Serum ceruloplasmin can predict liver fibrosis in hepatitis B virus-infected patients

Table 1 Demographic characteristics and clinical features in our patient cohort

		ALL (n = 275)	Training group (n = 138)	Validation group (n = 137)	P value
Age (yr)		40.25 ± 9.65	40.90 ± 9.90	39.61 ± 9.37	0.267
Gender	Male	194 (70.5%)	101 (73.2%)	93 (67.9%)	0.335
	Female	81 (29.5%)	37 (26.8%)	44 (32.1%)
CP (mg/L)		213.01 ± 43.28	212.72 ± 42.68	213.29 ± 44.03	0.914
Total bilirubin (μmol/L)		13.51± 7.16	13.31 ± 6.46	13.71 ± 7.80	0.652
Albumin (g/L)		42.84 ± 3.68	42.93 ± 3.74	42.75 ± 3.63	0.692
Globulin (g/L)		28.19 ± 18.49	29.43 ± 6.04	27.01 ± 4.28	0.291
ALT (IU/L)		29.56 ± 9.86	29.65 ± 9.69	29.46 ± 10.07	0.872
AST (IU/L)		26.91 ± 7.17	26.71 ± 7.19	27.11 ± 7.16	0.645
GGT (IU/L)		29.48 ± 21.87	29.23 ± 24.34	29.71 ± 19.28	0.860
TCHO (mmol/L)		4.69 ± 0.89	4.61 ± 0.75	4.77 ± 1.00	0.149
TG (mmol/L)		1.15 ± 0.68	1.25 ± 0.80	1.05 ± 0.50	0.113
CHE (IU/mL)		8215.20 ± 2312.22	8409.96 ± 2358.01	8027.75 ± 2260.29	0.182
WBC (109/L)		5.68 ± 1.48	5.74 ± 1.48	5.62 ± 1.49	0.509
PLT (109/L)		191.96 ± 51.77	193.78 ± 51.91	190.11 ± 51.76	0.558
HBsAg (Log IU/mL)		3.95 ± 0.95	3.89 ± 0.99	3.40 ± 0.90	0.346
HBV-DNA (Log IU/mL)		5.13 ± 2.02	5.08 ± 2.01	5.19 ± 2.03	0.666
PT (s)		12.11 ± 2.31	12.04 ± 2.56	12.18 ± 2.04	0.626
INR		1.00 ± 0.19	0.99 ± 0.21	1.01 ± 0.17	0.662
Fibrosis stage, n (%)					0.670
F0		19 (6.9)	12 (8.7)	7 (5.1)
F1		106 (38.5)	52 (37.7)	54 (39.4)
F2		57 (20.7)	26 (18.8)	31 (22.6)
F3		40 (14.5)	19 (13.8)	21 (15.3)
F4		53 (19.3)	29 (21.0)	24 (17.5)

CP: Ceruloplasmin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma glutamyl transpeptidase; TCHO: Total cholesterol; TG: Triglyceride; CHE: Cholinesterase; WBC: White blood cell count; PLT: Platelet count; HBV: Hepatitis B virus; PT: Prothrombin time; INR: International normalized ratio.

Table 2 Accuracy of serum ceruloplasmin in diagnosing F ≥ 2, F ≥ 3, and F = 4 as measured by area under the receiver operating characteristic curve (n = 138)

Steatosis degree	AUC (95%CI)	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	Cut-off point
F ≥ 2	0.774 (0.696-0.851)	81.3	64.9	66.7	80	≤ 203.5
F ≥ 3	0.812 (0.732-0.892)	82.8	65.9	83.7	64.4	≤ 190.5
F = 4	0.853 (0.781-0.925)	89.3	65.4	91.7	58.6	≤ 182.5

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

Table 3 Clinical parameters associated with significant fibrosis in the training group (138 patients)

		No significant fibrosis (n = 64)	Significant fibrosis (n = 74)	P value
Age (yr)		39.88 ± 9.68	39.61 ± 9.37	0.260
Gender	Male	47 (73.4%)	54 (73.0%)	0.951
	Female	17 (26.6%)	20 (27.0%)
CP (mg/L)		231.22 ± 35.26	196.73 ± 42.27	< 0.0001
Total bilirubin (μmol/L)		13.11 ± 6.97	13.48 ± 6.05	0.747
Albumin (g/L)		44.27 ± 3.29	41.79 ± 3.75	<0.0001
Globulin (g/L)		27.15 ± 5.15	31.35 ± 5.03	0.363
ALT (IU/L)		29.25 ± 10.32	30.00 ± 9.17	0.652
AST (IU/L)		25.77 ± 7.21	27.53 ± 7.11	0.152
GGT (IU/L)		23.69 ± 13.96	33.90 ± 29.78	0.017
TCHO (mmol/L)		4.82 ± 0.83	4.44 ± 0.62	0.004
TG (mmol/L)		1.31 ± 0.74	1.21 ± 0.85	0.474
CHE (IU/mL)		9254.48 ± 2583.76	7710.21 ± 1903.41	< 0.0001
WBC (109/L)		5.78 ± 1.36	5.71 ± 1.59	0.766
PLT (109/L)		212.63 ± 50.24	177.49 ± 47.94	< 0.0001
HBsAg (Log IU/mL)		4.40 ± 0.78	3.45 ± 0.96	< 0.0001
HBV-DNA (Log IU/mL)		5.17 ± 2.33	5.00 ± 1.70	0.614
PT (s)		11.71 ± 2.81	12.33 ± 2.31	0.161
INR		0.96 ± 0.23	1.02 ± 0.19	0.103

CP: Ceruloplasmin; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma glutamyl transpeptidase; TCHO: Total cholesterol; TG: Triglyceride; CHE: Cholinesterase; WBC: White blood cell count; PLT: Platelet count; HBV: Hepatitis B virus; PT: Prothrombin time; INR: International normalized ratio.

Table 4 Diagnostic value of ceruloplasmin hepatitis B virus in the training and validation groups

Variable	Training group (n = 138)			Validation group (n = 137)
	F ≥ 2	F ≥ 3	F = 4	F ≥ 2	F ≥ 3	F = 4
AUC	0.842	0.920	0.904	0.805	0.886	0.863
95%CI	0.777-0.907	0.872-0.967	0.842-0.955	0.733-0.877	0.827-0.946	0.784-0.943
Cut-off	0.0304	0.496	0.553	0.174	0.176	0.206
Sensitivity, %	81.1	90.9	96.2	72.4	89.1	97.1
Specificity	71.9	78.7	71.4	80.3	72.5	70.6
Youden’s index	0.530	0.696	0.676	0.527	0.616	0.677
PPV	76.9	66.7	43.9	82.1	62.1	53.1
NPV	76.7	94.9	98.8	70.0	93.0	98.6

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

Table 5 Comparisons of ceruloplasmin hepatitis B virus with other predictive models for assessing F ≥ 2 (n = 275)

Model	AUC (95%CI)	Youden index	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)	P value
CPHBV	0.839 (0.792-0.886)	0.512	80.1	71.1	76.2	72.4
APRI	0.704 (0.639-0.768)	0.355	75.9	59.6	68.5	66.1	< 0.001
FIB-4	0.678 (0.612-0.745)	0.330	71.9	61.4	68.8	64.2	< 0.001
GPR	0.704 (0.640-0.768)	0.350	74.5	60.5	70.1	66.7	< 0.001
Forn’s index	0.687 (0.622-0.753)	0.359	63.1	72.8	74.2	61.5	< 0.001
S-index	0.722 (0.659-0.784)	0.357	78.7	57.0	69.9	69.7	0.0034

AUC: Area under the receiver operating characteristic curve; NPV: Negative predictive value; PPV: Positive predictive value; CPHBV: Ceruloplasmin hepatitis B virus; APRI: Aspartate aminotransferase-to-platelet ratio index; FIB-4: Fibrosis-4; GPR: Gamma-glutamyl transpeptidase-to-platelet ratio.