A new index for non-invasive assessment of liver fibrosis

Table 1 Characteristics of the 165 patients in the estimation group and the 120 patients in the validation group (mean ± SD)

	All patients (n = 285)	Estimation group (n = 165)	Validation group (n = 120)	P-value
Male gender, n (%)	149 (52.3)	92 (55.8)	57 (47.5)	NS
Age (yr)	52.4 ± 13.3	53.2 ± 12.6	51.5 ± 14.2	NS
Liver stiffness (kPa)	9.99 ± 6.99	10.29 ± 7.33	9.58 ± 6.51	NS
Platelet count (× 104/mL)	16.54 ± 5.28	16.53 ± 5.41	16.57 ± 5.13	NS
Prothrombin time (%)	9.35 ± 11.3	92.4 ± 10.2	95.1 ± 12.6	NS
AST (IU/L)	52.5 ± 34.0	53.0 ± 34.6	51.8 ± 33.4	NS
ALT (IU/L)	70.8 ± 52.6	72.4 ± 54.9	68.7 ± 49.4	NS
Total protein (g/dL)	7.81 ± 0.52	7.79 ± 0.49	7.85 ± 0.57	NS
Albumin (g/dL)	4.31 ± 0.34 (n = 283)	4.31 ± 0.31 (n = 163)	4.31 ± 0.38	NS
γ-GTP (IU/L)	59.8 ± 62.0	58.1 ± 57.9	62.1 ± 67.5	NS
γ-globulin (g/dL)	1.57 ± 0.41 (n = 276)	1.54 ± 0.38 (n = 146)	16.1 ± 0.44	NS
Total cholesterol (mg/dL)	178.1 ± 31.9	177.2 ± 31.1	179.5 ± 33.0	NS
Hyaluronic acid (ng/mL)	104.1 ± 128.3 (n = 281)	114.5 ± 140.0 (n = 161)	90.0 ± 109.3	NS
Fibrosis stage, n (%)
F0	28 (9.8)	14 (8.5)	14 (11.7)
F1	85 (29.8)	52 (31.5)	33 (27.5)
F2	82 (28.8)	42 (25.5)	40 (33.3)
F3	53 (18.6)	33 (20.0)	20 (16.7)
F4	37 (13.0)	24 (14.5)	13 (10.8)

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; γ-GTP: γ-glutamyl transpeptidase; NS: Not significant.

Table 2 Variables associated with fibrosis stage in the estimation group (165 patients ) in univariate analysis (mean ± SD)

	F0 (n = 14)	F1 (n = 52)	F2 (n = 42)	F3 (n = 33)	F4 (n = 24)	P-value
Liver stiffness (kPa)	5.58 ± 1.96	5.76 ± 1.91	9.02 ± 4.11	13.40 ± 4.95	20.77 ± 10.81	< 0.0001
Platelet count (× 104/mL)	20.80 ± 4.77	18.79 ± 5.19	15.66 ± 4.54	15.72 ± 5.58	11.75 ± 2.63	< 0.0001
Prothrombin time (%)	101.8 ± 10.3	96.1 ± 7.9	92.5 ± 7.9	88.7 ± 10.5	83.6 ± 9.6	< 0.0001
AST (IU/L)	30.3 ± 17.3	40.1 ± 23.7	46.9 ± 31.8	73.2 ± 40.3	77.0 ± 33.3	< 0.0001
ALT (IU/L)	44.4 ± 34.2	58.1 ± 47.1	62.5 ± 42.9	103.0 ± 72.9	94.6 ± 47.9	< 0.0001
Total protein (g/dL)	7.61 ± 0.30	7.78 ± 0.58	7.74 ± 0.44	7.83 ± 0.44	7.91 ± 0.48	0.4459
Albumin (g/dL)	4.52 ± 0.26 (n = 13)	4.44 ± 0.23 (n = 51)	4.32 ± 0.32	4.15 ± 0.24	4.12 ± 0.38	< 0.0001
γ-GTP (IU/L)	40.07 ± 26.10	57.52 ± 84.73	49.29 ± 32.91	75.79 ± 47.91	61.25 ± 40.46	0.2409
γ-globulin (g/dL)	1.22 ± 0.25 (n = 12)	1.44 ± 0.32 (n = 45)	1.52 ± 0.33 (n = 36)	1.62 ± 0.35 (n = 30)	1.83 ± 0.43 (n = 23)	< 0.0001
Total cholesterol (mg/dL)	179.5 ± 29.4	186.7 ± 31.5	173.8 ± 32.0	176.4 ± 26.8	162.3 ± 30.4	0.0251
Hyaluronic acid (ng/mL)	59.6 ± 83.1	49.64 ± 41.1 (n = 50)	110.3 ± 113.3	136.0 ± 138.4	266.6 ± 217.9 (n = 23)	< 0.0001

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase; γ-GTP: γ-glutamyl transpeptidase.

Table 3 Multiple regression predicting liver fibrosis stage with liver stiffness and laboratory data in the estimation group

	Estimated value	Standard error	χ2	P-value
Liver stiffness (n = 165)	-0.2661602	0.0481713	30.53	< 0.0001
Platelet count (n = 165)	0.0748652	0.0366051	4.18	0.0408
Prothrombin time (n = 165)	0.0560460	0.0206514	7.37	0.0066
AST (n = 165)	-0.0093853	0.0100069	0.88	0.3483
ALT (n = 165)	0.0007594	0.0058897	0.02	0.8974
Albumin (n = 163)	-1.1130330	0.7353340	2.29	0.1301
γ-globulin (n = 146)	-0.6349751	0.5201549	1.49	0.2222
Total cholesterol (n = 165)	0.0011393	0.0057519	0.04	0.8430
Hyaluronic acid (n = 161)	-0.0019629	0.0017064	1.32	0.2500

AST: Aspartate aminotransferase; ALT: Alanine aminotransferase.

Table 4 Assessment of liver fibrosis stages classification by liver fibrosis indices

	AUCs (95% CI)	Optimal cutoff value	Sensitivity (%)	Specificity (%)	Accuracy (%)	Positive predictive value (%)	Negative predictive value (%)	Positive likelihood ratio
F ≥ 1 (F0 vs F1-2-3-4)
Fibro-Stiffness index	0.82 (0.715-0.928)	11.07	77.5	78.6	77.6	97.5	24.4	3.62
Fibro-Stiffness index and AST	Non	11.07 and 51 (IU/L)	85.4	78.6	84.8	97.7	33.3	3.99
Liver stiffness	0.77 (0.666-0.867)	6.6 (kPa)	64.2	85.7	66.1	97.8	18.2	4.49
APRI	0.81 (0.680-0.934)	0.44	88.1	64.3	86.1	96.4	33.3	2.47
Forns index	0.77 (0.640-0.908)	4.72	82.1	71.4	81.2	96.9	27.0	2.87
FibroIndex	0.85 (0.757-0.932)	1.19	82.1	75.0	81.5	97.3	27.3	3.28
F ≥ 2 (F0-1 vs F2-3-4)
Fibro-Stiffness index	0.90 (0.847-0.943	10.12	78.8	89.4	83.0	91.8	73.8	7.43
Liver stiffness	0.88 (0.826-0.929)	7.1 (kPa)	80.8	80.3	80.6	86.0	73.6	4.10
APRI	0.78 (0.714-0.851)	1.06	64.6	84.8	72.7	86.5	61.5	4.27
Forns index	0.82 (0.757-0.890)	6.22	76.8	83.3	79.4	87.4	70.5	4.61
FibroIndex	0.82 (0.754-0.888)	17.00	74.2	80.7	76.7	85.7	66.7	3.84
F ≥ 3 (F0-2 vs F3-4)
Fibro-Stiffness index	0.90 (0.851-0.953)	9.87	93.0	79.6	84.2	70.7	96.7	4.56
Liver stiffness	0.90 (0.856-0.952)	9.6 (kPa)	87.7	82.4	84.2	72.5	92.7	4.98
APRI	0.84 (0.767-0.904)	1.13	80.7	80.6	80.6	68.7	88.8	4.15
Forns index	0.80 (0.732-0.874)	6.36	82.5	70.4	74.5	59.5	88.4	2.78
FibroIndex	0.85 (0.749-0.901)	1.85	73.6	80.6	81.4	68.4	84.3	3.80
F = 4 (F0-1-2-3 vs F4)
Fibro-Stiffness index	0.92 (0.871-0.965)	8.51	91.7	83.7	84.8	48.9	98.3	5.62
Fibro-Stiffness index and HA	Non	8.51 and 68 (ng/mL)	91.3	87.9	88.4	55.3	98.4	7.26
Liver stiffness	0.90 (0.844-0.957)	11.6 (kPa)	91.7	78.0	80.0	41.5	98.2	4.17
APRI	0.84 (0.759-0.915)	1.30	91.7	74.5	77.0	37.9	98.1	3.59
Forns index	0.87 (0.816-0.923)	7.07	95.8	75.9	78.8	40.4	99.1	3.97
FibroIndex	0.89 (0.830-0.943)	1.90	91.3	78.0	80.1	43.8	98.0	4.16

AUCs: Area under the receiver operating characteristics; CI: Confidence interval; HA: Hyaluronic acid; AST: Aspartate aminotransferase; APRI: Aminotransferase-to-platelet ratio index.

Table 5 Validation of liver fibrosis stages classification by liver fibrosis indices

	AUCs (95% CI)	Sensitivity (%)	Specificity (%)	Accuracy (%)	Positive predictive value (%)	Negative predictive value (%)	Positive likelihood ratio
F ≥ 1 (F0 vs F1-2-3-4)
Fibro-Stiffness index	0.80 (0.712-0.878)	73.6	78.6	74.2	94.0	27.7	3.52
Fibro-Stiffness index and AST	Non	78.3	78.6	78.3	96.5	32.4	3.64
Liver stiffness	0.82 (0.727-0.907)	63.2	85.7	65.8	97.1	23.5	4.42
APRI	0.80 (0.704-0.899)	87.7	35.7	81.7	91.2	27.8	1.36
Forns index	0.77 (0.659-0.880)	72.4	71.4	72.3	95.0	25.6	2.53
FibroIndex	0.83 (0.723-0.937)	89.6	50.5	85.8	93.1	38.9	1.79
F ≥ 2 (F0-1 vs F2-3-4)
Fibro-Stiffness index	0.82 (0.750-0.898)	65.7	96.6	76.7	90.6	63.8	10.31
Liver stiffness	0.85 (0.787-0.920)	76.7	83.0	79.2	87.5	69.6	4.51
APRI	0.82 (0.741-0.893)	50.7	89.4	65.8	88.1	53.8	4.76
Forns index	0.78 (0.700-0.864)	58.3	80.9	67.2	82.4	55.9	3.05
FibroIndex	0.79 (0.713-0.875)	69.5	83.0	74.2	86.2	62.9	4.02
F ≥ 3 (F0-2 vs F3-4)
Fibro-Stiffness index	0.93 (0.876-0.986)	93.9	83.9	86.7	68.9	97.3	5.84
Liver stiffness	0.92 (0.871-0.977)	81.8	82.8	82.5	64.3	92.3	4.75
APRI	0.83 (0.753-0.922)	75.8	81.6	80.0	61.0	89.9	4.12
Forns index	0.84 (0.759-0.912	78.1	71.3	73.1	50.0	90.0	2.72
FibroIndex	0.85 (0.772-0.928)	76.6	80.5	80.0	60.5	90.9	4.03
F = 4 (F0-1-2-3 vs F4)
Fibro-Stiffness index	0.97 (0.934-0.997)	100	84.1	85.8	43.3	100	6.29
Fibro-Stiffness index and HA	Non	100	86.9	88.3	48.1	100	7.63
Liver stiffness	0.97 (0.942-0.999)	100	83.2	85.0	41.9	100	5.94
APRI	0.92 (0.867-0.972)	100	75.7	78.3	33.3	100	4.12
Forns index	0.88 (0.798-0.968)	83.3	72.9	73.9	25.6	97.5	3.07
FibroIndex	0.92 (0.874-0.971)	100	77.6	80.0	35.0	100	4.46

AUCs: Area under the receiver operating characteristics; CI: Confidence interval; HA: Hyaluronic acid; AST: Aspartate aminotransferase; APRI: Aminotransferase-to-platelet ratio index.