Chronic hepatitis B with type 2 diabetes mellitus: Association between glycemic control and liver fibrosis

Table 1 General clinical data of patients with chronic hepatitis B combined with type 2 diabetes mellitus, n (%)

Variable		Classifications	Cases	mean ± SD/mean (Q1-Q3)
Age (years)		18-44	59 (14.0)	54 (48, 62)
		45-59	230 (54.8)
		60-74	117 (27.9)
		75-89	14 (3.3)
Number of days of hospitalization (days)				17 (12-24)
FIB-4				1.04 (0.58-2.04)
ALT (U/L)				40 (26-65)
AST (U/L)				40 (29-57)
ALP (U/L)				100 (77-144)
GGT (U/L)				64 (30.5-115.5)
S/L				1 (0.7-1.4)
TP (g/L)				67.63 ± 8.28
ALB (g/L)				37.27 ± 6.62
Glo (g/L)				29.9 (26.8-34)
A/G				1.25 (1.03-1.5)
TBIL (μmol/L)				16 (9.8-27.65)
Bc-Tr (μmol/L)				1.59 (0.82-4.17)
Fer (ng/mL)				222 (94-447)
NEFA (mmol/L)				0.52 (0.36-0.7)
PIIIP (ng/mL)				56.25 (15.97-148.53)
CG (μg/mL)				4.75 (1.78-15.72)
CIV (ng/mL)				49.11 (22.28-113.97)
LN (ng/mL)				87.95 (58.37-125.66)
HA (ng/mL)				118.03 (75.56-260.73)
FBG (g/L)				2.3 (1.85-2.81)
PT (s)				13.4 (12.4-14.6)
Pa (%)				79.3 (67-90.5)
PT-INR				1.12 (1.04-1.25)
APTT (seconds)				30.1 (27.2-34.35)
TT (seconds)				17.6 (16.6-18.95)
Admission glucose status	HbA1c (%)	Favorable	155 (36.9)	7.3 (6.2-9)
		Normal	92 (21.9)
	Admission FPG (mmol/L)	Poor	168 (40.0)	7.57 (6.32-10.19)
		Defective	5 (1.2)
BMI (kg/m2)		Thin (BMI < 18.5 kg/m2)	11 (2.6)	24.13 ± 3.5
		Normal (18.5-24 kg/m2)	187 (44.5)
		Overweight (24-28 kg/m2)	160 (38.1)
		Obese (BMI ≥ 28 kg/m2)	47 (11.2)
		Defective	15 (3.6)
Duration of diabetes mellitus (years)				2 (0.01-6)
Duration of liver disease (years)				7 (0.5-20)
LSM (kPa)		Liver fibrosis exclusion group	27 (6.4)	16.6 (9.13-26.98)
		Liver fibrosis group	121 (28.8)
		Cirrhosis group	272 (64.8)
Discharge FPG (mmol/L)		Standard	224 (53.3)	6.42 (5.47-8)
		Non standard	146 (34.8)
		Not examined	50 (11.9)
Ethnicity		The Han nationality	407 (96.9)
		Tibetan nationality	12 (2.9)
		Yi nationality	1 (0.2)
Smoking history		Chronic smoking	148 (35.2)
		Occasional smoker	16 (3.8)
		Quit smoking	54 (12.9)
		Never smoked	202 (48.1)
Drinking history		Drinking alcohol for a long time	76 (18.1)
		Occasional drinker	62 (14.8)
		Quit drinking	68 (16.2)
		Never drank alcohol	214 (51)
Gender		Female	99 (23.6)
		Male	321 (76.4)
Diabetes treatment program		Insulin	172 (41)
		Drugs	71 (16.9)
		Insulin + drugs	34 (8.1)
		Untreated	143 (34)

FIB-4: Fibrosis 4 score; ALT: Alanine aminotransferase; AST: Aspartate transaminase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; S/L: Aspartate transaminase/alanine aminotransferase ratio; TP: Total protein; ALB: Albumin; Glo: Globulin; A/G: Albumin/globulin; TBIL: Total bilirubin; Bc-Tr: True conjugated bilirubin; Fer: Ferritin; NEFA: Nonestesterified fatty acid; PIIIP: Procollagen III peptide; CG: Cholyglycine; CIV: Collage type IV; LN: Laminin; HA: Hyaluronic acid; FBG: Fibrinogen; PT: Prothrombin time; Pa: Prothrombin activation; PT-INR: Prothrombin time-international normalized ratio; APTT: Activated partial thromboplastin time; TT: Thrombin time; HbA1c: Glycated hemoglobin A1c; FPG: Fasting plasma glucose; BMI: Body mass index; LSM: Liver stiffness measurement.

Table 2 Comparison between groups in various stages of liver fibrosis, n (%)

Variable		Excluded liver fibrosis group	Hepatic fibrosis group	Cirrhosis group	F/H/χ2	P value
TP (g/L)		65.96 ± 8.33	66.87 ± 7.8	68.14 ± 8.46	1.555	0.212
ALB (g/L)		35.46 ± 6.35	37.1 ± 5.78	37.53 ± 6.97	1.248	0.288
BMI (kg/m2)		23.72 ± 3.44	24.33 ± 3.98	24.07 ± 3.28	0.392	0.676
Age (years)		55 (50, 63)	54 (48, 62)	54.5 (48, 62.75)	0.173	0.917
Days of hospitalization (days)		15 (10, 21)	17 (12.5, 26)	17 (11.25, 23)	2.067	0.356
FIB-4		1.49 (0.7, 2.71)	1.12 (0.62, 2.48)	1 (0.52, 1.96)	5.097	0.078
ALT (U/L)		12 (10, 42)	23 (18.5, 50)	47.5 (29.75, 79)	70.894	< 0.001
AST (U/L)		29 (19, 39)	32 (23.5, 50.5)	43.5 (33, 64)	40.724	< 0.001
ALP (U/L)		108 (82, 130)	89 (71, 114.5)	104 (80, 149)	10.275	0.006
GGT (U/L)		65 (30, 97)	53 (26, 118)	66 (33, 121)	1.906	0.386
S/L		1.5 (0.9, 2.4)	1.2 (0.9, 1.55)	0.9 (0.7, 1.3)	26.964	< 0.001
Glo (g/L)		29.3 (25.5, 34.4)	29.2 (26.35, 33.05)	30.4 (27.2, 34.1)	3.613	0.164
A/G		1.29 (1.02, 1.47)	1.26 (1.02, 1.51)	1.23 (1.03, 1.5)	0.27	0.872
TBIL (μmol/L)		10.4 (7, 19.4)	14.5 (9.1, 28.35)	16.7 (10.53, 28.8)	8.975	0.011
Bc-Tr (μmol/L)		0.87 (0.38, 1.9)	1.52 (0.75, 3.28)	1.67 (0.95, 4.73)	10.182	0.006
Fer (ng/mL)		110 (29, 479.3)	196.5 (65.75, 415.75)	230.5 (119, 468.43)	5.686	0.058
NEFA (mmol/L)		0.59 (0.39, 0.7)	0.48 (0.3, 0.67)	0.54 (0.38, 0.72)	4.379	0.112
PIIIP (ng/mL)		61.8 (6.45, 142.33)	64.48 (13.1, 157.77)	52.9 (18.1, 146.41)	0.708	0.702
CG (μg/mL)		2.54 (1.39, 11.39)	4.47 (1.7, 21.19)	4.99 (1.83, 14.84)	1.249	0.535
CIV (ng/mL)		46.47 (29.1, 84.15)	53.12 (18.62, 115.61)	48.89 (22.64, 114.62)	0.039	0.981
LN (ng/mL)		79.15 (56.39, 152.71)	91.78 (61.28, 125.74)	86.91 (57.66, 123.61)	0.537	0.765
HA (ng/mL)		104.85 (81.46, 286.29)	117.28 (73.01, 264.51)	123.05 (73.25, 250.3)	0.246	0.884
FBG (g/L)		2.64 (1.9, 3.44)	2.32 (1.88, 2.76)	2.29 (1.83, 2.81)	3.242	0.198
PT (seconds)		13.1 (12.1, 15)	13.5 (12.6, 14.3)	13.4 (12.4, 14.7)	0.280	0.869
Pa (%)		79.1 (64.2, 97.2)	78 (67.4, 89.2)	80.3 (65.8, 91)	0.019	0.991
PT-INR		1.06 (1.02, 1.27)	1.12 (1.03,1.24)	1.12 (1.05, 1.25)	1.477	0.478
APTT (seconds)		30 (26.8, 40.5)	30.1 (27.1, 34.3)	30.2 (27.3, 33.9)	0.545	0.762
TT (seconds)		17 (15.6, 18.3)	17.7 (16.7, 18.8)	17.7 (16.6, 19)	6.327	0.042
HbA1c (%)		6.7 (6.6, 8.5)	7.3 (6.1, 9.5)	7.3 (6.2, 9)	0.162	0.922
Duration of diabetes mellitus (years)		2 (0.42, 7)	2 (0.05, 7.5)	2 (0.01, 6)	0.857	0.651
Duration of liver disease (years)		6 (0.08, 11)	8 (1, 20)	7 (0.44, 20)	1.214	0.545
Admission FPG (mmol/L)		6.81 (6.3, 9.9)	7.62 (6.28, 9.37)	7.63 (6.33, 10.62)	1.121	0.571
Discharge FPG (mmol/L)		6.11 (5.44, 7.47)	6.58 (5.76, 7.96)	6.42 (5.36, 8.29)	0.727	0.695
Ethnicity	The Han nationality	26 (96.3)	118 (97.5)	263 (96.7)	4.322	0.386
	Tibetan nationality	1 (3.7)	2 (1.7)	9 (3.3)
	Yi nationality		1 (0.8)
Smoking history	Chronic smoking	10 (37.0)	34 (28.1)	104 (38.2)	5.035	0.516
	Occasional smoker		6 (5.0)	10 (3.7)
	Quit smoking	3 (11.1)	19 (15.7)	32 (11.8)
	Never smoked	14 (51.9)	62 (51.2)	126 (46.3)
Drinking history	Drinking alcohol for a long time	3 (11.1)	17 (14.0)	56 (20.6)	7.467	0.272
	Occasional drinker	2 (7.4)	17 (14.0)	43 (15.8)
	Quit drinking	8 (29.6)	21 (17.4)	39 (14.3)
	Never drank alcohol	14 (51.9)	66 (54.5)	134 (49.3)
Gender	Female	8 (29.6)	31 (25.6)	60 (22.1)	1.177	0.587
	Male	19 (70.4)	90 (74.4)	212 (77.9)
Diabetes treatment program	Insulin	9 (33.3)	36 (29.8)	127 (46.7)	13.892	0.026
	Drugs	3 (11.1)	26 (21.5)	42 (15.4)
	Insulin + drugs	1 (3.7)	12 (9.9)	21 (7.7)
	Untreated	14 (51.9)	47 (38.8)	82 (30.1)

TP: Total protein; ALB: Albumin; BMI: Body mass index; FIB-4: Fibrosis 4 score; ALT: Alanine aminotransferase; AST: Aspartate transaminase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; S/L: Aspartate transaminase/alanine aminotransferase ratio; Glo: Globulin; A/G: Albumin/globulin; TBIL: Total bilirubin; Bc-Tr: True conjugated bilirubin; Fer: Ferritin; NEFA: Nonestesterified fatty acid; PIIIP: Procollagen III peptide; CG: Cholyglycine; CIV: Collage type IV; LN: Laminin; HA: Hyaluronic acid; FBG: Fibrinogen; PT: Prothrombin time; Pa: Prothrombin activation; PT-INR: Prothrombin time-international normalized ratio; APTT: Activated partial thromboplastin time; TT: Thrombin time; HbA1c: Glycated hemoglobin A1c; FPG: Fasting plasma glucose.

Table 3 Comparison of liver-related characteristics of patients with different admission glycemic states

Variable	Good glucose control group	Normal blood glucose group	Poor glycemic control group	F/H/χ2	P value
TP (g/L)	67.44 ± 7.09	68.9 ± 7.47	67.35 ± 8.05	1.403	0.247
ALB (g/L)	37.31 ± 6.17	38.29 ± 6.25	36.28 ± 6.39	3.127	0.045
FIB-4	1.49 (0.7, 2.71)	1.12 (0.62, 2.48)	1 (0.52, 1.96)	0.534	0.766
ALT (U/L)	12 (10, 42)	23 (18.5, 50)	47.5 (29.75, 79)	1.098	0.577
AST (U/L)	29 (19, 39)	32 (23.5, 50.5)	43.5 (33, 64)	2.419	0.298
ALP (U/L)	108 (82, 130)	89 (71, 114.5)	104 (80, 149)	5.128	0.077
GGT (U/L)	65 (30, 97)	53 (26, 118)	66 (33, 121)	6.439	0.040
S/L	1.5 (0.9, 2.4)	1.2 (0.9, 1.55)	0.9 (0.7, 1.3)	5.337	0.069
Glo (g/L)	29.3 (25.5, 34.4)	29.2 (26.35, 33.05)	30.4 (27.2, 34.1)	0.910	0.635
A/G	1.29 (1.02, 1.47)	1.26 (1.02, 1.51)	1.23 (1.03, 1.5)	2.672	0.263
TBIL (μmol/L)	10.4 (7, 19.4)	14.5 (9.1, 28.35)	16.7 (10.53, 28.8)	0.740	0.691
Bc-Tr (μmol/L)	0.87 (0.38, 1.9)	1.52 (0.75, 3.28)	1.67 (0.95, 4.73)	2.249	0.325
Fer (ng/mL)	110 (29, 479.3)	196.5 (65.75, 415.75)	230.5 (119, 468.43)	5.556	0.062
NEFA (mmol/L)	0.59 (0.39, 0.7)	0.48 (0.3, 0.67)	0.54 (0.38, 0.72)	3.798	0.150
PIIIP (ng/mL)	61.8 (6.45, 142.33)	64.48 (13.1, 157.77)	52.9 (18.1, 146.41)	1.725	0.422
CG (μg/mL)	2.54 (1.39, 11.39)	4.47 (1.7, 21.19)	4.99 (1.83, 14.84)	1.692	0.429
CIV (ng/mL)	46.47 (29.1, 84.15)	53.12 (18.62, 115.61)	48.89 (22.64, 114.62)	0.844	0.656
LN (ng/mL)	79.15 (56.39, 152.71)	91.78 (61.28, 125.74)	86.91 (57.66, 123.61)	1.037	0.595
HA (ng/mL)	104.85 (81.46, 286.29)	117.28 (73.01, 264.51)	123.05 (73.25, 250.3)	2.197	0.333
FBG (g/L)	2.64 (1.9, 3.44)	2.32 (1.88, 2.76)	2.29 (1.83, 2.81)	0.817	0.665
PT (seconds)	13.1 (12.1, 15)	13.5 (12.6, 14.3)	13.4 (12.4, 14.7)	2.433	0.296
Pa (%)	79.1 (64.2, 97.2)	78 (67.4, 89.2)	80.3 (65.8, 91)	2.440	0.295
PT-INR	1.06 (1.02, 1.27)	1.12 (1.03, 1.24)	1.12 (1.05, 1.25)	3.747	0.154
APTT (seconds)	30 (26.8, 40.5)	30.1 (27.1, 34.3)	30.2 (27.3, 33.9)	0.339	0.844
TT (seconds)	17 (15.6, 18.3)	17.7 (16.7, 18.8)	17.7 (16.6, 19)	2.271	0.321
LSM (kPa)	5.3 (4.8, 5.6)	8.3 (7.35, 9.95)	23.35 (16.95, 36.2)	0.147	0.929

TP: Total protein; ALB: Albumin; FIB-4: Fibrosis 4 score; ALT: Alanine aminotransferase; AST: Aspartate transaminase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; S/L: Aspartate transaminase/alanine aminotransferase ratio; Glo: Globulin; A/G: Albumin/globulin; TBIL: Total bilirubin; Bc-Tr: True conjugated bilirubin; Fer: Ferritin; NEFA: Nonestesterified fatty acid; PIIIP: Procollagen III peptide; CG: Cholyglycine; CIV: Collage type IV; LN: Laminin; HA: Hyaluronic acid; FBG: Fibrinogen; PT: Prothrombin time; Pa: Prothrombin activation; PT-INR: Prothrombin time-international normalized ratio; APTT: Activated partial thromboplastin time; TT: Thrombin time; LSM: Liver stiffness measurement.

Table 4 Generalized linear regression model for liver-related indicators and diabetes mellitus indicators

Model I1	HbA1c			Admission FPG			Discharge FPG
	B2	Wald χ2	P value	B2	Wald χ2	P value	B2	Wald χ2	P value
FIB-4	-0.006	0.002	0.967	0.001	4.056	0.044	-0.230	2.285	0.131
ALT	0.010	3.535	0.060	< 0	1.325	0.250	-0.005	1.160	0.281
AST	-0.015	3.762	0.052	> 0	0.238	0.626	0.017	4.807	0.028
ALP	-0.002	0.286	0.593	> 0	0.016	0.900	0.001	0.089	0.765
GGT	0.002	1.031	0.310	> 0	0.359	0.549	< 0	0.007	0.935
S/L	-0.049	0.019	0.889	-0.002	2.571	0.109	-0.229	0.299	0.584
TP	-10.462	0.924	0.336	-0.001	0.179	0.672	0.195	0.116	0.733
ALB	10.416	0.916	0.339	0.001	0.236	0.627	-0.254	0.153	0.696
Glo	10.511	0.933	0.334	0.001	0.144	0.704	-0.159	0.108	0.743
A/G	0.459	0.063	0.801	-0.003	0.196	0.658	0.773	0.115	0.735
TBIL	-0.012	1.157	0.282	< 0	0.516	0.473	0.003	0.118	0.731
Bc-Tr	0.021	0.913	0.339	> 0	1.423	0.233	-0.014	0.888	0.346
Fer	< 0	0.015	0.902	> 0	5.516	0.019	> 0	0.007	0.935
NEFA	0.908	2.279	0.131	> 0	0.348	0.556	-0.017	0.208	0.648
PIIIP	< 0	0.146	0.703	> 0	3.953	0.047	-0.002	3.208	0.073
CG	-0.001	0.011	0.916	< 0	2.509	0.113	-0.014	0.600	0.439
CIV	-0.001	1.301	0.254	< 0	0.345	0.557	0.001	0.644	0.422
LN	0.001	0.125	0.724	< 0	0.024	0.876	-0.003	0.894	0.344
HA	0.001	1.003	0.317	> 0	0.291	0.590	0.001	0.609	0.435
FBG	0.590	6.540	0.011	> 0	0.690	0.406	0.085	0.690	0.406
PT	-0.502	3.504	0.061	-0.002	3.454	0.063	0.563	4.491	0.034
Pa	-0.019	1.436	0.231	< 0	1.049	0.306	0.036	4.431	0.035
PT-INR	4.709	5.712	0.017	0.018	3.758	0.053	-4.251	3.306	0.069
APTT	-0.034	0.694	0.405	< 0	2.603	0.107	0.061	1.736	0.188
TT	0.096	0.641	0.423	> 0	0.361	0.548	0.104	0.766	0.381
LSM	-0.002	0.057	0.811	< 0	0.722	0.395	0.002	0.029	0.865
Model II3
FIB-4	-0.023	0.024	0.876	0.001	4.595	0.032	-0.250	2.437	0.119
ALT	0.009	2.597	0.107	< 0	3.959	0.047	-0.003	0.427	0.514
AST	-0.015	3.143	0.076	> 0	0.234	0.629	0.016	4.109	0.043
ALP	-0.002	0.326	0.568	< 0	0.025	0.873	0.002	0.334	0.563
GGT	0.001	0.894	0.344	> 0	0.379	0.538	> 0	0.005	0.945
S/L	-0.184	0.258	0.612	-0.003	4.536	0.033	-0.214	0.259	0.611
TP	-12.240	1.257	0.262	-0.002	1.045	0.307	0.025	0.001	0.969
ALB	12.243	1.258	0.262	0.002	1.093	0.296	-0.036	0.002	0.961
Glo	12.229	1.256	0.262	0.002	0.991	0.319	-0.046	0.007	0.933
A/G	-0.862	0.155	0.694	-0.008	1.071	0.301	0.078	0.001	0.976
TBIL	-0.007	0.342	0.559	< 0	0.138	0.711	< 0	0.000	0.994
Bc-Tr	0.012	0.273	0.602	> 0	0.864	0.353	-0.008	0.117	0.732
Fer	< 0	0.099	0.752	> 0	4.091	0.043	> 0	0.199	0.656
NEFA	0.986	2.448	0.118	> 0	0.397	0.529	-0.020	0.312	0.576
PIIIP	< 0	0.022	0.883	> 0	4.719	0.030	-0.002	3.487	0.062
CG	-0.003	0.035	0.851	< 0	3.592	0.058	-0.022	1.319	0.251
CIV	-0.001	1.120	0.290	< 0	0.742	0.389	0.002	1.585	0.208
LN	0.003	0.766	0.382	< 0	0.031	0.859	< 0	0.011	0.915
HA	> 0	0.144	0.704	< 0	0.015	0.902	0.002	1.954	0.162
FBG	0.618	6.920	0.009	> 0	0.650	0.420	0.121	1.407	0.236
PT	-0.513	3.180	0.075	-0.002	1.861	0.172	0.277	0.793	0.373
Pa	-0.018	1.107	0.293	< 0	0.346	0.556	0.021	1.234	0.267
PT-INR	4.871	5.484	0.019	0.018	3.213	0.073	-2.868	1.303	0.254
APTT	-0.041	0.880	0.348	< 0	4.926	0.026	0.077	2.621	0.105
TT	0.110	0.782	0.376	> 0	0.486	0.486	0.162	1.518	0.218
LSM	-0.002	0.026	0.871	< 0	0.400	0.527	0.002	0.028	0.866

¹Non-adjusted model.

²β > 0 indicates a positive correlation between the independent and dependent variables, while β < 0 indicates a negative correlation.

³Adjusted for age, sex, ethnicity, smoking history, alcohol consumption history and body mass index model.

HbA1c: Glycated hemoglobin A1c; FPG: Fasting plasma glucose; FIB-4: Fibrosis 4 score; ALT: Alanine aminotransferase; AST: Aspartate transaminase; ALP: Alkaline phosphatase; GGT: Gamma-glutamyl transferase; S/L: Aspartate transaminase/alanine aminotransferase ratio; TP: Total protein; ALB: Albumin; Glo: Globulin; A/G: Albumin/globulin; TBIL: Total bilirubin; Bc-Tr: True conjugated bilirubin; Fer: Ferritin; NEFA: Nonestesterified fatty acid; PIIIP: Procollagen III peptide; CG: Cholyglycine; CIV: Collage type IV; LN: Laminin; HA: Hyaluronic acid; FBG: Fibrinogen; PT: Prothrombin time; Pa: Prothrombin activation; PT-INR: Prothrombin time-international normalized ratio; APTT: Activated partial thromboplastin time; TT: Thrombin time; LSM: Liver stiffness measurement.