Ceruloplasmin, a reliable marker of fibrosis in chronic hepatitis B virus patients with normal or minimally raised alanine aminotransferase

Table 1 Demographic, biological, and histological features for the training and validation groups

Variable	All (n = 193)	Training group (n = 97)	Validation group (n = 96)	P value
Age, in yr	39.11 ± 9.31	38.70 ± 9.46	39.52 ± 9.18	0.542
Sex, n (%)				0.601
Male	138 (71.5)	71 (73.2)	67 (69.8)
Female	55 (28.5)	26 (26.8)	29 (30.2)
Total bilirubin, in μmol/L	12.3 (8.7-18.2)	11.4 (8.6-16.9)	12.9 (8.8-18.8)	0.352
Albumin, in g/L	42.21 ± 4.16	42.46 ± 3.91	41.94 ± 4.41	0.387
Globulin, in g/L	27.25 ± 4.36	27.54 ± 4.84	26.95 ± 3.81	0.345
ALT, in IU/L	37 (27-51)	35 (26.0-48.5)	38.5 (28-52)	0.378
AST, in IU/L	30 (25.0-37.5)	30 (26-38)	29 (25-37)	0.806
GGT, in IU/L	27 (18.0-40.5)	25 (18-38)	27 (19-43)	0.577
TBA, in mmol/L	5.9 (3.85-12.05)	6.5 (4.10-15.25)	5.45 (3.73-9.83)	0.146
ALP, in IU/L	69 (57.5-82.5)	69 (58.0-83.5)	68.5 (57.0-81.8)	0.990
CHE, in IU/L	8407.62 ± 2722.19	8393.56 ± 2423.51	8421.83 ± 3006.82	0.943
AFP, in ng/mL	3.25 (2.19-6.32)	3.30 (2.30-6.70)	3.20 (2.03-5.08)	0.377
PT, in s	12.4 (11.9-13.1)	12.4 (11.95-13.15)	12.3 (11.80-12.97)	0.061
INR	1.03 (0.98-1.09)	1.03 (0.99-1.10)	1.03 (0.98-1.08)	0.553
HBsAg levels, in log IU/mL	3.49 (3.12-3.97)	3.46 (3.08-3.90)	3.52 (3.16-4.03)	0.501
HBV DNA levels, in logIU/mL	5.27 ± 1.70	5.30 ± 1.67	5.24 ± 1.74	0.791
WBC, in 109/L	5.63 ± 1.49	5.66 ± 1.54	5.59 ± 1.44	0.723
PLT, in 109/L	179 (144.5-214.5)	179 (153.5-214.5)	177 (128.0-214.8)	0.208
CP, in mg/L	195.67 ± 35.62	196.86 ± 35.45	196.86 ± 35.45	0.643
Stage of fibrosis, n (%)				0.164
F1	76 (39.38)	42 (43.30)	34 (35.42)
F2	44 (22.80)	23 (23.71)	21 (21.88)
F3	42 (21.76)	18 (18.56)	24 (25.00)
F4	31 (16.06)	14 (14.43)	17 (17.70)

AFP: α-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CHE: Cholinesterase; CP: Ceruloplasmin; GGT: Gamma glutamyl transpeptidase; HBV: Hepatitis B virus; PLT: Platelet count; PT: Prothrombin time; TBA: Total bile acid; WBC: White blood cell count.

Table 2 Serum ceruloplasmin levels distinguish different stages of fibrosis as measured by area under the curve values (n = 97)

Fibrosis stages	AUC (95%CI)	Cut-off point	Sensitivity	Specificity	PPV	NPV
F ≥ 2	0.776 (0.711-0.841)	≤ 194	86.84%	58.98%	28.83%	95.91%
F = 4	0.767 (0.691-0.843)	≤ 186	54.32%	90.33%	51.80%	91.18%

AUC: Area under the receiver operator characteristic curve; NPV: Negative predictive value; PPV: Positive predictive value.

Table 3 Variables associated with the presence of cirrhosis (F4) in the training group

Variable	≤F3	≥F4	P value
Age, in yr	38.9 ± 8.9	37.6 ± 12.6	0.632
Male sex, in %	70.37%	77.41%	0.255
TB, in μmol/L	11.1 (8.6-17.5)	13.5 (10.1-15.8)	0.429
Albumin, in g/L	42.8 ± 3.7	40.5 ± 4.5	0.039
Globulin, in g/L	27.4 ± 5.1	28.2 ± 3.2	0.590
ALT, in IU/L	34 (26-46)	44.5 (24.3-56.8)	0.281
AST, in IU/L	29 (24-37)	32.5 (29.5-44.0)	0.064
ALP, in IU/L	69 (58-83)	70 (61-93)	0.528
GGT, in IU/L	24 (17-34)	55 (33.5-79.3)	< 0.001
TBA, in mmol/L	6.3 (4.1-14.6)	9.8 (4.7-20.6)	0.216
CHE, in IU/L	8669.1 ± 2421.8	6760.2 ± 1737.5	0.006
PT, in s	12.4 (11.9-12.9)	13.5 (12.4-14.5)	0.011
INR	1.03 (0.98-1.08)	1.12 (1.02-1.20)	0.019
WBC, in 109/L	5.69 ± 1.54	5.49 ± 1.60	0.649
PLT, in 109/L	183 (163-218)	155 (131-175)	0.002
AFP, in ng/mL	2.9 (2.1-5.0)	10.75 (5.10-28.45)	< 0.001
HBsAg levels, in logIU/mL	3.44 (3.05-4.0)	3.49 (3.39-3.67)	0.910
HBV DNA levels, in logIU/mL	5.26 ± 1.69	5.57 ± 1.56	0.515
CP, in mg/L	201.9 ± 34.6	167.0 ± 24.9	< 0.001

AFP: α-fetoprotein; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; CHE: Cholinesterase; CP: Ceruloplasmin; GGT: Gamma glutamyl transpeptidase; HBV: Hepatitis B virus; PLT: Platelet count; PT: Prothrombin time; TBA: Total bile acid; WBC: White blood cell count.

Table 4 Summary of CG model validity in training and validation groups

Variable	Training group (n = 97)		Validation group (n = 96)
	F = 4	F ≥ 2	F = 4	F ≥ 2
AUC	0.84	0.797	0.792	0.778
Sensitivity	83.10%	83.30%	74.70%	79.40%
Specificity	78.60%	67.30%	88.20%	67.70%
PPV	39.60%	76.94%	57.70%	76.29%
NPV	96.50%	75.48%	94.20%	71.51%

AUC: Area under the receiver operating characteristic curve; NPV: Negative predictive value; PPV: Positive predictive value.

Table 5 Validity of APRI, FIB-4, PPT, and APPCI models for prediction of cirrhosis, and comparison with the CG model (n = 193)

Model	AUC (95%CI)	Youden’s index	Sensitivity	Specificity	PPV	NPV	Z value	P value
CG	0.812 (0.740-0.883)	0.567	72.84%	83.88%	46.37%	94.17%	-	-
FIB-4	0.679 (0.581-0.777)	0.318	52.23%	80.65%	34.06%	89.82%	2.138	0.0331
APRI	0.775 (0.698-0.852)	0.416	64.20%	77.43%	34.52%	91.46%	0.688	0.491
PPT	0.777 (0.671-0.883)	0.512	80.25%	70.97%	34.59%	94.94%	0.535	0.593
APPCI	0.859 (0.789-0.929)	0.592	75.31%	83.89%	47.21%	94.67%	-0.910	0.363
GP	0.742 (0.647-0.838)	0.420	70.99%	70.97%	31.87%	92.75%	1.140	0.254

¹Indicates significant differences compared with the CG model. AUC: Area under the receiver operating characteristic curve; NPV: Negative predictive value; PPV: Positive predictive value.

Table 6 Validity of APRI, FIB-4, PPT, and APPCI models for prediction of minimal fibrosis (F0-F1), and comparison with the CG model (n = 193)

Model	AUC (95%CI)	Youden’s index	Sensitivity	Specificity	PPV	NPV	Z value	P value
CG	0.789 (0.727-0.852)	0.486	80.26%	68.38%	62.25%	84.21%	-	-
FIB-4	0.671 (0.595-0.747)	0.271	72.37%	54.69%	50.92%	75.29%	2.339	0.0191
APRI	0.736 (0.666-0.805)	0.354	78.95%	56.42%	54.06%	80.49%	1.100	0.271
PPT	0.741 (0.672-0.810)	0.380	64.47%	73.51%	61.26%	76.10%	1.012	0.312
APPCI	0.818 (0.760-0.877)	0.544	89.47%	64.96%	62.39%	90.47%	-0.661	0.509
GP	0.675 (0.601-0.749)	0.325	82.89%	49.58%	51.64%	81.69%	2.295	0.0221

¹Indicates significant differences compared with the CG model. AUC: Area under the receiver operating characteristic curve; NPV: Negative predictive value; PPV: Positive predictive value.