Liver histopathological lesions is severe in patients with normal alanine transaminase and low to moderate hepatitis B virus DNA replication

doi:10.3748/wjg.v29.i16.2479

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Retrospective Cohort Study

World J Gastroenterol. Apr 28, 2023; 29(16): 2479-2494
Published online Apr 28, 2023. doi: 10.3748/wjg.v29.i16.2479

Table 1 Distribution of baseline characteristics in 634 chronic hepatitis B patients with alanine transaminase < upper limit of normal

Parameters	All patients (n = 634)	HBV DNA levels (EASL guidelines)				HBV DNA levels (CMA guidelines)
Parameters	All patients (n = 634)	Low/moderate replication (n = 336)	High replication (n = 298)	χ²*/t /Z/u*	P value	Low/moderate replication (n = 377)	High replication (n = 257)	χ²*/t/Z/u*	P value
Age, mean ± SD, yr	35.61 ± 10.30	38.09 ± 9.99	32.82 ± 9.95	6.640	< 0.001	37.34 ± 10.17	33.07 ± 9.99	5.222	< 0.001
Male, n (%)	349 (55.05)	192 (57.14)	157 (52.68)	1.269	0.260	209 (55.44)	140 (54.47)	0.057	0.811
HBeAg positive, n (%)	432 (68.14)	142 (42.26)	290 (97.31)	220.486	< 0.001	180 (47.74)	252 (98.05)	178.165	< 0.001
ALB, mean ± SD, g/L	42.72 ± 4.45	42.91 ± 4.97	42.49 ± 3.78	1.189	0.235	42.75 ± 4.88	42.67 ± 3.74	0.220	0.826
GLB, mean ± SD, g/L	27.82 ± 4.20	27.96 ± 4.11	27.66 ± 4.30	0.893	0.372	28.11 ± 4.19	27.40 ± 4.18	2.105	0.036
AGR, mean ± SD	1.57 ± 0.29	1.57 ± 0.30	1.57 ± 0.28	-0.148	0.882	1.56 ± 0.30	1.59 ± 0.28	-1.581	0.114
ALT, mean ± SD, U/L	23.77 ± 8.58	24.84 ± 8.66	22.56 ± 8.34	3.372	0.001	24.38 ± 8.69	22.87 ± 8.35	2.186	0.029
AST, mean ± SD, U/L	24.15 ± 8.91	25.00 ± 7.52	23.20 ± 10.18	2.558	0.011	25.04 ± 10.28	22.85 ± 6.17	3.069	0.002
ALP, mean ± SD, U/L	71.26 ± 26.06	71.52 ± 24.85	70.96 ± 27.39	0.269	0.788	71.21 ± 24.99	71.32 ± 27.60	-0.054	0.957
GGT, median (Q1-Q3), U/L	18.00 (13.00-25.00)	20.00 (15.00-30.00)	16.00 (13.00-23.00)	4.966	< 0.001	19.00 (14.00-29.00)	16.00 (13.00-23.00)	4.069	< 0.001
WBC count, mean ± SD, × 10⁹/L	5.39 ± 1.42	5.33 ± 1.39	5.47 ± 1.45	-1.208	0.228	5.33 ± 1.44	5.48 ± 1.39	-1.321	0.187
NLR, mean ± SD	2.03 ± 1.24	2.05 ± 1.37	2.01 ± 1.08	0.443	0.658	2.04 ± 1.33	2.01 ± 1.09	0.298	0.766
PLT count, mean ± SD, × 10⁹/L	175.67 ± 48.83	163.93 ± 47.39	188.90 ± 47.09	-6.641	< 0.001	166.86 ± 47.55	188.58 ± 47.90	-5.629	< 0.001
HBV DNA, mean ± SD, log IU/mL	6.18 ± 1.87	4.68 ± 1.26	7.88 ± 0.50	-41.111	< 0.001	4.95 ± 1.41	7.99 ± 0.44	-33.427	< 0.001
APRI, median (Q1–Q3)	0.33 (0.25-0.44)	0.36 (0.28-0.51)	0.29 (0.23-0.38)	6.936	< 0.001	0.36 (0.27-0.48)	0.30 (0.23-0.38)	5.725	< 0.001
FIB-4, median (Q1-Q3)	0.99 (0.69-1.38)	1.13 (0.83-1.61)	0.80 (0.58-1.13)	8.109	< 0.001	1.09 (0.79-1.56)	0.81 (0.59-1.13)	6.877	< 0.001
LIF-5, mean ± SD	0.40 ± 0.15	0.45 ± 0.15	0.36 ± 0.14	7.832	< 0.001	0.44 ± 0.15	0.35 ± 0.14	7.195	< 0.001
Liver inflammatory activity
A0, n (%)	117 (18.45)	58 (17.26)	59 (19.80)	4.189	< 0.001	61 (16.18)	56 (21.79)	4.426	< 0.001
A1, n (%)	381 (60.10)	174 (51.79)	207 (69.46)			206 (54.64)	175 (68.09)
A2, n (%)	97 (15.30)	73 (21.73)	24 (8.05)			78 (20.69)	19 (7.39)
A3, n (%)	39 (6.15)	31 (9.23)	8 (2.68)			32 (8.49)	7 (2.72)
≥ A2, n (%)	136 (21.45)	104 (30.95)	32 (10.74)	38.299	< 0.001	110 (29.18)	26 (10.12)	32.952	< 0.001
Liver fibrosis
F0, n (%)	148 (23.34)	61 (18.15)	87 (29.19)	6.382	< 0.001	70 (18.57)	78 (30.35)	6.053	< 0.001
F1, n (%)	332 (52.37)	153 (45.54)	179 (60.07)			179 (47.48)	153 (59.53)
F2, n (%)	87 (13.72)	65 (19.35)	22 (7.38)			70 (18.57)	17 (6.61)
F3, n (%)	37 (5.84)	29 (8.63)	8 (2.68)			30 (7.96)	7 (2.72)
F4, n (%)	30 (4.73)	28 (8.33)	2 (0.67)			28 (7.43)	2 (0.78)
≥ F2, n (%)	154 (24.29)	122 (36.31)	32 (10.74)	56.155	< 0.001	128 (33.95)	26 (10.12)	47.212	< 0.001
Treatment indication
< A2 and < F2, n (%)	442 (69.72)	191 (56.85)	251 (84.23)	56.089	< 0.001	224 (59.42)	218 (84.82)	46.730	< 0.001
≥ A2 or/and ≥ F2, n (%)	192 (30.28)	145 (43.15)	47 (15.77)			153 (40.58)	39 (15.18)

Quantitative data of normal distribution were expressed as mean ± standard deviation, non-normal distribution data were expressed as median (Q1-Q3), and categorical data were expressed as frequency and percentage. A: Liver inflammatory activity; AGR: Albumin–globulin ratio; ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APRI: Aspartate transaminase to platelet ratio index, APRI = [(AST/ULN)/platelet counts (10⁹/L)] × 100[16]; AST: Aspartate aminotransferase; CMA: Chinese Medical Association; EASL: European Association for the Study of the Liver; F: Liver fibrosis; GLB: Globulin; FIB-4: Fibrosis-4, FIB-4 = [age (year) × AST (U/L)]/(platelet count (10⁹/L) × [ALT (U/L)^1/2][17]; GGT: Gamma-glutamyl transpeptidase; HBeAg: Hepatitis B e antigen; LIF-5: Liver inflammation and fibrosis-5, LIF-5 = 0.725 + 0.005 × age (year) + 0.003 × ALT (U/L) + 0.004 × AST (U/L) - 0.201 × (A/G) - 0.002 × PLT (10⁹/L)[18]; NLR: Neutrophils lymphocytes ratio; PLT: Platelets; WBC: White blood cell.

Table 2 Comparison of parameters among patients with alanine transaminase < upper limit of normal and different pathological states (Entire cohort)

Parameters	Liver inflammatory activity		Liver fibrosis		Treatment indication		P value
Parameters	< A2 (n = 498)	≥ A2 (n = 136)	< F2 (n = 480)	≥ F2 (n = 154)	< A2 and < F2 (n = 442)	≥ A2 or/and ≥ F2 (n = 192)	P value
Age, mean ± SD, yr	34.68 ± 9.88	39.02 ± 11.10	34.36 ± 9.86	39.52 ± 10.71	34.28 ± 9.84	38.69 ± 10.70	< 0.001, < 0.001, < 0.001
Male, n (%)	268 (53.82)	81 (59.56)	253 (52.71)	96 (62.34)	234 (52.94)	115 (59.90)	0.232, 0.037, 0.105
HBeAg positive, n (%)	354 (71.08)	78 (57.35)	350 (72.92)	82 (53.25)	323 (73.08)	109 (56.77)	0.002, < 0.001, < 0.001
ALB, mean ± SD, g/L	43.06 ± 3.96	41.45 ± 5.75	42.96 ± 4.32	41.95 ± 4.75	43.06 ± 4.01	41.92 ± 5.24	< 0.001, 0.014, 0.003
GLB, mean ± SD, g/L	27.46 ± 4.09	29.14 ± 4.35	27.54 ± 4.06	28.70 ± 4.51	27.49 ± 4.08	28.57 ± 4.38	< 0.001, 0.003, 0.003
AGR, mean ± SD	1.60 ± 0.27	1.46 ± 0.33	1.59 ± 0.28	1.50 ± 0.31	1.60 ± 0.27	1.50 ± 0.32	< 0.001, 0.001, < 0.001
ALT, mean ± SD, U/L	22.81 ± 8.48	27.26 ± 8.07	22.80 ± 8.48	26.80 ± 8.20	22.45 ± 8.43	26.80 ± 8.16	< 0.001, < 0.001, < 0.001
AST, mean ± SD, U/L	22.93 ± 6.24	28.62 ± 14.26	22.79 ± 6.41	28.41 ± 13.26	22.64 ± 6.26	27.63 ± 12.45	< 0.001, < 0.001, < 0.001
ALP, mean ± SD, U/L	68.68 ± 24.45	80.67 ± 29.48	68.62 ± 23.35	79.49 ± 31.80	68.58 ± 23.86	77.41 ± 29.68	< 0.001, < 0.001, < 0.001
GGT, mean ± SD, U/L	20.24 ± 13.58	34.91 ± 33.78	19.87 ± 13.63	34.34 ± 31.87	19.91 ± 13.78	31.38 ± 29.60	< 0.001, < 0.001, < 0.001
WBC count, mean ± SD, × 10⁹/L	5.40 ± 1.41	5.33 ± 1.53	5.43 ± 1.44	5.26 ± 1.40	5.41 ± 1.42	5.33 ± 1.46	0.622, 0.210, 0.491
NLR, mean ± SD	2.05 ± 1.21	1.96 ± 1.35	2.07 ± 1.31	1.91 ± 0.99	2.04 ± 1.21	2.02 ± 1.32	0.447, 0.158, 0.824
PLT count, mean ± SD, × 10⁹/L	184.72 ± 44.67	142.52 ± 49.26	186.16 ± 44.28	142.94 ± 47.99	187.73 ± 43.49	147.90 ± 49.24	< 0.001, < 0.001, < 0.001
HBV DNA, mean ± SD, log IU/mL	6.35 ± 1.91	5.56 ± 1.59	6.44 ± 1.87	5.39 ± 1.64	6.47 ± 1.88	5.52 ± 1.67	< 0.001, < 0.001, < 0.001
APRI, mean ± SD	0.33 ± 0.14	0.59 ± 0.42	0.32 ± 0.13	0.58 ± 0.39	0.32 ± 0.12	0.54 ± 0.37	< 0.001, < 0.001, < 0.001
FIB-4, mean ± SD	1.01 0.53	1.81 ± 1.34	0.97 ± 0.49	1.81 ± 1.28	0.96 ± 0.49	1.67 ± 1.21	< 0.001, < 0.001, < 0.001
LIF-5, mean ± SD	0.37 ± 0.13	0.54 ± 0.17	0.36 ± 0.12	0.53 ± 0.16	0.36 ± 0.12	0.51 ± 0.16	< 0.001, < 0.001, < 0.001

Quantitative data of normal distribution were expressed as mean ± standard deviation, and categorical data were expressed as frequency and percentage. A: Liver inflammatory activity; AGR: Albumin–globulin ratio; ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APRI: Aspartate transaminase to platelet ratio index, APRI = [(AST/ULN)/platelet counts (10⁹/L)] × 100[16]; AST: Aspartate aminotransferase; F: Fibrosis; FIB-4: Fibrosis-4, FIB-4 = [age (year) × AST (U/L)]/(platelet count (10⁹/L) × [ALT (U/L)^1/2][17]; GGT: Gamma-glutamyl transpeptidase; HBeAg: Hepatitis B e antigen; GLB, globulin; LIF-5: Liver inflammation and fibrosis-5, LIF-5 = 0.725 + 0.005 × age (year) + 0.003 × ALT (U/L) + 0.004 × AST (U/L) - 0.201 × (A/G) - 0.002 × PLT (10⁹/L)[18]; NLR: Neutrophils lymphocytes ratio; PLT: Platelets; WBC: White blood cell.

Table 3 Predictors of significant liver histology in 634 patients with chronic hepatitis B and alanine transaminase < upper limit of normal detected using a step-forward binary logistic regression model

Variables		Regression coefficient	Standard error	Wald’s value	P value	OR	OR 95%CI
Variables		Regression coefficient	Standard error	Wald’s value	P value	OR	Upper limit	Lower limit
< A2 vs ≥ A2	Age	-0.039	0.014	7.853	0.005	0.962	0.936	0.988
	GGT	0.015	0.006	5.970	0.015	1.015	1.003	1.027
	HBV DNA	-0.147	0.064	5.306	0.021	0.863	0.761	0.978
	LIF-5	9.616	1.152	69.727	0.000	15002.994	1570.174	143353.477
	Constant	-3.643	0.685	28.240	0.000	0.026
Eliminate diagnostic models	HBV DNA	-0.161	0.063	6.429	0.011	0.851	0.752	0.964
< F2 vs ≥ F2	GGT	0.016	0.006	5.968	0.015	1.016	1.003	1.029
	HBV DNA	-0.229	0.061	14.251	0.000	0.796	0.707	0.896
	APRI	2.747	0.921	8.890	0.003	15.593	2.563	94.859
	LIF-5	4.759	1.285	13.708	0.000	116.591	9.390	1447.723
	Constant	-3.392	0.577	34.608	0.000	0.034
Eliminate diagnostic models	HBV DNA	-0.247	0.061	16.523	0.000	0.781	0.693	0.880
< A2 and < F2 vs ≥ A2 or/and ≥ F2	HBV DNA	-0.199	0.055	13.233	0.000	0.820	0.737	0.913
	APRI	3.124	0.888	12.393	0.000	22.747	3.995	129.530
	LIF-5	4.733	1.182	16.038	0.000	113.618	11.207	1151.897
	Constant	-2.903	0.522	30.931	0.000	0.055
Eliminate diagnostic models	HBV DNA	-0.221	0.056	15.782	0.000	0.801	0.718	0.894

A: Liver inflammatory activity; APRI: Aspartate transaminase to platelet ratio index, APRI = [(AST/ULN)/platelet counts (10⁹/L)] × 100[16]; AST: Aspartate aminotransferase; F: Fibrosis; GGT: Gamma-glutamyl transpeptidase; LIF-5: Liver inflammation and fibrosis-5, LIF-5 = 0.725 + 0.005 × age (year) + 0.003 × ALT (U/L) + 0.004 × AST (U/L) - 0.201 × (A/G) - 0.002 × PLT (10⁹/L)[18]; HBV: Hepatitis B virus.

Table 4 Predictors of significant liver histology in propensity score-matched pairs

Variables	EASL guidelines (316 pairs)				CMA guidelines (277 pairs)
Variables	≥ A2 or/and ≥ F2	< A2 and < F2	χ²*/t/Z*	SMD	≥ A2 or/and ≥ F2	< A2 and < F2	χ²*/t/Z*	SMD
Male, n (%)	171 (54.11)	168 (53.16)	0.057	0.811	138 (49.82)	153 (55.23)	1.629	0.202
HBeAg positive, n (%)	305 (96.52)	306 (96.84)	0.049	0.824	271 (97.83)	271 (97.83)	0	1.000
Age, mean ± SD, yr	32.92 ± 10.13	33.06 ± 9.96	-0.178	0.859	32.54 ± 9.04	33.31 ± 10.07	-0.937	0.349
ALB, mean ± SD, g/L	42.30 ± 4.59	42.65 ± 3.78	-1.046	0.296	42.35 ± 4.81	42.79 ± 3.76	-1.187	0.236
GLB, mean ± SD, g/L	27.74 ± 4.83	27.74 ± 4.26	0.019	0.985	27.23 ± 4.56	27.53 ± 4.25	-0.809	0.419
AGR, mean ± SD	1.57 ± 0.33	1.57 ± 0.28	-0.037	0.971	1.59 ± 0.29	1.59 ± 0.28	0.198	0.843
ALT, mean ± SD, U/L	23.81 ± 8.29	22.78 ± 8.29	1.569	0.117	23.18 ± 9.10	23.00 ± 8.38	0.235	0.814
AST, mean ± SD, U/L	22.13 ± 8.55	22.57 ± 5.76	-0.769	0.442	21.87 ± 7.74	22.72 ± 5.70	-1.465	0.143
ALP, mean ± SD, U/L	71.64 ± 27.61	70.56 ± 27.09	0.495	0.621	72.15 ± 25.92	71.37 ± 27.39	0.345	0.730
GGT, median (Q1-Q3), U/L	16.00 (13.00–23.00)	16.00 (13.00–23.00)	0.780	0.435	16.00 (13.00-24.00)	17.00 (13.00-23.00)	0.590	0.555
WBC count, mean ± SD, ×10⁹/L	5.44 ± 1.27	5.47 ± 1.38	-0.276	0.783	5.51 ± 1.31	5.48 ± 1.30	0.274	0.784
NLR, mean ± SD	1.91 ± 0.80	2.01 ± 1.04	-1.431	0.153	1.89 ± 1.01	2.00 ± 1.04	-1.334	0.183
PLT count, mean ± SD, ×10⁹/L	183.43 ± 42.01	187.96 ± 47.38	-1.272	0.204	184.38 ± 49.39	187.11 ± 48.08	-0.659	0.510
HBV DNA, mean ± SD, log IU/mL	5.81 ± 1.23	7.90 ± 0.49	-27.967	< 0.001	5.78 ± 1.42	8.01 ± 0.43	-24.922	< 0.001
APRI, median (Q1– Q3)	0.31 (0.23-0.38)	0.29 (0.23-0.38)	0.507	0.612	0.32 (0.22–0.39)	0.30 (0.23-0.38)	-0.147	0.883
FIB-4, median (Q1–Q3)	0.80 (0.49-1.11)	0.80 (0.58-1.12)	1.460	0.144	0.74 (0.50-1.17)	0.82 (0.59-1.13)	-1.110	0.267
LIF-5, mean ± SD	0.37 ± 0.14	0.36 ± 0.14	0.903	0.367	0.35 ± 0.14	0.36± 0.14	-0.187	0.852

Low/moderate replication, hepatitis B virus (HBV) DNA ≤ 10⁷ IU/mL; high replication, HBV DNA > 10⁷ IU/mL. Quantitative data of normal distribution were expressed as mean ± standard deviation, non-normal distribution data were expressed as median (Q1-Q3), and categorical data were expressed as frequency and percentage. AGR: Albumin–globulin ratio; ALB: Albumin; ALP: Alkaline phosphatase; ALT: Alanine aminotransferase; APRI: Aspartate transaminase to platelet ratio index, APRI = [(AST/ULN)/platelet counts (10⁹/L)] × 100[16]; AST: Aspartate aminotransferase; CMA: Chinese Medical Association; EASL: European Association for the Study of the Liver; F: Liver fibrosis; GLB: Globulin; FIB-4: Fibrosis-4, FIB-4 = [age (year) × AST (U/L)]/(platelet count (10⁹/L) × [ALT (U/L)^1/2][17]; GGT: Gamma-glutamyl transpeptidase; HBeAg: Hepatitis B e antigen; LIF-5: Liver inflammation and fibrosis-5, LIF-5 = 0.725 + 0.005 × age (year) + 0.003 × ALT (U/L) + 0.004 × AST (U/L) - 0.201 × (A/G) - 0.002 × PLT (10⁹/L)[18]; NLR: Neutrophils lymphocytes ratio; PLT: Platelets; WBC: White blood cell; HBV: Hepatitis B virus.

Citation: Jiang SW, Lian X, Hu AR, Lu JL, He ZY, Shi XJ, Zhu DD, Wang ZY, Huang GC. Liver histopathological lesions is severe in patients with normal alanine transaminase and low to moderate hepatitis B virus DNA replication. World J Gastroenterol 2023; 29(16): 2479-2494
URL: https://www.wjgnet.com/1007-9327/full/v29/i16/2479.htm
DOI: https://dx.doi.org/10.3748/wjg.v29.i16.2479