Baseline hepatocyte ballooning is a risk factor for adverse events in patients with chronic hepatitis B complicated with nonalcoholic fatty liver disease

Table 1 Basic information of total chronic hepatitis B (n = 456), n (%)

Parameters	Results
Age (yr)	41.08 ± 10.41
Sex female	160 (45.1)
BMI (kg/m2)
< 23	196 (43.0)
23-25	127 (27.9)
≥ 25	133 (29.2)
Diabetes	42 (9.2)
Hypertension	38 (8.3)
NAFLD	152 (33.3)
Duration of follow-up (mo)	70.5 (29-133)
Antiviral therapy	330 (72.4)
HBV DNA (+), log10 (IU/mL)	4.56 (3-6.92)
HBV DNA (-)1	98 (21.5)
HBeAg (-)	301 (66.0)

¹Hepatitis B virus DNA (-): < 500 IU/mL.

NAFLD: Nonalcoholic fatty liver disease; BMI: Body mass index; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen.

Table 2 Comparison of baseline characteristics of chronic hepatitis B patients with and without nonalcoholic fatty liver disease, n (%)

Parameters	NAFLD	No NAFLD	P value
	n = 152	n = 304
Age (yr)	41.87 ± 9.44	40.69 ± 10.85	0.24
< 40	67 (44.1)	141 (46.4)	0.64
40-60	77 (50.7)	148 (48.7)
≥ 60	8 (5.3)	15 (4.9)
Sex female	41 (27)	119 (39.1)	0.01
BMI (kg/m2)			< 0.001
< 23	31 (20.4)	165 (54.3)
23-25	49 (32.2)	78 (25.7)
≥ 25	72 (47.4)	61 (20.1)
Diabetes	27 (17.8)	15 (4.9)	< 0.001
Hypertension	18 (11.8)	20 (6.6)	0.07
Cirrhosis	24 (15.8)	43 (14.1)	0.64
Duration of follow-up (mo)	71 (27-118)	73 (32-114)	0.08
HBV DNA (IU/mL)			0.08
< 500 IU/mL	29 (19.1)	69 (22.7)
< 4 log10	21 (13.8)	60 (19.7)
≥ 4 log10	102 (67.1)	175 (57.6)
HBeAg (-)	91 (59.9)	210 (69.1)	0.05
TBil (µmol/L)	15.69 ± 9.06	15.91 ± 9.1	0.8
ALB (g/L)	44.22 ± 3.42	43.62 ± 3.81	0.1
PB (mg/L)	241.53 ± 67.19	224.74 ± 73.69	0.02
ALT (U/L)	85 (32-275)	77 (26-263)	0.002
≤ 40	67 (44.1)	172 (56.6)	0.012
> 40	85 (55.9)	132 (43.4)
AST (U/L)	76 (27-248)	83 (26.5-247)	0.28
ALP (U/L)	84.7 ± 26.3	83.92 ± 31.68	0.8
GGT (U/L)	40.88 ± 36.95	36.31 ± 38.17	0.23
GLU (mmol/L)	5.48 ± 1.07	5.34 ± 1.02	0.2
TC (mmol/L)	4.32 ± 0.88	4.17 ± 0.71	0.08
TG (mmol/L)	1.54 ± 1.04	1.23 ± 0.5	0.001
LDL (mmol/L)	2.7 ± 0.68	2.56 ± 0.7	0.049
HDL (mmol/L)	1.32 ± 0.4	1.35 ± 0.31	0.27
PLT (× 109/L)	167.05 ± 54.18	159.13 ± 56.02	0.15
AFP (ng/mL)	3.25 (2.15-5.83)	2.93 (2.03-5.81)	0.33

NAFLD: Nonalcoholic fatty liver disease; BMI: Body mass index; TBil: Total bilirubin; ALB: Albumin; PB: Prealbumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; ALP: Alkaline phosphatase; GLU: Fasting blood glucose; TC: Total cholesterol; TG: Triglyceride; LDL: Low density lipoprotein; HDL: High density lipoprotein; PLT: Platelet; AFP: Alpha-fetoprotein; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen.

Table 3 Comparison of baseline characteristics of chronic hepatitis B patients (without cirrhosis) with and without nonalcoholic fatty liver disease, n (%)

Parameters	P values before PSM	PSM		P value
		NAFLD	No NAFLD
		(n = 109)	(n = 109)
Age (yr)	0.58			0.63
< 40		52 (47.7)	47 (43.1)
40-60		51 (46.8)	58 (53.2)
≥ 60		6 (5.5)	4 (3.7)
Sex female	< 0.05	29 (26.6)	37 (33.9)	0.24
BMI (kg/m2)	< 0.05			< 0.05
< 23		21 (19.3)	58 (53.2)
23-25		35 (32.1)	30 (27.5)
≥ 25		53 (48.6)	21 (19.3)
Diabetes	< 0.05	4 (3.7)	4 (3.7)	1
Hypertension	0.07	12 (11)	6 (5.5)	0.14
Duration of follow-up (mo)	< 0.05	71 (28-119.5)	52 (25-111)	0.3
Antiviral drugs	0.59			0.3
Entecavir		49 (61.3)	56 (71.8)
Tenofovir		26 (32.5)	19 (24.4)
Other		5 (6.3)	3 (3.8)
Antiviral duration	0.48			0.46
Never		29 (26.6)	31 (28.4)
< 5 yr		50 (45.9)	54 (49.5)
≥ 5 yr		30 (27.5)	24 (22)
HBV DNA (IU/mL)	< 0.05			0.06
< 500 IU/mL		18 (19.3)	24 (22)
< 4 log10		13 (32.1)	21 (19.3)
≥ 4 log10		78 (48.6)	64 (58.7)
HBeAg (-)	0.12	65 (59.6)	75 (68.8)	0.16
TBil (µmol/L)	0.94	15.73 ± 7.17	14.25 ± 5.73	0.09
ALB (g/L)	0.21	44.15 ± 3.32	44.29 ± 3.78	0.78
PB (mg/L)	0.28	243.24 ± 65.74	225.67 ± 62.19	< 0.05
ALT (U/L)	< 0.05			0.89
≤ 40		43 (19.3)	44 (40.4)
> 40		66 (32.1)	65 (59.6)
AST (U/L)	0.16	36 (27.5-49.5)	37 (26.5-50)	0.95
ALP (U/L)	0.1	85.55 ± 26.37	82.82 ± 22.08	0.41
GGT (U/L)	0.12	37.44 ± 25.34	34.76 ± 33.13	0.5
GLU (mmol/L)	0.06	5.25 ± 0.68	5.41 ± 0.89	0.15
TC (mmol/L)	< 0.05	4.37 ± 0.88	4.22 ± 0.64	0.16
TG (mmol/L)	< 0.05	1.47 ± 0.75	1.22 ± 0.51	< 0.05
LDL (mmol/L)	< 0.05	2.77 ± 0.65	2.62 ± 0.61	0.09
HDL (mmol/L)	0.38	1.31 ± 0.36	1.32 ± 0.3	0.82
PLT (× 109/L)	0.12	174.29 ± 51.81	162.83 ± 47.49	0.09
AFP (ng/mL)	0.29	3.1 (2.1-5.3)	2.9 (2.1-5.5)	0.74
NASH		15 (13.7)

PSM: Propensity score matching; BMI: Body mass index; TBil: Total bilirubin; ALB: Albumin; PB: Prealbumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; ALP: Alkaline phosphatase; GLU: Fasting blood glucose; TC: Total cholesterol; TG: Triglyceride; LDL: Low density lipoprotein; HDL: High density lipoprotein; PLT: Platelet; AFP: Alpha-fetoprotein; NASH: Nonalcoholic steatohepatitis; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen.

Table 4 Comparison of pathological features of chronic hepatitis B patients with and without nonalcoholic fatty liver disease, n (%)

Pathological features	Total	NAFLD	No NAFLD	P value
	(n = 456)	(n = 152)	(n = 304)
Fibrosis				0.045
F0	109 (23.9)	30 (19.7)	79 (26)
F1	129 (28.3)	36 (23.7)	93 (30.6)
F2	93 (20.4)	41 (27)	52 (17.1)
F3	58 (12.7)	21 (13.8)	37 (12.2)
F4	67 (14.7)	24 (15.8)	43 (14.1)
Steatosis
0	304 (66.7)		304 (100)
1	89 (19.5)	89 (58.6)
2	48 (10.5)	48 (31.6)
3	15 (3.3)	15 (9.9)
Portal tract inflammation				< 0.001
0	35 (7.7)	8 (5.3)	27 (8.9)
1	275 (60.3)	79 (52)	196 (64.5)
2	117 (25.7)	50 (32.9)	67 (22)
3	29 (6.3)	15 (9.9)	14 (4.6)
Lobular inflammation				0.13
0	91 (20)	28 (18.4)	63 (20.7)
1	315 (69.1)	101 (66.4)	214 (70.4)
2	50 (11)	23 (15.1)	27 (8.9)
Ballooning degeneration				0.004
0	153 (33.6)	58 (38.2)	165 (54.3)
1	195 (42.8)	61 (40.1)	96 (31.6)
2	108 (23.7)	33 (21.7)	43 (14.1)
NASH	32 (21.1)	32 (21.1)
NAS score	1.7 ± 1.2	2.7 ± 1.2	1.2 ± 0.8	< 0.001

NASH: Nonalcoholic steatohepatitis; NAS: Activity score of nonalcoholic fatty liver disease; NAFLD: Nonalcoholic fatty liver disease.

Table 5 Comparison of antiviral data of chronic hepatitis B virus infection with and without nonalcoholic fatty liver disease, n (%)

Parameters	NAFLD	No NAFLD	P value
	(n = 152)	(n = 304)
Antiviral	116 (76.3)	215 (70.7)	0.21
Antiviral drugs			0.5
Entecavir	73 (62.9)	131 (60.9)
Tenofovir	35 (30.2)	68 (31.6)
Others	8 (6.9)	16 (7.4)
Antivirus duration			0.31
< 5 yr	70 (46.1)	129 (42.4)
≥ 5 yr	46 (30.3)	86 (28.3)

NAFLD: Nonalcoholic fatty liver disease.

Table 6 Univariate and multivariate Cox regression analysis of cirrhosis

Parameters	Univariate	P value	Multivariate	P value
	HR (95%CI)		HR (95%CI)
Clinical factors
Sex	1.36 (0.63-2.92)	0.43
Age (yr)	1.08 (1.04-1.12)	< 0.001	1.06 (1.02-1.10)	0.003
BMI (kg/m2)	0.96 (0.64-1.45)	0.86
Diabetes	2.57 (0.78-8.52)	0.12
Hypertension	2.71 (0.95-7.76)	0.06
Duration of antiviral (≥ 5 yr/never or < 5 yr)	1.65 (1.07-2.54)	0.02	1.32 (0.84-2.06)	0.23
Pathological factors
NAFLD	1.12 (0.53-2.37)	0.76
NASH	1.38 (0.33-5.86)	0.66
Lobular inflammation	2.35 (1.19-4.66)	0.01	0.77 (0.33-1.80)	0.54
Portal tract inflammation	1.40 (0.90-2.20)	0.14
Ballooning degeneration	3.34 (1.65-6.75)	0.001	2.57 (1.05-6.28)	0.04
Fibrosis	1.49 (1.08-2.06)	0.02	1.39 (1.04-1.87)	0.028
Laboratory examination
TBil (µmol/L)	0.99 (0.95-1.04)	0.8
ALB (g/L)	0.94 (0.85-1.04)	0.25
PB (mg/L)	1.00 (0.997-1.00)	0.83
ALT (> 40/≤ 40U/L)	1.00 (0.996-1.00)	0.64
AST (U/L)	1.00 (0.99-1.01)	0.54
ALP (U/L)	1.01 (1.00-1.02)	0.008	1.01 (1.00-1.02)	0.08
GGT (U/L)	1.01 (1.00-1.01)	0.13
GLU (mmol/L)	1.31 (0.96-1.78)	0.09
TG (mmol/L)	0.57 (0.28-1.18)	0.13
TC (mmol/L)	0.95 (0.61-1.49)	0.83
HDL (mmol/L)	1.71 (0.65-4.49)	0.28
LDL (mmol/L)	0.46 (0.27-0.79)	0.005	0.76 (0.45-1.29)	0.31
PLT (× 109/L)	0.99 (0.98-0.99)	0.001	0.98 (0.97-0.99)	0.001
AFP (ng/mL)	0.99 (0.96-1.03)	0.63
HBeAg (-)	0.91 (0.43-1.90)	0.79
HBV DNA (≥ 4 log IU/mL)	0.82 (0.55-1.23)	0.34

BMI: Body mass index; TBil: Total bilirubin; ALB: Albumin; PB: Prealbumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; ALP: Alkaline phosphatase; GLU: Fasting blood glucose; TC: Total cholesterol; TG: Triglyceride; LDL: Low density lipoprotein; HDL: High density lipoprotein; PLT: Platelet; AFP: Alpha-fetoprotein; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen.

Table 7 Univariate and multivariate Cox regression analysis of cirrhosis after propensity score matching

Parameters	Univariate	P value	Multivariate	P value
	HR (95%CI)		HR (95%CI)
Age (yr)	1.06 (1.01-1.11)	0.02	1.05 (0.99-1.11)	0.11
Hypertension	3.26 (0.89-11.90)	0.07	0.59 (0.12-2.97)	0.52
Diabetes	6.74 (0.77-58.81)	0.08	12.21 (1.1-134.4)	0.04
Lobular inflammation	2.63 (1.02-6.82)	0.046	1.20 (0.26-5.57)	0.82
Ballooning degeneration	4.33 (1.01-5.15)	0.006	1.80 (0.86-4.48)	0.02
Portal tract inflammation	2.37 (1.18-4.75)	0.02	72.61 (2.16-2436)	0.48
Fibrosis	1.57 (0.96-2.56)	0.07	1.03 (0.48-2.25)	0.93
ALT(U/L)	1.00 (1.00-1.01)	0.06	1.00 (0.99-1.01)	0.26
PLT (× 109/L)	0.98 (0.96-0.99)	< 0.001	0.98 (0.96-0.99)	0.001

ALT: Alanine aminotransferase; PLT: Platelet.

Table 8 Univariate and multivariate Cox regression analysis of hepatocellular carcinoma occurrence

Parameters	Univariate	P value	Multivariate	P value
	HR (95%CI)		HR (95%CI)
Clinical factors
Sex	40.03 (0.17-9369.3)	0.19
Age (yr)	1.06 (0.99-1.13)	0.054	0.29 (0.03-2.50)	0.26
BMI (kg/m2)	0.97 (0.78-1.21)	0.8
Diabetes	14.36 (4.01-51.47)	< 0.001	34.8 (2.27-534.1)	0.01
Hypertension	1.99 (0.25-15.71)	0.52
Antivirus duration (≥ 5 yr, never or < 5 yr)	1.32 (0.38-4.56)	0.66
Pathological factors
NAFLD (steatosis ≥ 5%)	4.29 (1.20-15.41)	0.025	2.28 (0.44-11.69)	0.33
NASH	4.36 (1.35-24.80)	0.002	0.53 (0.01-1.84)	0.39
Lobular inflammation	7.2 (2.16-23.91)	0.001	5.16 (0.53-49.96)	0.16
Portal tract inflammation	2.02 (0.98-4.15)	0.056	0.49 (0.31-1.85)	0.29
Ballooning degeneration	8.69 (1.57-29.64)	0.008	5.16 (0.83-19.96)	0.03
Fibrosis stage	14.25 (13.68-55.14)	< 0.001	8.37 (1.39-50.44)	0.02
Laboratory examination
TBil (µmol/L)	1.02 (0.97-1.09)	0.37
PB (mg/L)	0.998 (0.99-1.01)	0.64
LB (g/L)	0.97 (0.82-1.14)	0.69
ALT (> 40/≤ 40 U/L)	0.999 (0.99-1.01)	0.71
AST (U/L)	0.999 (0.98-1.01)	0.89
ALP (U/L)	1.01 (0.99-1.03)	0.42
GGT (U/L)	0.99 (0.96-1.02)	0.46
GLU (mmol/L)	1.45 (1.08-1.94)	0.01	0.64 (0.37-1.12)	0.12
TG (mmol/L)	0.18 (0.04-0.92)	0.04	0.085 (0.004-1.7)	0.11
TC (mmol/L)	0.36 (0.15-0.85)	0.02	0.39 (0.15-1.01)	0.053
HDL (mmol/L)	0.39 (0.04-3.67)	0.41
LDL (mmol/L)	0.47 (0.18-1.26)	0.13
PLT (× 109/L)	0.97 (0.96-0.99)	0.004	0.99 (0.97-1.01)	0.26
AFP (ng/mL)	0.99 (0.91-1.07)	0.77
HBeAg (-) (%)	1.43 (0.40-5.08)	0.58
HBV DNA (≥ 4 log IU/mL)	1.49 (0.39-5.77)	0.56

BMI: Body mass index; TBil: Total bilirubin; ALB: Albumin; PB: Prealbumin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: γ-glutamyl transferase; ALP: Alkaline phosphatase; GLU: Fasting blood glucose; TC: Total cholesterol; TG: Triglyceride; LDL: Low density lipoprotein; HDL: High density lipoprotein; PLT: Platelet; AFP: Alpha-fetoprotein; NAFLD: Nonalcoholic fatty liver disease; NASH: Nonalcoholic steatohepatitis; HBV: Hepatitis B virus; HBeAg: Hepatitis B e antigen.