Liver histological changes in untreated chronic hepatitis B patients in indeterminate phase

Table 1 Clinical characteristics of chronic hepatitis B patients in the different phases, n (%)

Phase	Immune-Tolerant CHB	HBeAg-positive immune active CHB	Inactive CHB	HBeAg-negative Immune Active CHB	Indeterminate	P value
N	118 (7.70)	197 (12.86)	317 (20.70)	86 (5.61)	814 (53.13)
Age, yr	33.11 ± 7.52	32.41 ± 7.15	40.13 ± 9.37	40.43 ± 9.48	39.15 ± 8.73	< 0.001
Male	53 (44.92)	131 (66.50)	222 (70.03)	68 (79.07)	598 (73.46)	< 0.001
HBsAg, log10, IU/mL	4.62 ± 0.59	4.18 ± 0.73	2.38 ± 1.26	3.28 ± 0.65	3.18 ± 1.02	< 0.001
HBeAg						< 0.001
Negative	0 (0.00)	0 (0.00)	317 (100.00)	86 (100.00)	592 (72.73)
Positive	118 (100.00)	197 (100.00)	0 (0.00)	0 (0.00)	222 (27.27)
HBV-DNA, log10, IU/mL	8.03 ± 0.54	7.60 ± 1.01	2.47 ± 0.56	5.68 ± 1.40	4.71 ± 1.73	< 0.001
ALT, (IQR), U/L	19.00 (15.00-23.00)	138.00 (88.00-233.00)	18.00 (14.00-25.00)	106.50 (79.00-245.00)	33.00 (23.00-45.00)	< 0.001
AST, (IQR), U/L	20.00 (17.00-22.75)	74.00 (50.00-129.00)	20.00 (17.00-23.00)	57.00 (42.25-108.00)	26.00 (21.00-33.00)	< 0.001
GGT, (IQR), U/L	15.00 (12.00-20.00)	52.00 (29.00-89.00)	18.00 (14.00-27.00)	50.50 (34.25-80.25)	25.00 (17.00-40.00)	< 0.001
TBIL, (IQR), umol/L	11.25 (8.20-14.47)	15.20 (10.90-21.60)	12.40 (9.30-16.70)	15.60 (11.83-21.20)	12.75 (9.90-17.30)	< 0.001
ALB, g/L	44.53 ± 3.42	42.52 ± 4.26	44.85 ± 3.23	43.57 ± 5.68	44.50 ± 3.91	< 0.001
WBC, 109/L	5.62 ± 1.24	5.55 ± 1.59	5.69 ± 1.44	5.85 ± 1.97	5.85 ± 1.60	0.062
PLT, 109/L	228.04 ± 58.84	198.12 ± 54.38	204.09 ± 57.04	200.98 ± 65.66	205.85 ± 59.42	< 0.001
Stage of Inflammation						< 0.001
0	2 (1.69)	0 (0.00)	11 (3.47)	0 (0.00)	14 (1.72)
1	90 (76.27)	31 (15.74)	271 (85.49)	23 (26.74)	506 (62.16)
2	26 (22.03)	113 (57.36)	33 (10.41)	48 (55.81)	263 (32.31)
3	0 (0.00)	51 (25.89)	2 (0.63)	15 (17.44)	26 (3.19)
4	0 (0.00)	2 (1.02)	0 (0.00)	0 (0.00)	5 (0.61)
Degree of fibrosis						< 0.001
0	3 (2.54)	5 (2.54)	14 (4.42)	1 (1.16)	17 (2.09)
1	82 (69.49)	72 (36.55)	181 (57.10)	28 (32.56)	390 (47.91)
2	29 (24.58)	65 (32.99)	80 (25.24)	32 (37.21)	219 (26.90)
3	4 (3.39)	31 (15.74)	25 (7.89)	8 (9.30)	96 (11.79)
4	0 (0.00)	24 (12.18)	17 (5.36)	17 (19.77)	92 (11.30)
≥ G2	26 (22.03)	166 (84.26)	35 (11.04)	63 (73.26)	294 (36.12)	< 0.001
≥ S2	33 (27.97)	120 (60.91)	122 (38.49)	57 (66.28)	407 (50.00)	< 0.001
G2/S2	44 (37.29)	171 (86.80)	129 (40.69)	71 (82.56)	488 (59.95)	< 0.001

IQR: Interquartile range; HBV: Hepatitis B virus; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Glutamate aminotransferase; TBIL: Total bilirubin; ALB: Albumin; WBC: White blood cell; PLT: Platelet; CHB: Chronic hepatitis B.

Table 2 Clinical characteristics of different indeterminate phase chronic hepatitis B, n (%)

Phase	Indeterminate-A	Indeterminate-B	Indeterminate-C	Indeterminate-D	P value
N	62 (7.62)	160 (19.66)	304 (37.35)	288 (35.38)
Age, yr	36.42 ± 7.56	34.30 ± 7.70	40.93 ± 8.08	40.56 ± 9.05	< 0.001
Male	46 (74.19)	111 (69.38)	211 (69.41)	230 (79.86)	0.019
HBsAg, log10, IU/mL	3.58 ± 0.81	4.12 ± 0.79	2.99 ± 0.73	2.77 ± 1.08	< 0.001
HBeAg					< 0.001
Negative	0 (0.00)	0 (0.00)	304 (100.00)	288 (100.00)
Positive	62 (100.00)	160 (100.00)	0 (0.00)	0 (0.00)
HBV-DNA, log10, IU/mL	4.33 ± 1.22	7.03 ± 1.72	4.28 ± 0.79	3.88 ± 1.40	< 0.001
ALT, (IQR), U/L	24.00 (18.25-28.00)	45.00 (38.00-55.00)	21.00 (16.00-26.00)	43.00 (37.00-57.25)	< 0.001
AST, (IQR), U/L	23.00 (20.00-26.38)	32.00 (27.80-40.00)	21.00 (18.00-24.00)	29.50 (25.00-38.00)	< 0.001
GGT, (IQR), U/L	20.00 (16.00-32.80)	32.15 (18.00-53.25)	19.00 (14.00-25.23)	32.00 (21.75-49.25)	0.167
TBIL, (IQR), umol/L	13.10 (8.98-16.71)	13.55 (10.50-17.42)	12.55 (9.70-16.35)	12.90 (10.07-17.72)	< 0.001
ALB, g/L	43.83 ± 4.28	43.96 ± 4.05	44.71 ± 3.65	44.73 ± 3.98	0.144
WBC, 109/L	6.14 ± 1.64	5.70 ± 1.49	5.76 ± 1.61	5.96 ± 1.62	0.085
PLT, 109/L	207.32 ± 69.37	203.07 ± 59.53	210.12 ± 55.75	202.57 ± 60.84	0.477
APRI stage					< 0.001
< 1	59 (95.16)	145 (90.62)	301 (99.01)	268 (93.06)
2	2 (3.23)	9 (5.62)	3 (0.99)	6 (2.08)
> 2	1 (1.61)	6 (3.75)	0 (0.00)	14 (4.86)
FIB-4 stage					0.136
< 1.45	49 (79.03)	131 (81.88)	257 (84.54)	225 (78.12)
1.45- 3.25	10 (16.13)	21 (13.12)	43 (14.14)	47 (16.32)
> 3.25	3 (4.84)	8 (5.00)	4 (1.32)	16 (5.56)
GPR stage					< 0.001
≤ 0.32	42 (67.74)	75 (46.88)	247 (81.25)	133 (46.18)
> 0.32	20 (32.26)	85 (53.12)	57 (18.75)	155 (53.82)
Stage of inflammation					< 0.001
0	4 (6.45)	2 (1.25)	4 (1.32)	4 (1.39)
1	23 (37.10)	80 (50.00)	231 (75.99)	172 (59.72)
2	28 (45.16)	67 (41.88)	68 (22.37)	100 (34.72)
3	7 (11.29)	10 (6.25)	0 (0.00)	9 (3.12)
4	0 (0.00)	1 (0.62)	1 (0.33)	3 (1.04)
Degree of fibrosis					< 0.001
0	2 (3.23)	2 (1.25)	6 (1.97)	7 (2.43)
1	23 (37.10)	81 (50.62)	164 (53.95)	122 (42.36)
2	12 (19.35)	34 (21.25)	89 (29.28)	84 (29.17)
3	8 (12.90)	16 (10.00)	33 (10.86)	39 (13.54)
4	17 (27.42)	27 (16.88)	12 (3.95)	36 (12.50)
≥ G2	35 (56.45)	78 (48.75)	69 (22.70)	112 (38.89)	< 0.001
≥ S2	37 (59.68)	77 (48.12)	134 (44.08)	159 (55.21)	0.019
G2/S2	41 (66.13)	105 (65.62)	156 (51.32)	186 (64.58)	0.002

IQR: Interquartile range; HBV: Hepatitis B virus; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Glutamate aminotransferase; TBIL: Total bilirubin; ALB: Albumin; WBC: White blood cell; PLT: Platelet; APRI: Aspartate aminotransferase-to-platelet ratio index; FIB-4: Fibrosis-4 index; GPR: Gamma- glutamyl- transpeptidase to platelet ratio.

Table 3 Predictors of liver histopathology changes in the indeterminate patients

	Univariable		Multivariable1
Significant necroinflammation	OR, (95%CI)	P value	Adjusted OR, (95%CI)	P value
Age, yr
< 40	Referent		Referent
≥ 40	1.29 (0.97, 1.72)	0.0846	1.75 (1.25, 2.44)	0.001
Sex
Male	Referent		Referent
Female	0.76 (0.54, 1.06)	0.1007	0.75 (0.52, 1.07)	0.1098
HBeAg
-	Referent		Referent
+	2.36 (1.72, 3.24)	< 0.0001	2.55 (1.77, 3.68)	< 0.0001
HBV-DNA log10, IU/mL
< 3	Referent		Referent
≥ 3	0.98 (0.63, 1.53)	0.9258	1.10 (0.67, 1.80)	0.7017
PLT, 109/L
> 150	Referent		Referent
≤ 150	3.16 (2.14, 4.66)	< 0.0001	2.77 (1.83, 4.19)	< 0.0001
ALT, U/L
< ULN	Referent		Referent
≥ ULN	1.85 (1.38, 2.49)	< 0.0001	1.60 (1.15, 2.25)	0.006
Significant fibrosis	OR, (95%CI)	P value	Adjusted OR, (95%CI)	P value
Age, yr
< 40	Referent		Referent
≥ 40	1.42 (1.07, 1.87)	0.0136	1.36 (1.00, 1.85)	0.049
Sex
Male	Referent		Referent
Female	0.88 (0.65, 1.20)	0.4272	0.97 (0.70, 1.35)	0.8752
HBeAg
-	Referent		Referent
+	1.08 (0.79, 1.47)	0.6367	1.14 (0.80, 1.62)	0.4734
HBV-DNA log10, IU/mL
< 3	Referent		Referent
≥ 3	0.85 (0.56, 1.31)	0.4636	0.93 (0.58, 1.49)	0.7537
PLT,109/L
> 150	Referent		Referent
≤ 150	4.30 (2.75, 6.71)	< 0.0001	3.92 (2.49, 6.17)	< 0.0001
ALT, U/L
< ULN	Referent		Referent
≥ ULN	1.27 (0.96, 1.68)	0.0907	1.15 (0.84, 1.59)	0.3758
Significant liver histological changes	OR, (95%CI)	P value	Adjusted OR, (95%CI)	P value
Age, yr
< 40	Referent		Referent
≥ 40	1.37 (1.03, 1.82)	0.0308	1.44 (1.06, 1.97)	0.0214
Sex
Male	Referent		Referent
Female	0.97 (0.71, 1.33)	0.8423	1.05 (0.76, 1.47)	0.7551
HBeAg
-	Referent		Referent
+	1.41 (1.03, 1.95)	0.0347	1.40 (0.97, 2.01)	0.0689
HBV-DNA log10, IU/mL
< 3	Referent		Referent
≥ 3	0.97 (0.63, 1.49)	0.8813	1.13 (0.70, 1.81)	0.626
PLT,109/L
> 150	Referent		Referent
≤ 150	3.34 (2.09, 5.35)	< 0.0001	2.99 (1.85, 4.83)	< 0.0001
ALT, U/L
< ULN	Referent		Referent
≥ ULN	1.57 (1.19, 2.09)	0.0016	1.48 (1.08, 2.05)	0.0163

¹Adjusted for age, sex, alanine aminotransferase level, HBeAg statue, platelet level, and hepatitis B virus DNA level.

HBV: Hepatitis B virus; ALT: Alanine aminotransferase; GGT: Glutamate aminotransferase; PLT: Platelet; ULN: Upper limits of normal.