	39.76 ± 19.91	22.26 ± 11.16	29.59 ± 15.21	ns	ns	ns
	(29.15-50.36)	(12.92-31.59)	(10.71-48.47)
CD3^-CD56⁺CD16^- (%)	8.31 ± 6.75	6.33 ± 4.13	17.22 ± 4.94	ns	0.0289	0.0030
	(2.07-14.56)	(2.88-9.79)	(13.09-21.35)
CD3^-CD56^lowCD16⁺ (%)	12.70 ± 8.93	11.38 ± 4.67	27.66 ± 3.49	ns	0.0061	0.007
	(4.44-20.96)	(7.05-15.71)	(22.11-33.21)
CD3⁺CD56⁺CD16⁺ (%)	13.66 ± 3.54	11.63 ± 3.01	8.52 ± 4.97	ns	ns	ns
	(11.77-15.55)	(9.11-14.15)	(2.35-14.70)
IL-6 (pg/mL)	2625.33 ± 3320	966 ± 622.6	1309 ± 851.6	ns	ns	ns
	(856.5-4394)	(445.5-1486.0)	(251.60-2366)
TNFα (pg/mL)	1675.20 ± 623.4	1497 ± 219.8	3217 ± 991.5	ns	0.0044	0.0016
	(1343-2007)	(1313-1681)	(1986-4448)
IL-10 (pg/mL)	528.86 ± 755.1	217.1 ± 159.1	152.1 ± 126.4	ns	ns	ns
	(126.5-931.2)	(84.12-350.2)	(-4.89-309.0)
IFNγ (pg/mL)	3379.1 ± 1869	2257 ± 2872	1378 ± 2533	ns	ns	ns
	(2383-4375)	(-143.3-4658)	(-1767-4524)
IL-8 (pg/mL)	273.9 ± 116.3	293.9 ± 120.2	733.1 ± 404.8	ns	0.0267	ns
	(211.9-335.9)	(193.4-394.4)	(230.4-1236)
IL-17 (pg/mL)	73.81 ± 107.0	36.31 ± 34.62	62.73 ± 5.78	ns	ns	ns
	(16.81-130.8)	(7.36-65.25)	(55.55-69.91)

The differences between the non-viral acute liver failure (ALF) patients, the self-limited acute hepatitis (AH) patients, and the healthy control (HC) subjects were evaluated by intergroup comparisons using the Mann-Whitney U-test. The significance cutoff for all statistical analyses was defined as P < 0.05. IL: Interleukin; IFNγ: Interferon gamma; TNFα: Tumor necrosis factor alpha; PI: Proliferation index; HC: Healthy control; ns: Not significant.

Citation: Melgaço JG, Soriani FM, Sucupira PHF, Pinheiro LA, Vieira YR, de Oliveira JM, Lewis-Ximenez LL, Araújo CCV, Pacheco-Moreira LF, Menezes GB, Cruz OG, Vitral CL, Pinto MA. Changes in cellular proliferation and plasma products are associated with liver failure. World J Hepatol 2016; 8(32): 1370-1383
URL: https://www.wjgnet.com/1948-5182/full/v8/i32/1370.htm
DOI: https://dx.doi.org/10.4254/wjh.v8.i32.1370