Proton nuclear magnetic resonance-based metabonomic models for non-invasive diagnosis of liver fibrosis in chronic hepatitis C: Optimizing the classification of intermediate fibrosis

Table 1 Main demographic and laboratory characteristics of 69 chronic hepatitis C patients from Pernambuco/Brazil

Characteristics	Total (n = 69)
Gender (n, %)
Male	28	40.60%
Female	41	59.40%
Age (yr)1	57.5	± 11.9
BMI (kg/m2)1	27.7	± 4.7
AST (U/L)2	51.5	(33.7-88)
ALT (U/L)2	54	(32.6-106)
AST/ALT1	1.03	± 0.44
GGT (U/L)2	81.8	(46.5-155)
Platelets (109/mm3)1	191	± 78
Albumin (g/dL)1	4.08	± 0.56
Total bilirubin (mg/dL)2	0.7	(0.50-1.09)
Alkaline phosphatase (U/L)1	94.6	± 49.2
INR1	1.09	± 0.14
APRI2	0.8	(0.44-2.18)
FIB-42	2.18	(1.29-4.72)
Liver fragment length (cm)2	1.5	(1.30-1.80)
Number of portal tracts2	15	(12.0-20.0)
Stage of fibrosis (n, %)
F0	2	2.90%
F1	25	36.20%
F2	14	20.30%
F3	10	14.50%
F4	18	26.10%

¹Mean ± standard deviation;

²Median (P₂₅-P₇₅). ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; GGT: Gamma glutamyl transferase; INR: International normalized ratio; APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fibrosis index based on four factors.

Table 2 Main demographic and laboratory characteristics of 69 chronic hepatitis C patients, in accordance with the fibrosis group, from Pernambuco/Brazil

	Fibrosis group				P value
	Significant (≥ F2) n = 42		Non-significant (< F2) n = 27
Gender (M/F, %)	16/26	(40.6/59.4)	12/15	(38.1/61.9)	0.600a
Age (yr)1	62.16	± 9.46	50.22	± 11.86	< 0.0001b
BMI (kg/m2)1	28.6	± 4.9	26.3	± 3.8	0.051b
AST (U/L)2	61.5	(45.5-103)	34	(29.6-47)	< 0 .0001c
ALT (U/L)2	57.5	(41.7-108)	39.1	(26-81)	0.04c
AST/ALT1	1.12	± 0.47	0.91	± 0.36	< 0.0001b
GGT (U/L)2	107.5	(65.8-168)	56	(32.8-82.9)	0.001c
Platelets (109/mm3)1	162	± 72	239	± 61	< 0.0001b
Albumin (g/dL)1	3.91	± 0.62	4.35	± 0.30	0.001b
Total bilirrubin (mg/dL)2	0.72	(0.60-1.30)	0.5	(0.40-0.80)	0.005c
Alkaline phosphatase (U/L)1	103.3	± 55.6	79.2	± 30.3	0.059b
INR1	1.13	± 0.17	1.03	± 0.06	0.002b
APRI2	1.14	(0.75-2.84)	0.48	(0.27-0.79)	< 0.0001c
FIB-42	3.45	(2.01-6.19)	1.37	(0.84-1.89)	< 0.0001c
	Advanced (≥ F3) n = 28		Non-advanced (< F3) n = 41
Gender (M/F, %)	14/14	(50.0/50.0)	14/27	(34.1-65.9)	0.188a
Age (yr)1	62.23	± 9.42	54.25	± 12.46	0.004b
BMI (kg/m2)1	27.6	± 3.9	27.9	± 5.2	0.802b
AST (U/L)2	79	(52.4-130)	40	(31.4-63)	0.001c
ALT (U/L)2	62	(42.5-113.3)	43	(29-84.8)	0.078c
AST/ALT1	1.19	± 0.54	0.93	± 0.33	0.031b
GGT (U/L)2	110.5	(76.1-159.3)	66.5	(36.2-137.8)	0.005c
Platelets (109/mm3)1	138	± 65	228	± 63	< 0.0001b
Albumin (g/dL)1	3.75	± 0.66	4.33	± 0.29	< 0.0001b
Total bilirrubin (mg/dL)2	0.94	(0.70-1.48)	0.5	(0.44-0.70)	< 0.0001c
Alkaline phosphatase (U/L)1	99.5	± 38.9	90.9	± 56.1	0.490b
INR1	1.18	± 0.17	1.03	± 0.07	< 0.0001b
APRI2	2.13	(0.99-3.75)	0.59	(0.39-0.92)	< 0.0001c
FIB-42	4.8	(2.56-9.30)	1.72	(1.10-2.21)	< 0.0001c
	Cirrhosis (F4) n = 18		Non-cirrhosis (< F4) n = 51
Gender (M/F, %)	7/11	(38.9/61.1)	21/30	(41.2/58.8)	0.865a
Age (yr)1	63.7	± 11.11	55.29	± 11.51	0.009b
BMI (kg/m2)1	27.7	± 3.4	27.7	± 5.1	0.983b
AST (U/L)2	69	(54.1-101.5)	43.2	(32.5-80)	0.059c
ALT (U/L)2	54	(36.4-71)	50	(31-114)	0.637c
AST/ALT1	1.38	± 0.56	0.91	± 0.31	0.003b
GGT (U/L)2	108.5	(73.8-156.3)	74.5	(41.3-151.2)	0.068c
Platelets (109/mm3)1	123	± 72	216	± 64	< 0.0001b
Albumin (g/dL)1	3.41	± 0.63	4.31	± 0.29	< 0.0001b
Total bilirrubin (mg/dL)2	1.27	(0.70-2.88)	0.6	(0.47-0.80)	< 0.0001c
Alkaline phosphatase (U/L)1	107.2	± 41.3	89.7	± 51.5	0.202b
INR1	1.21	± 0.20	1.05	± 0.08	0.003b
APRI2	2.35	(1.04-4.36)	0.69	(0.40-1.11)	< 0.0001c
FIB-42	5.63	(4.37-11.27)	1.85	(1.17-2.38)	0.001c

¹Mean ± standard deviation;

²Median (P₂₅-P₇₅),

^aχ² test;

^bT test;

^cMann-Whitney test. ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; GGT: Gamma glutamyl transferase; INR: International normalized ratio; APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fibrosis index based on four factors.

Table 3 Linear discriminant analysis metabonomic models, APRI and FIB-4 performances to predict significant fibrosis, advanced fibrosis and cirrhosis in 69 chronic hepatitis C patients from Pernambuco/Brazil

	Biopsy		P value	Sensitivity		Specificity		LR+		LR-		A (%)
Significant fibrosis
Model (n = 69)	F2-F4	F0-F1		(%)	95%CI	(%)	95%CI		95%CI		95%CI
≥ F2	41	2	< 0.0011	97.6	87.4-99.9	92.6	75.7-99.1	13.2	3.5-50.1	0.03	0.004-0.2	95.7
< F2	1	25
APRI (n = 68)
> 0.5	36	13	0.0012	85.7	71.5-94.6	50	29.9-0.70	1.71	1.2-2.6	0.3	0.1-0.7	72
≤ 0.5	6	13
> 1.5	19	2	0.0011	45.2	29.9-61.3	92.3	74.9-99.0	5.9	1.5-23.2	0.6	0.4-0.8	63.2
≤ 1.5	23	24
Advanced fibrosis
Model (n = 69)	F3-F4	F0-F2		(%)	95%CI	(%)	95%CI		95%CI		95%CI
≥ F3	27	2	< 0.0011	96.4	81.7-99.1	95.1	83.5-99.4	19.8	5.1-76.5	0.04	0.005-0.3	95.7
< F3	1	39
FIB-4 (n = 68)
> 1.45	25	24	0.0121	89.3	71.8-97.7	40	24.9-56.7	1.5	1.1-2.0	0.3	0.1-0.8	60.3
≤ 1.45	3	16
> 3.25	21	3	< 0.0011	75	55.1-89.3	92.5	79.6-98.4	10	3.3-30.3	0.3	0.1-0.5	85.3
≤ 3.25	7	37
Cirrhosis
Model (n = 69)	F4	F0-F3		(%)	95%CI	(%)	95%CI		95%CI		95%CI
F4	18	1	< 0.0011	100	81.5-100	98	89.6-99.9	33.83	6.9-163.7	0.033	0.002-0.4	98.6
< F4	0	50
APRI (n = 68)
> 1.00	14	16	0.0021	77.8	52.4-93.6	68	53.3-80.5	2.4	1.5-3.9	0.3	0.1-0.8	70.6
≤ 1.00	4	34
> 2.00	9	9	0.0082	50	26.0-74.0	82	68.6-91.4	2.8	1.3-5.9	0.6	0.4-1.0	73.5
≤ 2.00	9	41

¹Fisher's exact test;

²χ² test;

³Estimated value. A: Accuracy; LR+: Positive likelihood ratio; LR-: Negative likelihood ratio; APRI: Aspartate aminotransferase to platelet ratio index; FIB-4: Fibrosis index based on four factors.