Association of Non-Invasive Markers with Significant Fibrosis in Patients with Nonalcoholic Fatty Liver Disease: A Cross-Sectional Study

Figures & data

Figure 1 Study flowchart.

Table 1 Clinical Features of Patients

Variables	Overall (n = 71)	Fibrosis Stages 0–1 (n = 48)	Fibrosis Stages 2–4 (n = 23)	Statistic	p
GENDER (Male)	48 (67.61%)	31 (64.58%)	17 (73.91%)	0.618	0.432
AGE (years)	45.51±12.31	43.90±12.06	48.87±12.42	−1.611	0.112
BMI (kg/m^2)	25.00 (23.47,26.74)	24.77 (23.26,26.71)	25.64 (24.56,29.20)	−1.345	0.178
WBC (10^9/L)	5.38 (4.61,6.53)	5.48 (4.70,6.56)	5.10 (4.58,6.20)	0.160	0.873
RBC (10^12/L)	4.62±0.54	4.65±0.58	4.56±0.45	0.662	0.511
HGB (g/L)	141.56±14.55	141.60±15.39	141.48±12.94	0.036	0.971
PLT (10^9/L)	200.86±62.59	207.19±59.63	187.65±67.83	1.235	0.221
ALT (U/L)	78.87±30.30	79.59±29.48	77.35±32.59	0.290	0.773
AST (U/L)	57.00 (43.50,70.00)	52.50 (42.25,65.00)	68.00 (46.50,84.50)	−2.360	0.018
ALP (U/L)	96.00 (80.00,132.50)	96.00 (78.75,134.75)	96.00 (81.50,115.00)	0.559	0.576
GGT (U/L)	99.50 (65.50,134.00)	106.00 (74.85,135.75)	86.00 (52.00,127.50)	1.223	0.221
TBIL (μmol/L)	14.70 (12.00,17.75)	14.55 (11.55,16.83)	16.20 (13.25,20.00)	−1.892	0.058
DBIL (μmol/L)	4.70 (3.65,5.60)	4.50 (3.40,5.40)	5.00 (4.25,6.15)	−1.469	0.142
IBIL (μmol/L)	10.39±3.75	9.97±3.83	11.26±3.49	−1.369	0.176
ALB (g/L)	44.82±3.90	45.40±3.22	43.60±4.90	1.605	0.118
FPG (mmol/L)	5.10 (4.80,5.55)	5.00 (4.70,5.30)	5.40 (4.80,5.85)	−1.465	0.143
TC (mmol/L)	4.55 (4.14,5.12)	4.45 (3.82,5.15)	4.79 (4.36,5.08)	−1.696	0.090
TG (mmol/L)	1.62 (1.08,1.96)	1.44 (1.05,1.94)	1.74 (1.34,1.90)	−1.622	0.105
CRP (mg/L)	1.86 (1.05,3.58)	1.70 (0.75,3.82)	2.10 (1.45,3.10)	−0.873	0.383
CREATININE (μmol/L)	71.59±15.28	73.53±15.19	67.55±15.01	1.559	0.123
UA (μmol/L)	333.30 (271.90,387.30)	330.95 (265.30,392.82)	333.70 (293.80,373.80)	−0.430	0.667
HA	69.30 (57.89,108.10)	64.50 (56.35,103.27)	89.65 (60.83,141.65)	−1.990	0.047
PC-III	30.76 (23.23,49.30)	27.66 (23.05,40.79)	46.16 (27.93,78.42)	−2.175	0.030
LN	13.76 (7.00,20.42)	12.39 (6.29,16.47)	18.52 (10.46,23.61)	−2.292	0.022
IV-C	28.51 (23.98,38.06)	27.34 (22.33,35.86)	32.98 (28.91,48.69)	−3.231	0.001
APRI	0.58 (0.45,0.71)	0.58 (0.38,0.66)	0.65 (0.52,1.11)	−2.341	0.019
FIB-4	1.32 (0.94,2.24)	1.20 (0.86,1.67)	2.25 (1.30,3.20)	−3.060	0.002
CHI3L1 (ng/mL)	116.87±46.45	105.34±45.12	140.92±40.26	−3.216	0.002
FERRITIN (ng/mL)	237.79 (114.90,376.80)	217.03 (92.85,297.76)	351.37 (214.05,479.45)	−2.728	0.006
FE (μmol/L)	22.00±6.55	21.93±6.52	22.14±6.77	−0.131	0.896
CAP (dB/m)	302.00 (281.31,325.50)	296.91 (259.50,321.50)	315.38 (294.50,341.50)	−2.120	0.034
LSM (kpa)	7.90 (6.55,12.50)	7.40 (6.35,9.58)	11.30 (7.90,15.75)	−3.023	0.003
FIBROSIS STAGE F0/F1/F2/F3/F4	8/40/12/7/4

Notes: Data are shown as mean ± SD for normally distributed variables, or as median (25th, 75th percentiles), the bold values indicated statistically significant.

Abbreviations: BMI, Body Mass Index; WBC, White blood cell; RBC, Red blood cell; HGB, Hemoglobin; PLT, platelet count; ALT, Alanine transaminase; AST, Aspartate aminotransferase; ALP, Alkaline phosphatase; GGT, glutamyl transferase; TBIL, Total bilirubin; DBIL, Direct bilirubin; IBIL, Indirect bilirubin; ALB, Albumin; FPG, Fasting plasma-glucose; TC, Total cholesterol; TG, Triglyceride; CRP, C-reactive protein; UA, Uric acid; HA, Hyaluronic acid; PC-III, Procollagen type III; LN, Laminin; IV-C, Collagen type IV; APRI, AST-to-platelet ratio index; FIB-4, Fibrosis score-4; CHI3L1, Chitinase-3-like protein 1; CAP, Controlled attenuation parameter; LSM, Liver stiffness measurement.

Table 2 Results of Univariate and Multivariate Analysis for Prediction of Significant Fibrosis

Variables	Univariate		Multivariate
	OR[95% CI]	p	OR[95% CI]	p
GENDER	1.55[0.52,4.68]	0.433
AGE	1.04[0.99,1.08]	0.115
BMI	1.07[0.94,1.20]	0.301
PLT	0.99[0.99,1.00]	0.221
ALT	1.00[0.98,1.01]	0.769
AST	1.03[1.01,1.06]	0.006	1.04[1.00,1.07]	0.043
TBIL	1.06[0.96,1.17]	0.233
DBIL	1.05[0.86,1.30]	0.626
IBIL	1.10[0.96,1.26]	0.178
FPG	1.52[0.83,2.76]	0.172
TC	1.65[0.93,2.93]	0.089
TG	1.09[0.71,1.69]	0.686
CRP	0.95[0.82,1.11]	0.515
HA	1.00[1.00,1.00]	0.770
PC-III	1.01[1.00,1.03]	0.103
LN	1.05[0.99,1.11]	0.088
IV-C	1.05[1.01,1.09]	0.018	1.06[1.00,1.12]	0.040
CHI3L1	1.02[1.01,1.03]	0.004	1.02[1.01,1.04]	0.012
FERRITIN	1.00[1.00,1.00]	0.033
FE	1.01[0.93,1.08]	0.895
CAP	1.01[1.00,1.03]	0.031
LSM	1.19[1.06,1.34]	0.004	1.18[1.01,1.37]	0.040

Note: The bold values indicated statistically significant.

Abbreviations: BMI, Body Mass Index; PLT, platelet count; ALT, Alanine transaminase; AST, Aspartate aminotransferase; TBIL, Total bilirubin; DBIL, Direct bilirubin; IBIL, Indirect bilirubin; FPG, Fasting plasma –glucose; TC, Total cholesterol; TG, Triglyceride; CRP, C-reactive protein; HA, Hyaluronic acid; PC-III, Procollagen type III; LN, Laminin; IV-C, Collagen type IV; CHI3L1, Chitinase-3-like protein 1; CAP, Controlled attenuation parameter; LSM, Liver stiffness measurement; OR, Odds ratio; CI, confidence interval.

Table 3 Performance Assessment of Our Developed Nomogram Model and Other Variables (IV-C, CHI3L1, LSM, APRI and FIB-4) for the Prediction of Significant Fibrosis

Variables	AUC[95% CI]	p	Cutoff Value	Sensitivity (%)	Specificity (%)	PPV (%)	NPV (%)
IV-C	0.738[0.626,0.850]	0.001	28.120	0.870	0.625	0.526	0.909
CHI3L1	0.716[0.596,0.836]	0.003	125.315	0.696	0.688	0.516	0.825
LSM	0.737[0.604,0.870]	0.001	7.450	0.870	0.542	0.465	0.893
APRI	0.673[0.530,0.816]	0.020	0.745	0.478	0.875	0.647	0.778
FIB-4	0.726[0.599,0.853]	0.002	2.225	0.565	0.854	0.650	0.804
Nomogram	0.864[0.766,0.962]	<0.001	−0.157	0.696	0.917	0.800	0.863

Note: The bold values indicated statistically significant.

Abbreviations: IV-C, Collagen type IV; CHI3L1, Chitinase-3-like protein 1; LSM, Liver stiffness measurement; APRI, AST-to-platelet ratio index; FIB-4, Fibrosis score-4; AUC, Area under receiver operating characteristics curve; CI, Confidence interval; PPV, Positive predictive value; NPV, Negative predictive value.

Table 4 The Comparation of AUROCs of IV-C, CHI3L1, LSM, APRI, FIB-4, and Nomogram for the Detection of Significant Fibrosis

Variables	AUC1	SE1	AUC2	SE2	z	p
IV-C VS CHI3L1	0.738	0.062	0.716	0.062	0.253	0.800
IV-C VS LSM	0.738	0.058	0.737	0.066	0.011	0.992
IV-C VS APRI	0.738	0.054	0.673	0.073	0.780	0.436
IV-C VS FIB-4	0.738	0.060	0.726	0.069	0.141	0.888
IV-C VS nomogram	0.738	0.058	0.864	0.046	−2.169	0.030
CHI3L1 VS LSM	0.716	0.063	0.737	0.062	−0.235	0.814
CHI3L1 VS APRI	0.716	0.062	0.673	0.072	0.491	0.623
CHI3L1 VS FIB-4	0.716	0.062	0.726	0.067	−0.101	0.919
CHI3L1 VS nomogram	0.716	0.065	0.864	0.050	−2.332	0.020
LSM VS APRI	0.737	0.069	0.673	0.072	0.670	0.503
LSM VS FIB-4	0.737	0.067	0.726	0.068	0.122	0.903
LSM VS nomogram	0.737	0.064	0.864	0.051	−2.133	0.033
APRI VS FIB-4	0.673	0.071	0.726	0.070	−0.915	0.360
APRI VS nomogram	0.673	0.070	0.864	0.049	−2.820	0.005
FIB-4 VS nomogram	0.726	0.068	0.864	0.048	−1.750	0.080

Note: The bold values indicated statistically significant.

Abbreviations: IV-C, Collagen type IV; CHI3L1, Chitinase-3-like protein 1; LSM, Liver stiffness measurement; APRI, AST-to-platelet ratio index; FIB-4, Fibrosis score-4; AUC, Area under receiver operating characteristics curve.

Figure 2 Receiver operating characteristics (ROC) curves for predicting significant fibrosis.

Abbreviations: IV-C, Collagen type IV; CHI3L1, Chitinase-3-like protein 1; LSM, Liver stiffness measurement; APRI, AST-to-platelet ratio index; FIB-4. Fibrosis score-4.

Figure 3 Nomogram: A nomogram was created to predict significant fibrosis in NAFLD.

Notes: Values for each variable are individually plotted and correspond to point values assigned from the point scale (top). A total score was obtained from the values of each index, and plotted on the total point scale (bottom), which is used to assign a corresponding value for the predicted rate of the nomogram.

Figure 4 The calibration curves for nomogram (1000 bootstrap resamples) for predicting significant fibrosis in NAFLD. Nomogram-predicted probability of significant fibrosis is plotted on the x-axis; actual probability is plotted on the y-axis.