The Utility of Retinol-Binding Protein 4 in Predicting Liver Fibrosis in Chronic Hepatitis C Patients in Response to Direct-Acting Antivirals

Figures & data

Table 1 A Laboratory Investigation and Fibroscan Findings in CHC Patients and Healthy Control

Parameter	Pre-Treatment	After Treatment	Control	P-value^¥
Fibroscan KPa*	8.8(3.2–13.6)	7.7(2.8–11.83)	–	0.0017
Fibroscan** F0–1 F2 F3–4	No(%) 8(16%) 26(52%) 16(32%)	No(%) 34(68%) 1(2%) 15(30%)	–	0.00001
Total protein (g/dl)	7.2(6–8.3)	7.4(6.4–8.3)	8(6.9–8.5)	0.00001
Albumin (g/dl)	3.8(2.8–5)	4(3.2–5)	4.1(3.8–4.4)	0.0015
PT-INR	1.02(1–1.8)	1(1–1.5)	1(1–1.05)	0.0224
Total bilirubin (mg/dl)	0.9(0.46–1.72)	0.7(0.2–1.25)	0.56(0.25–0.75)	0.00001
AST (U/L)	46.5(16–291)	34(10–109)	14(10–30)	0.00001
ALT (U/L)	45(10–228)	30(10–58)	13.5(8–32)	0.00001
GGT (U/L)	34.5(15–58)	26.5(11–51)	13.5(9–31)	0.00001
ALP (U/L)	119.5(46,191)	103(40–160)	49.5 (36–62)	0.00001
LDH (U/L)	175.5(110–250)	153(97–190)	116(100–155)	0.00001
AFP (ng/mL)	8.5(3.7–23)	5(2–15)	1.8(1.30–3.30)	0.00001
RBP4 (mg/l)	38.4(34.4–47.1)	45.5(40.4–51.3)	55.57(47.50–62.30)	0.00001
APRI	0.59(0.18–5.18)	0.35(0.11–1.22)	0.1(0.07–0.26)	0.00001
CDS	5(1–9)	4(2–8)	2.5(1–4)	0.00001
Fib-4 score	2.13(0.28–8.17)	1.35(0.05–4.2)	0.65(0.44–1.19)	0.00001
GUCI	0.62(0.18–6.22)	0.35(0.11–1.4)	0.11(0.07–0.26)	0.00001
Lok index	0.4(0.1–1)	0.27(0.06–0.96)	0.16(0.06–0.29)	0.00001
Platelets (10^9/L)	182.5(60–415)	350.5(121–411)	332(236–411)	0.00001
WBCs (10^9/L)	5600(3200–11,020)	6850(4500–14,070)	5460(4250–10,900)	0.005
^#Neutrophil count	2742(961–7163)	3660(1440–10,975)	3537(2233–7725)	0.0097
^#Lymphocyte count	2130(735–5220)	2567(1140–4800)	1703(796–3509)	0.0002
^#Monocyte count	321(105–746)	333(84–846)	254(87–763)	0.2208
NLR	1.27(0.44–5.33)	1.35(0.5–4.70)	2.14(0.64–4.76)	0.0012
PLR	81.04(26.89–204.44)	85.59(38.65–310.75)	198.88(70.96–474.87)	0.00001

Notes: ^¥Kruskal–Wallis test; *Man Mann–Whitney U-Test; **Chi-Square; n (%): number (percentage); ^#Absolute. Bold:P < 0.05

Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate amino-transferase; AFP, alpha-fetoprotein; APRI, aspartate transaminase-to-platelet ratio index; CDS, cirrhosis discriminant score; Fib-4, fibrosis index based on the four factors; GGT, gamma-glutamyl transpeptidase; GUCI, Göteborg University Cirrhosis Index; INR, international normalized ratio; LDH, kPa: kilopascal; lactate dehydrogenase; PT-NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; RBP4, Retinol-binding protein 4; WBCs, white blood cell.

Table 2 The Laboratory Investigation and Noninvasive Fibrosis Indices in CHC Patients Concerning Fibroscan Fibrosis Grades

Mean ±SD	F0-F1 (n=8)	F2 (n=26)	F3-F4 (n=16)	P-value
Age (years)	52.25±17.24	55.77±17.24	57.19±8.12	0.874
BMI (kg/m^2)	22.80±1.72	23.53±1.05	23.07±1.45	0.635
Fibroscan (kPa)	4.68±1.20	8.66±0.21	12.19±1.12	< 0.00001
Viral load	1,511,700±1,196,509	1,400,648.34±1,154,236.60	1,400,648.31±1,154,236.60	0.951
Albumin (g/dl)	4.2±0.5	3.89±0.39	3.66±0.43	0.036
PT-INR	1.05±0.07	1.04±0.07	1.17±0.2	0.004
AST (U/L)	30.5±12.38	47.19±20.38	101.12±84.31	0.003
ALT (U/L)	42.87±27.05	47.19±30.5	87.75±66.79	0.124
ALP (U/L)	77.12±26.42	116.96±38.87	116.06±49.7	0.060
GGT (U/L)	27.62±13.04	30.27±11.40	37.87±11.70	0.096
LDH (U/L)	174±37.44	164.08±35.34	171.29±30.96	0.549
AFP (ng/mL)	7.88±1.77	7.98±2.46	9.71±3.63	0.132
RBP4 (mg/l)	41.24±3.08	39.32±1.43	35.31±0.50	< 0.00001
APRI	0.25±0.6	0.61±0.38	1.80±1.26	< 0.00001
Fib-4 score	0.79±0.34	2.01±0.65	4.60±1.92	< 0.00001
CDS	2.88±1.64	4.77±0.86	6.75±1.44	< 0.00001
Lok index	0.19±0.13	0.39±0.12	0.65±0.20	< 0.00001
GUCI	0.26±0.07	0.63±0.38	2.06±1.41	< 0.00001
Platelets (10^9/L)	297±86	205±57	136±52	< 0.00001
WBCs (10^9/L)	6240±1550	6040±1770	5440±2130	0.511
NLR	1.35±0.58	1.32±0.66	2.01±1.45	0.079
PLR	132.99±61.38	88.94±29.50	81.97±40.95	0.012

Notes: Bold:P < 0.05.

Abbreviations: ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate amino-transferase; AFP, alpha-fetoprotein; APRI, aspartate transaminase-to-platelet ratio index; CDS, cirrhosis discriminant score; Fib-4, fibrosis index based on the four factors; GGT, gamma-glutamyl transpeptidase; GUCI, Göteborg University Cirrhosis Index; INR, international normalized ratio; LDH, kPa, kilopascal; lactate dehydrogenase; PT-NLR, neutrophil to lymphocyte ratio; PLR, platelet to lymphocyte ratio; RBP4, Retinol-binding protein 4; WBCs, white blood cells.

Table 3 Spearman Correlation Analysis Between Viral Load, AFP, RBP4, and PLR, and Noninvasive Fibrosis Indices; Fib-4, APRI, CDS, Lok Index, and GUCI

	Viral Load		AFP		RBP4		PLR
	r	P-value	r	P-value	r	P-value	r	P-value
Age (years)	−0.041	0.6942	−0.035	0.733	−0.016	0.871	−0.1045	0.301
FibroScan (kPa)	0.312	0.0015	0.337	0.001	−0.5249	0.0001	−0.323	0.001
Viral load	-	-	0.639	0.0001	−0.781	0.0001	−0.0037	0.713
AFP (ng/mL)	0.639	0.0001	-	-	−0.632	0.0001	0.0395	0.696
RBP4 (mg/l)	−0.586	0.00001	−0.632	0.00001	-	-	0.154	0.126
APRI	0.192	0.0553	0.360	0.0002	−0.546	0.0001	−0.307	0.002
Fib-4 score	0.187	0.0630	0.277	0.005	−0.538	0.0001	−0.450	0.001
CDS	0.124	0.218	0.130	0.197	−0.405	0.0001	−0.520	0.0001
Lok index	0.133	0.1861	0.223	0.025	−0.481	0.0001	−0.518	0.0001
GUCI	0.186	0.0642	0.364	0.0002	−0.543	0.0001	−0.269	0.003

Notes: r: Spearman correlation coefficient; Bold: P<0.05.

Abbreviations: AFP, alpha-fetoprotein; APRI, aspartate transaminase-to-platelet ratio index; CDS, cirrhosis discriminant score; Fib-4, fibrosis index based on the four factors; GUCI, Göteborg University Cirrhosis Index; PLR, platelet to lymphocyte ratio; RBP4, Retinol-binding protein 4.

Table 4 The Performance of Fibrosis Serum Markers in Detecting Fibrosis Stage

No or Mild Liver Fibrosis (F0-F1) Versus Significant and Advanced Liver Fibrosis (F2-F3-F4)
	AUC	Cutoff	Sensitivity	95% CI	Specificity	+LR	-LR	PPV	NPV	Accuracy	P -value
FibroScan (kPa)	1	> 6.4	100	0.929–1	100	–	0	100	100	100	<0.001
FIB-4 score	0.985	> 1.17	95.24	0.902–1	100		0.048	100	80	97.62	<0.001
GUCI	0.948	> 0.37	90.48	0.846–0.991	100		0.095	100	66.7	95.24	<0.001
APRI	0.946	> 0.35	90.48	0.843–0.990	100		0.095	100	66.7	95.24	<0.001
LOK INDEX	0.921	> 0.18	100	0.809–0.978	75	4	0	95.5	100	87.5	<0.001
CDS	0.893	> 3	97.62	0.773–0.963	75	3.9	0.032	95.3	85.7	86.31	<0.001
RBP4 (mg/l)	0.811	≤ 40.6	90.48	0.675–0.908	62.5	2.41	0.15	92.7	55.6	76.49	0.004
PLR	0.738	≤115.8	85.71	0.594–0.852	62.5	2.29	0.23	92.3	45.5	74.11	0.042
AFP (ng/mL)	0.577	> 6	83.33	0.409–0.697	37.5	1.33	0.44	87.5	30	60.415	0.604
Mild & moderate (F0-F1-F2) versus advanced liver fibrosis and cirrhosis (F3-F4)
	AUC	Cutoff	Sensitivity	95% CI	Specificity	+LR	-LR	PPV	NPV	Accuracy	P- value
FibroScan (kPa)	1.000	> 8.9	100	0.929–1	100	–	0	100	100	100	<0.001
RBP4 (mg/l)	1.000	≤ 35.9	100	0.929–1	100	–	0	100	100	100	<0.001
FIB-4 score	0.940	> 2.31	93.75	0.835–0.988	88.24	7.97	0.071	78.9	96.8	90.995	<0.001
GUCI	0.935	> 1.27	75	0.827–0.985	97.06	25.5	0.26	92.3	89.2	86.03	<0.001
APRI	0.923	> 0.59	100	0.811–0.979	76.47	4.25	0	66.7	100	88.235	<0.001
LOK INDEX	0.893	> 0.55	81.25	0.774–0.963	85.29	5.52	0.22	72.2	90.6	83.27	<0.001
CDS	0.882	> 5	75	0.760–0.956	94.12	12.75	0.27	85.7	88.9	84.56	<0.001
PLR	0.650	≤ 77.36	62.50	0.502–0.779	70.59	2.13	0.53	50.0	80.0	66.55	<0.001
AFP (ng/mL)	0.638	> 7	100	0.490–0.769	35.29	1.55	0	42.1	100	67.645	0.067

Note: Bold: P<0.05.

Abbreviations: AFP, alpha-fetoprotein; APRI, aspartate transaminase-to-platelet ratio index; AUC, area under the curve; CDS, cirrhosis discriminant score; CI, confidence intervals; Fib-4, fibrosis index based on the four factors; GUCI, Göteborg University Cirrhosis Index; NPV, NPV, negative predictive value; LR, likelihood ratio; PLR, platelet-to-lymphocyte ratio; PPV, positive predictive value; RBP4, Retinol-binding protein 4.

Figure 1 The area under the receiver operating characteristic (ROC) curves of RBP4, FIB-4, GUCI, APRI, LOK index, CDS, PLR, and  AFP for the diagnosis of advanced liver fibrosis using Fibroscan as the reference.

Figure 2 The area under the receiver operating characteristic (ROC) curves of RBP4, FIB-4, GUCI, APRI, LOK index, CDS, PLR, and  AFP for the diagnosis of advanced liver fibrosis using Fibroscan as the reference.

Abbreviations: AFP, alpha-fetoprotein; APRI, aspartate transaminase-to-platelet ratio index; CDS, cirrhosis discriminant score; Fib-4, fibrosis index based on the four factors; GUCI, Göteborg University Cirrhosis Index; PLR, platelet-to-lymphocyte ratio; RBP4, retinol-binding protein 4.