Angiopoietin-2/angiopoietin-1 as non-invasive biomarker of cirrhosis in chronic hepatitis C

Table 1 Baseline characteristics of chronic hepatitis C patients

Patients	Cirrhotic (n = 31)	Non-cirrhotic (n = 148)	P value
Sex (M/F)	23/8	92/56	0.20
Age (yr)	48 (24-63)	44 (22-67)	0.23
Viral load (× 105 IU/mL)	5.0 (3.5-11.0)	7.1 (1.8-13.0)	0.68
HCV genotype, n (%)			-
1	27 (87.1)	117 (79.1)
Non-1	4 (12.9)	31 (20.9)
Stage of liver fibrosis, n (%)			-
F1	-	42 (28.4)
F2	-	66 (44.6)
F3	-	40 (27.0)
F4	31 (100.0)	-
AST (UI/L)	99.0 (60.0-123.0)	48.0 (33.0-65.0)	< 0.001
ALT (UI/L)	116.0 (87.0-161.0)	74.0 (55.3-111.5)	< 0.001
ALP (UI/L)	116.0 (75.0-220.0)	126.5 (77.5-164.8)	0.39
GGT (UI/L)	91.0 (68.0-172.0)	36.0 (23.0-65.8)	< 0.001
INR	1.1 (1.1-1.2)	1.0 (0.9-1.1)	< 0.001
Bilirubin (mg/dL)	0.9 (0.7-1.1)	0.6 (0.5-0.8)	< 0.001
Platelet count (× 109/L)	141.0 (120.0-167.0)	204.0 (167.0-241.0)	< 0.001
Cholesterol total (mg/dL)	163.0 (141.0-180.0)	171.0 (154.3-191.5)	0.06
Albumin (g/dL)	4.2 (4.0-4.4)	4.3 (4.2-4.6)	0.03

Data are shown as number of patients (percentage) or median value (25^th-75^th percentile), except for age (median and range). HCV: Hepatitis C virus; AST: Aspartate transaminase; ALT: Alanine transaminase.

Table 2 Association between angiopoietins and liver fibrosis in chronic hepatitis C patients

	n	Rho spearman coefficient	P value
Ang1	179	-0.297	5.25 × 10-5
Ang2	179	0.402	2.37 × 10-9
Ang2/Ang1	179	0.474	2.14 × 10-11

Ang1: Angiopoietin 1; Ang2: Angiopoietin 2.

Table 3 Accuracy of angiopoietins to discriminate significant fibrosis (F > 1), advanced fibrosis (F > 2) and cirrhosis (F > 3) in chronic hepatitis C patients

	AUC-ROC (95%CI)	Criterion	Se	95%CI	Sp	95%CI	+LR	95% CI	-LR	95%CI	+PV	95%CI	-PV	95%CI	Cost	ACC
F > 1
Ang1	0.650 (0.575 -0.720)	≤ 54337.63	60.58%	51.9-68.8	69.05%	52.9-82.4	1.96	1.2-3.1	0.57	0.4-0.8	64.40	52.9-74.7	65.5	55.2-74.8	0.35	65.00%
Ang2	0.664 (0.589-0.732)	> 4041.67	49.64%	41.0-58.3	83.33%	68.6-93.0	2.98	1.5-6.0	0.60	0.5-0.7	73.30	60.1-84.1	64.2	55.0-72.7	0.33	67.20%
Ang2/ Ang1	0.724 (0.652- 0.788)	> 7.162	57.66%	48.9-66.1	78.57%	63.2-89.7	2.69	1.5-4.9	0.54	0.4-0.7	71.30	59.2-81.5	66.8	57.1-75.5	0.32	68.50%
F > 2
Ang1	0.635 (0.560-0.705)	≤ 47573.25	49.3%	37.2-61.4	75.93%	66.7-83.6	2.05	1.4-3.1	0.67	0.5-0.9	41.80	28.7-55.9	81.0	73.0-87.5	0.31	69.00%
Ang2	0.712 (0.639-0.777)	> 4256	60.56%	48.3-72.0	76.85%	67.8-84.4	2.62	1.8-3.9	0.51	0.4-0.7	47.90	34.7-61.3	84.7	77.0-90.6	0.27	72.60%
Ang2/ Ang1	0.740 (0.669-0.802)	> 9.262	56.34%	44.0-68.1	85.19%	77.1-91.3	3.80	2.3-6.2	0.51	0.4-0.7	57.20	41.7-71.7	84.7	77.5-90.4	0.22	77.70%
F > 3
Ang1	0.734 (0.663-0.797)	≤ 47573.25	70.97%	52.0-85.8	73.65%	65.8-80.5	2.69	1.9-3.8	0.39	0.2-0.7	37.90	25.9-51.2	91.8	85.3-96.1	0.27	73.20%
Ang2	0.761 (0.691-0.821)	> 4256	74.19%	55.4-88.1	69.59%	61.5-76.9	2.44	1.8-3.4	0.37	0.2-0.7	35.60	24.5-48.1	92.2	85.6-96.5	0.30	70.40%
Ang2/ Ang1	0.810 (0.744- 0.864)	> 10.33	70.97%	52.0-85.8	84.46%	77.6-89.9	4.57	2.9-7.1	0.34	0.2-0.6	50.90	35.8-65.9	92.8	87.0-96.5	0.18	82.00%

Youden index criterion. AUC-ROC: Area under the curve of receiver operator characteristics; Se: Sensitivity; Sp: Specificity; +LR: Positive Likelihood ratio; -LR: Negative Likelihood ratio; +PV: Positive predictive value; -PV: Negative predictive value; ACC: Accuracy, n = 179 chronic hepatitis C; Ang1: Angiopoietin 1; Ang2: Angiopoietin 2.

Table 4 Comparisons among area under the curve of receiver operator characteristics from angiopoietin-2/angiopoietin-1 ratio and other non-invasive cirrhosis indices

Indices	AUC-ROC (95%CI)	Standard error	P value
Cirrhosis
Ang2/Ang1	0.810 (0.744-0.864)	0.040	-
AAR	0.643 (0.568-0.713)	0.050	0.010
APRI	0.887 (0.831-0.930)	0.025	0.106
FIB4	0.858 (0.798-0.906)	0.031	0.349
FI	0.805 (0.737-0.861)	0.047	0.995
FCI	0.750 (0.677-0.813)	0.053	0.372

Two-sided P values by De Long test. AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; AAR: AST to ALT ratio; APRI: Aspartate aminotransferase-to-platelet ratio index; FIB4: Combination of biochemical values (platelets, ALT, AST) and age; FI: Fibrosis index; FCI: Fibrosis-cirrhosis index; AUC-ROC: Area under the curve of receiver operator characteristics; Ang1: Angiopoietin 1; Ang2: Angiopoietin 2.