MAFLD is Associated with the Risk of Liver Fibrosis and Inflammatory Activity in HBeAg-Negative CHB Patients

Figures & data

Table 1 Comparison of Clinical Characteristics of CHB with and without MAFLD, Stratified by HBeAg Status

	HBeAg-			HBeAg+
	Non-MAFLD-CHB (n=155)	MAFLD-CHB (n=64)	P	Non-MAFLD-CHB (n=142)	MAFLD-CHB (n=38)	P
Male (n [%])	106[68.4]	56[87.5]	0.003	94[66.2]	35[92.1]	0.002
Age (Y)	39(34–46)	39(34–46)	0.733	33(29–37)	34(30–38)	0.440
T2DM (n [%])	3[1.9]	3[4.7]	0.497	1[0.7]	1[2.6]	0.379
BMI (kg/m^2)	22.58(20.89–24.61)	25.37(23.95–27.33)	<0.001	22.04(20.23–24.4)	25.43(24.22–27.8)	<0.001
HBP (n [%])	25[16.1]	26[40.6]	<0.001	17[12.0]	15[39.5]	<0.001
HBV DNA (log10 IU/mL)	4.27(3.05–5.4)	3.93(3.31–5.14)	0.671	7.47(5.99–8.23)	7.37(6.03–8.23)	0.864
AST (U/L)	27(22–34)	27(22–33)	0.920	32(25–47)	31(24–38)	0.461
ALT (U/L)	32(23–41)	38(27–48)	0.016	40(28–60)	49(34–81)	0.082
GGT (U/L)	24(18–36)	32(23–44)	0.002	26(18–39)	37(25–53)	0.002
ALP (U/L)	64(52–76)	74(62–88)	0.003	67(55–79)	70(62–86)	0.066
TBA (µmol/L)	3.7(2.1–9.1)	4.2(2.1–7.58)	0.922	4.5(2.6–10.6)	4.8(2.3–9.2)	0.446
CHE (U/L)	8731(7056–9969)	9388(8387–10,692)	0.001	7974(6827–9132)	9410(8688–10,480)	<0.001
FBG (mmol/L)	5.12(4.68–5.47)	5.25(4.93–6.28)	0.011	4.9(4.44–5.36)	4.95(4.59–5.92)	0.186
CREAT (µmol/L)	71(59–84)	78.5(70–90)	0.003	70.5(56.8–82)	78.8(71.7–84.5)	0.003
UA (µmol/L)	358(288–400)	403(343–472)	<0.001	360(301–401)	373(328–468)	0.027
TRIG (mmol/L)	1(0.8–1.35)	1.49(1.08–2.23)	<0.001	1.04(0.81–1.39)	1.53(1.07–2.11)	<0.001
HDL (mmol/L)	1.23(1.04–1.47)	1.08(0.93–1.25)	<0.001	1.28(1.08–1.56)	1.01(0.89–1.28)	<0.001
LDL (mmol/L)	3.12(2.63–3.76)	3.24(2.75–3.78)	0.581	3.12(2.69–3.74)	3.33(2.63–3.81)	0.488

Notes: All data are expressed as medians (interquartile range), or n [%], as appropriate; P-values <0.05 were considered statistically significant and have been bolded; Non-MAFLD-CHB, defined as patients who met the diagnostic criteria for CHB but did not meet the diagnostic criteria for MAFLD; MAFLD-CHB, defined as patients fulfilling the criteria for both MAFLD and CHB.

Abbreviations: CHB, chronic hepatitis B; MAFLD, metabolic associated fatty liver disease; HBeAg, hepatitis B e antigen; T2DM, type 2 diabetes mellitus; BMI, body mass index; HBP, high blood pressure; AST, serum aspartate aminotransferase; ALT, alanine aminotransferase; GGT, gamma-glutamyl transpeptidase; ALP, alkaline phosphatase; TBA, total bile acid; CHE, cholinesterase, FBG, fasting blood glucose; CREAT, creatinine; UA, uric acid; TRIG, triacylglycerol; HDL-c, high-density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol.

Table 2 Comparison of Pathological Characteristics of CHB with and without MAFLD, Stratified by HBeAg Status

	HBeAg-			HBeAg+
	Non-MAFLD-CHB (n=155)	MAFLD-CHB (n=64)	P	Non-MAFLD-CHB (n=142)	MAFLD-CHB (n=38)	P
NASH CRN
Steatosis			<0.001			<0.001
S0	149[96.1]	0[0.0]		135[95.1]	0[0.0]
S1	6[3.9]	53[82.8]		7[4.9]	30[78.9]
S23	0[0.0]	11[17.2]		0[0.0]	8[21.1]
Lobular inflammation			0.023			0.126
0	24[15.5]	3[4.7]		18[12.7]	1[2.6]
1	101[65.2]	39[60.9]		70[49.3]	19[50.0]
2	21[13.5]	14[21.9]		31[21.8]	13[34.2]
3	9[5.8]	8[12.5]		23[16.2]	5[13.2]
Ballooning			<0.001			<0.001
0	129[83.2]	20[31.3]		124[87.3]	15[39.5]
1	21[13.5]	39[60.9]		16[11.3]	19[50.0]
2	5[3.2]	5[7.8]		2[1.4]	4[10.5]
Activity score			<0.001			0.004
A≥3	16[10.3]	21[32.8]	<0.001	30[21.1]	17[44.7]	0.003
A≥4	6[3.9]	7[10.9]	0.089	5[3.5]	5[13.2]	0.057
Fibrosis stage			0.006			0.615
F0	16[10.3]	4[6.3]		15[10.6]	1[2.6]
F1	67[43.2]	19[29.7]		61[43.0]	16[42.1]
F2	28[18.1]	26[40.6]		33[23.2]	11[28.9]
F3	23[14.8]	11[17.2]		19[13.4]	6[15.8]
F4	21[13.5]	4[6.3]		14[9.9]	4[10.5]
F≥2	72[46.5]	41[64.1]	0.018	33[23.2]	10[26.3]	0.693
Scheuer
Activity grade			0.201			0.579
G01	85[54.8]	31[48.4]		56[39.4]	17[44.7]
G2	43[27.7]	23[35.9]		53[37.3]	13[34.2]
G3	13[8.4]	8[12.5]		22[15.5]	7[18.4]
G4	14[9.0]	2[3.1]		11[7.7]	1[2.6]
Fibrosis stage			0.538			0.276
S`0	16[10.3]	5[7.8]		16[11.3]	1[2.6]
S`1	30[19.4]	13[20.3]		33[23.2]	14[36.8]
S`2	67[43.2]	31[48.4]		60[42.3]	13[34.2]
S`3	21[13.5]	11[17.2]		19[13.4]	6[15.8]
S`4	21[13.5]	4[6.3]		14[9.9]	4[10.5]

Notes: All data are expressed as n [%]; P-values <0.05 were considered statistically significant and have been bolded; Non-MAFLD-CHB, defined as patients who met the diagnostic criteria for CHB but did not meet the diagnostic criteria for MAFLD; MAFLD-CHB, defined as patients fulfilling the criteria for both MAFLD and CHB.

Abbreviations: CHB, chronic hepatitis B; MAFLD, metabolic associated fatty liver disease; HBeAg, hepatitis B e antigen; NASH CRN, the Nonalcoholic Steatohepatitis Clinical Research Network.

Figure 1 Comparison of liver activity score and fibrosis stage distributions between MAFLD-CHB and non-MAFLD-CHB groups under the NASH CRN system, stratified by HBeAg status (A) Comparison of liver activity score distribution; (B) Comparison of liver fibrosis stage distribution; (C) Comparison of proportion of A ≥3; (D) Comparison of proportion of F ≥2; MAFLD-CHB, defined as patients fulfilling the criteria for both MAFLD and CHB; Non-MAFLD-CHB, defined as patients who met the diagnostic criteria for CHB but did not meet the diagnostic criteria for MAFLD.

Abbreviations: MAFLD, metabolic associated fatty liver disease; CHB, chronic hepatitis B; NASH CRN, the Nonalcoholic Steatohepatitis Clinical Research Network; HBeAg, hepatitis B e antigen; A, liver activity score; F, fibrosis stages; *p < 0.05, **p < 0.01, and ***p < 0.001.

Table 3 Univariate Analysis of Factors Associated with Moderate-to-Severe Liver Activity (A ≥3) and Significant Fibrosis (F ≥2) in Patients with CHB

Variates	Moderate-to-Severe Liver Activity (A ≥3)		Significant Fibrosis (F ≥2)
	OR (95% CI)	P	OR (95% CI)	P
Male	0.63 (0.35–1.12)	0.115	1.68 (1.07–2.63)	0.023
Age	0.99 (0.96–1.02)	0.391	1.00 (0.98–1.03)	0.802
MAFLD	3.24 (1.95–5.39)	<0.001	1.84 (1.19–2.87)	0.007
T2DM	0.53 (0.06–4.37)	0.555	3.05 (0.61–15.28)	0.176
BMI≥23 kg/m^2	1.87 (1.13–3.09)	0.015	1.24 (0.83–1.83)	0.293
HBP	1.05 (0.58–1.89)	0.873	0.91 (0.56–1.47)	0.692
Hypertriglyceridemia	0.98 (0.54–1.78)	0.936	0.83 (0.51–1.34)	0.442
Low HDL cholesterolemia	1.29 (0.79–2.13)	0.309	1.04 (0.69–1.57)	0.862
Prediabetes	1.76 (1.02–3.03)	0.043	1.34 (0.83–2.16)	0.234
HBV DNA quantitative >6 log10 IU/mL	2.31 (1.42–3.76)	<0.001	0.72 (0.48–1.08)	0.114
HBeAg (+)	1.74 (1.07–2.82)	0.026	0.88 (0.59–1.30)	0.516

Notes: Data were expressed as odds ratios (OR) and 95% confidence interval (CI); P-values <0.15 were considered statistically significant and have been bolded; Variables with P <0.15 in the univariate analysis were included in the multivariate analysis; All variables of variance inflation factor (VIF: 1.037–2.018) were less than 5–10; Hypertriglyceridemia, triacylglycerol (TRIG) ≥1.70 mmol/L; Low HDL cholesterolemia, HDL-c < 1.0 mmol/L for males and < 1.3 mmol/L for females.

Abbreviations: CHB, chronic hepatitis B; OR, odds ratio; MAFLD, metabolic associated fatty liver disease; T2DM, type 2 diabetes mellitus; BMI, Body mass index; HBP, high blood pressure; HBeAg, hepatitis B e antigen; VIF, variance inflation factor; TRIG, triacylglycerol; HDL-c, high-density lipoprotein cholesterol.

Table 4 Multivariate Analysis of Factors Associated with Moderate-to-Severe Liver Activity (A≥3) in Patients with CHB and Stratified by HBeAg Status

Variates	Total		HBeAg (-)		HBeAg (+)
	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	P^a
HBeAg(+)	1.18 (0.58–2.41)	0.656
Male	1.19 (0.63–2.24)	0.597	0.79 (0.31–2.04)	0.631	1.53 (0.64–3.65)	0.339	0.311
HBV DNA quantitative >6 log10 IU/mL	2.40 (1.18–4.88)	0.015	4.44 (1.49–13.19)	0.007	1.59 (0.68–3.72)	0.280	0.146
BMI≥23 kg/m^2	1.23 (0.69–2.21)	0.489	1.25 (0.52–3.00)	0.612	1.26 (0.56–2.81)	0.581	0.990
Prediabetes	1.58 (0.88–2.84)	0.128	2.33 (1.04–5.25)	0.041	0.99 (0.4–2.44)	0.987	0.167
MAFLD	3.06 (1.69–5.54)	<0.001	3.97 (1.71–9.22)	0.001	2.44 (1.03–5.79)	0.044	0.429
Constant	0.08	<0.001	0.08	<0.001	0.13	<0.001

Notes: Data were expressed as odds ratios (OR) and 95% confidence interval (CI); All variables of variance inflation factor (VIF: 1.054–1.903) were less than 5–10; ^aP-values for difference in associations among HBeAg positive and HBeAg negative were calculated with 2-sample t-tests based on the estimated changes and standard errors; P-values <0.05 were considered statistically significant and have been bolded.

Abbreviations: CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; OR, odds ratio; MAFLD, metabolic associated fatty liver disease; BMI, Body mass index; VIF, variance inflation factor.

Table 5 Multivariate Analysis of Factors Associated with Significant Fibrosis (F≥2) in Patients with CHB and Stratified by HBeAg Status

Variates	Total		HBeAg (-)		HBeAg (+)
	OR (95% CI)	P	OR (95% CI)	P	OR (95% CI)	P	P^a
HBeAg(+)	1.22 (0.7–2.12)	0.482
Male	1.49 (0.94–2.36)	0.093	1.13 (0.60–2.12)	0.698	2.13 (1.04–4.36)	0.038	0.194
HBV DNA quantitative >6 log10 IU/mL	0.66 (0.37–1.15)	0.143	2.91 (1.00–8.49)	0.051	0.31 (0.15–0.64)	0.002	0.001
MAFLD	1.64 (1.02–2.63)	0.040	2.02 (1.09–3.73)	0.026	1.22 (0.57–2.61)	0.618	0.313
Constant	0.72	0.134	0.73	0.260	1.28	0.566

Notes: Data were expressed as odds ratios (OR) and 95% confidence interval (CI); All variables of variance inflation factor (VIF: 1.054–1.885) were less than 5–10; ^aP-values for difference in associations among HBeAg positive and HBeAg negative were calculated with 2-sample t-tests based on the estimated changes and standard errors; P-values <0.05 were considered statistically significant and have been bolded.

Abbreviations: CHB, chronic hepatitis B; HBeAg, hepatitis B e antigen; OR, odds ratio; MAFLD, metabolic associated fatty liver disease; VIF, variance inflation factor.