Diagnostic accuracy of noninvasive steatosis biomarkers with magnetic resonance imaging proton density fat fraction as gold standard

Table 1 Noninvasive biomarkers for predicting hepatic steatosis and fibrosis in this study

Biomarkers	Component and formula
Steatosis biomarkers
FLI	FLI = 100/ (1 + e-z); Z = 0.953 × lnTG (mg/dL) + 0.139 × BMI (kg/m2) + 0.718 × lnGGT (IU/L) + 0.053 × WC (cm) - 15.745
HSI	HSI = 8 × ALT/AST + BMI (kg/m2) + 2 (if diabetes) + 2 (if female)
ZJU index	ZJU index = BMI (kg/m2) + FBG (mmol/L) + TG (mmol/L) + 3 × ALT/AST + 2 (if female)
FSI	FSI = 100/ (1 + e-z); Z = -7.981 + 0.011 × age (years) – 0.146 × sex (female = 1, male = 0) + 0.173 × BMI + 0.007 × TG (mg/dL) + 0.593 × hypertension (yes = 1, no = 0) + 0.789 × diabetes (yes = 1, no = 0) + 1.1 × ALT/AST ratio ≥ 1.33 (yes = 1, no = 0)
TyG index	TyG index = ln (TG (mg/dL) × FBG (mg/dL)/2)
VAI	VAI (male)= [WC (cm)/39.68 + (1.88 × BMI (kg/m2))] × (TG (mmol/L)/1.03) × (1. 31/HDL (mmol/L)); VAI (female) = [WC (cm)/36.58 + (1.89 × BMI (kg/m2))] × (TG (mmol/L)/0.81) × (1.52/HDL (mmol/L))
Fibrosis biomarkers
NFS	NFS = -1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m2) + 1.13 × (hyperglycemia; yes = 1, no = 0) + 0.99 × AST/ALT ratio - 0.013 × platelet (× 109/L) - 0.66 × albumin (g/dL)
FIB-4	FIB-4 = age (years)× AST (IU/L)/platelet (× 109/L) × ALT (IU/L)1/2

FLI: Fatty liver index; HSI: Hepatic steatosis index; FSI: Framingham steatosis index; TyG: Triglycerides and glucose; VAI: Visceral adiposity index; NFS: Nonalcoholic fatty liver disease fibrosis score; FIB-4: Fibrosis-4 index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; BMI: Body mass index; TG: Triglyceride; GGT: Gamma-glutamyl transpeptidase; HDL: High-density lipoprotein; WC: Waist circumference.

Table 2 Baseline characteristics

Characteristics	Total	None (PDFF < 5%)	Mild (5% ≤ PDFF < 11%)	Moderate (11% ≤ PDFF < 17%)	Severe (PDFF ≥ 17%)	P value for trend3
Number	131 (100)	35 (26.7)	48 (36.6)	25 (19.1)	23 (17.6)
MRI-PDFF	9.6 ± 7.4	2.5 ± 0.9	7.1 ± 1.8	12.5 ± 1.7	22.7 ± 5.1	< 0.001
Median (IQR)	7.7 (4.1-12.1)	2.3 (1.8-3.3)	6.9 (5.5-8.7)	11.9 (11.4-13.9)	20.9 (18.9-25.5)	< 0.001
Demographics
Age, years	36 (32-47)	34 (31-38)	39 (33-51)	42 (35-54)	33 (29-42)	0.487
Male	78 (59.5)	13 (37.1)	29 (60.4)	16 (64.0)	20 (87.0)	< 0.001
Current smoking	25 (19.1)	5 (14.3)	11 (22.9)	6 (24.0)	3 (13.0)	0.978
Anthropometrics
BMI, kg/m2	27 ± 4	24 ± 3	27 ± 3	28 ± 3	30 ± 3	< 0.001
Overweight1	105 (80.2)	17 (48.6)	42 (87.5)	23 (92.0)	23 (100.0)	< 0.001
Obesity2	43 (32.8)	5 (14.3)	10 (20.8)	12 (48.0)	16 (69.6)	< 0.001
Waist circumference, cm	94.0 ± 10.8	85.9 ± 11.2	95.0 ± 8.8	99.8 ± 8.8	101.8 ± 6.8	< 0.001
Waist-to-hip ratio	0.90 ± 0.06	0.86 ± 0.06	0.91 ± 0.04	0.94 ± 0.05	0.94 ± 0.04	< 0.001
Metabolic diseases
Abdominal obesity	99 (75.6)	15 (42.9)	37 (77.1)	25 (100.0)	22 (95.7)	< 0.001
Arterial hypertension	68 (51.9)	12 (34.3)	25 (52.1)	17 (68.0)	14 (60.9)	0.017
Type 2 diabetes mellitus	12 (9.2)	2 (5.7)	3 (6.2)	5 (20.0)	2 (8.7)	0.283
Hyperglycemia	19 (14.5)	2 (5.7)	6 (12.5)	8 (32.0)	3 (13.0)	0.108
High TG	69 (52.7)	6 (17.1)	29 (60.4)	18 (72.0)	16 (69.6)	< 0.001
Low HDL-C	33 (25.2)	6 (17.1)	15 (31.2)	6 (24.0)	6 (26.1)	0.573
Metabolic syndrome	58 (44.3)	8 (22.9)	21 (43.8)	18 (72.0)	11 (47.8)	0.007
Laboratory tests
ALT, IU/L	28 (19-43)	14 (11-23)	26 (21-38)	34 (27-49)	53 (37-100)	< 0.001
AST, IU/L	22 (18-26)	18 (16-22)	21 (17-26)	22 (20-26)	31 (24-40)	< 0.001
Total bilirubin, μmol/L	13.5 ± 6.4	12.5 ± 6.0	13.0 ± 5.0	14.9 ± 6.2	14.2 ± 8.9	0.292
GGT, IU/L	29 (21-50)	17 (11-25)	29 (22-50)	28 (23-55)	50 (35-72)	< 0.001
Albumin, g/L	47 ± 2	47 ± 3	48 ± 2	47 ± 2	48 ± 2	0.519
TC, mmol/L	4.61 ± 0.86	4.26 ± 0.77	4.76 ± 0.86	4.71 ± 0.96	4.71 ± 0.81	0.073
TG, mmol/L	1.87 ± 1.20	0.96 ± 0.56	2.02 ± 1.04	2.09 ± 1.05	2.70 ± 1.54	< 0.001
HDL-C, mmol/L	1.24 ± 0.29	1.38 ± 0.37	1.22 ± 0.27	1.19 ± 0.22	1.12 ± 0.17	0.001
LDL-C, mmol/L	2.76 ± 0.77	2.45 ± 0.59	2.92 ± 0.78	2.87 ± 0.91	2.80 ± 0.73	0.126
FBG, mmol/L	5.23 (4.93-5.81)	4.94 (4.68-5.31)	5.23 (5.02-5.81)	5.50 (4.97-6.16)	5.44 (5.21-5.93)	< 0.001
Uric acid, μmol/L	343 ± 88	299 ± 99	344 ± 66	353 ± 86	397 ± 86	< 0.001
Platelet count, × 109/L	265 ± 60	255 ± 64	265 ± 61	270 ± 52	273 ± 61	0.243
Steatosis biomarkers
FLI	53 ± 28	24 ± 22	56 ± 21	66 ± 17	78 ± 18	< 0.001
HSI	39 ± 7	33 ± 5	39 ± 5	42 ± 4	47 ± 6	< 0.001
ZJU index	39 ± 5	34 ± 4	40 ± 4	42 ± 3	45 ± 4	< 0.001
FSI	30 (14-55)	6 (3-15)	29 (20-42)	52 (37-64)	62 (50-87)	< 0.001
TyG index	8.8 ± 0.7	8.1 ± 0.5	9.0 ± 0.5	9.0 ± 0.5	9.3 ± 0.5	< 0.001
VAI	2.07 (1.33-3.17)	1.04 (0.71-1.44)	2.25 (1.66-3.25)	2.28 (1.76-3.88)	2.97 (2.02-4.88)	< 0.001
Fibrosis biomarkers
NFS	-3.204 ± 1.001	-3.231 ± 1.111	-3.205 ± 1.096	-2.950 ± 1.134	-3.593 ± 1.066	0.316
NFS < -1.455	125 (95.4)	33 (94.3)	47 (97.9)	23 (92.0)	22 (95.7)	0.888
-1.455 ≤ NFS ≤ 0.676	6 (4.6)	2 (5.7)	1 (2.1)	2 (8.0)	1 (4.3)
NFS > 0.676	0	0	0	0	0
FIB-4	0.58 (0.48-0.76)	0.69 (0.52-0.76)	0.65 (0.44-0.82)	0.56 (0.47-0.91)	0.49 (0.42-0.67)	0.239
FIB-4 < 1.30	122 (93.1)	34 (97.1)	42 (87.5)	24 (96.0)	22 (95.7)	0.876
1.30 ≤ FIB-4 ≤ 2.67	9 (6.9)	1 (2.9)	6 (12.5)	1 (4.0)	1 (4.3)
FIB-4 > 2.67	0	0	0	0	0

¹Overweight was defined as body mass index ≥ 24 kg/m².

²Obesity was defined as body mass index ≥ 28 kg/m².

³P value for trend was determined by comparing the baseline characteristics of subjects from four ordinal steatosis grade groups (none, mild, moderate, severe) using a one-way analysis of variance for trend analysis, Jonchheere-Terpstra trend test, or Mantel-Haenszel χ² test for linear trend analysis.

Data are expressed as the mean ± SD or median (IQR) or n (%). PDFF: Proton density fat fraction; MRI-PDFF: Magnetic resonance imaging proton density fat fraction; BMI: Body mass index; TG: Triglyceride; TC: Total cholesterol; HDL-C: High-density lipoprotein cholesterol; LDL-C: Low-density lipoprotein cholesterol; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; GGT: Gamma-glutamyl transpeptidase; FBG: Fasting blood glucose; FLI: Fatty liver index; HSI: Hepatic steatosis index; FSI: Framingham steatosis index; TyG: Triglycerides and glucose; VAI: Visceral adiposity index; NFS: Nonalcoholic fatty liver disease fibrosis score; FIB-4: Fibrosis-4 index.

Table 3 The diagnostic accuracy of each steatosis biomarkers in identifying nonalcoholic fatty liver disease as defined by magnetic resonance imaging proton density fat fraction ≥ 5%

Biomarkers	AUC (95%CI)	Cut-off1	Youden index	SE, %	SP, %	PLR	NLR	PPV, %	NPV, %	Accuracy, %
FLI	0.899 (0.832-0.966)	≥ 42	0.701	84.4	85.7	5.91	0.18	94.2	66.7	84.0
HSI	0.898 (0.839-0.955)	≥ 34	0.641	92.7	71.4	3.24	0.10	89.9	78.1	86.3
ZJU index	0.903 (0.843-0.962)	≥ 37	0.688	91.7	77.1	4.01	0.11	91.7	77.1	87.0
FSI	0.912 (0.849-0.954)	≥ 15	0.688	91.7	74.3	4.01	0.11	91.7	77.1	87.8
TyG index	0.902 (0.839-0.966)	≥ 8.5	0.649	90.6	74.3	3.52	0.13	90.6	74.3	86.3
VAI	0.857 (0.774-0.937)	≥ 1.49	0.675	87.5	80.0	4.38	0.16	92.3	70.0	85.5

¹The optimal cut-off with the highest Youden index.

AUC: Area under the receiver operating characteristic curve; 95%CI: 95% confidence interval; FLI: Fatty liver index; HSI: Hepatic steatosis index; FSI: Framingham steatosis index; TyG: Triglycerides and glucose; VAI: Visceral adiposity index; SE: Sensitivity; SP: Specificity; PLR: Positive likelihood ratio; NLR: Negative likelihood ratio; PPV: Positive predictive value; NPV: Negative predictive value.

Table 4 The diagnostic accuracy of noninvasive steatosis biomarkers in excluding or confirming the presence of nonalcoholic fatty liver disease as defined by magnetic resonance imaging proton density fat fraction ≥ 5%

Biomarkers	AUC (95%CI)	SE, %	SP, %	PLR	NLR	PPV, %	NPV, %	Accuracy, %	Overall accuracy to exclude1 and confirm2 NAFLD, %
FLI (n = 131)
Exclusionary cut-off < 20	0.766 (0.684-0.836)	99.0	54.3	2.16	0.02	85.6	95.0	87.0
Confirmatory cut-off ≥ 68	0.701 (0.614-0.777)	45.8	94.3	8.02	0.57	95.7	38.8	58.8	48.1
HSI (n = 131)
Exclusionary cut-off < 33	0.781 (0.700-0.848)	99.0	57.1	2.31	0.02	86.4	95.2	87.8
Confirmatory cut-off ≥ 39	0.790 (0.711-0.857)	66.7	91.4	7.78	0.36	95.5	50.0	73.3	64.1
ZJU index (n = 131)
Exclusionary cut-off < 34	0.766 (0.684-0.836)	99.0	54.3	2.16	0.02	85.6	95.0	87.0
Confirmatory cut-off ≥ 41	0.732 (0.647-0.805)	52.1	94.3	9.11	0.51	96.2	41.8	63.3	52.7
FSI (n = 131)
Exclusionary cut-off < 7	0.775 (0.694-0.844)	97.9	57.1	2.28	0.04	86.2	90.9	87.0
Confirmatory cut-off ≥ 42	0.711 (0.625-0.787)	47.9	94.3	8.39	0.55	95.8	39.8	60.3	50.4
TyG index (n = 131)
Exclusionary cut-off < 8.0	0.700 (0.614-0.777)	100.0	40.0	1.67	0.00	82.1	100.0	84.0
Confirmatory cut-off ≥ 9.2	0.664 (0.576-0.744)	38.5	94.3	6.74	0.65	94.9	35.9	53.4	38.9
VAI (n = 131)
Exclusionary cut-off < 0.79	0.638 (0.549-0.720)	99.0	28.6	1.39	0.04	79.2	90.9	80.2
Confirmatory cut-off ≥ 3.29	0.617 (0.528-0.701)	29.2	94.3	5.10	0.75	93.3	32.7	46.6	29.0

¹Criteria for the exclusionary cut-off were sensitivity > 90% and negative likelihood ratio ≤ 0.1.

²Criteria for the confirmatory cut-off were specificity > 90% and positive likelihood ratio ≥ 10.

AUC: Area under the receiver operating characteristic curve; 95%CI: 95% confidence interval; FLI: Fatty liver index; HSI: Hepatic steatosis index; FSI: Framingham steatosis index; TyG: Triglycerides and glucose; VAI: Visceral adiposity index; SE: Sensitivity; SP: Specificity; PLR: Positive likelihood ratio; NLR: Negative likelihood ratio; PPV: Positive predictive value; NPV: Negative predictive value; NAFLD: Nonalcoholic fatty liver disease.