Liver Fibrosis Scores and Coronary Artery Disease: Novel Findings in Patients with Metabolic Dysfunction-Associated Fatty Liver Disease

Figures & data

Box 1 Metabolic Risk Abnormalities - 2 Out of 7

1. Waist circumference ≥102/88 cm in Caucasian men and women, (or≥90/80 cm in Asian men or women);

2. Blood pressure ≥130/85 mmHg or specific drug treatment;

3. Plasma triglycerides ≥150 mg/dL (≥1.70 mmol/L) or specific drug treatment;

4. Plasma HDL-C <40 mg/dL (<1.0 mmol/L) for men and <50 mg/dL (<1.3 mmol/L) for women or specific drug treatment;

5. Prediabetes (ie fasting glucose levels 100–125 mg/dL (5.6–6.9 mmol/L) or 2-hour post-load glucose levels 140–199 mg/dL (7.8–11.0 mmol/L) or HbA1c of 5.7–6.4% (39–47 mmol/mol);

6. Homeostasis model assessment of insulin resistance score ≥2.5;

7. Plasma high-sensitivity C-reactive protein level >2 mg/L.

Abbreviations: HDL-C, high-density lipoprotein cholesterol; HbA1c, glycosylated hemoglobin.

Table 1 Baseline Characteristics of the Participants

Characteristic	Normal	Non-Obstructive	CAD	p-value
	n=214	n=925	n=207
Age (years)	50.91±11.53	59.01±10.61*	62.73±10.48*^+	<0.001
Male	98(45.8%)	437(47.2%)	127(61.4%)*^+	<0.001
BMI (kg/m^2)	27.71±3.26	27.61±3.31	27.52±2.87	0.661
Systolic pressure (mmHg)	135.44±19.55	140.02±19.67*	143.58±20.33*^+	<0.001
Diastolic pressure (mmHg)	88.95±14.50	88.42±12.46	88.85±13.46	0.956
HTN	103(48.1%)	614(66.4%)*	151(72.9%)*	<0.001
T2DM	32(15.0%)	194(21.0%)	70(33.8%)*^+	<0.001
Carotid atherosclerosis	52(24.3%)	389(42.1%)*	151(72.9%)*^+	<0.001
Fasting glucose (mmol/L)	5.69(5.17, 6.61)	5.89(5.25, 7.25)	6.25(5.44, 8.06)*^+	<0.001
HbA1c (100%)	5.7(5.5, 6.1)	5.9(5.6, 6.4)*	6.1(5.8, 6.8)*^+	<0.001
Platelet (×109/L)	237.55±57.83	231.19±53.86	231.89±72.72	0.327
Creatinine (umol/L)	65.19±15.20	65.12±14.04	69.04±16.23*^+	0.003
eGFR	107.26±21.43	103.93±20.62*	101.28±24.41*	0.021
UA (umo/L)	370.40±90.92	360.31±87.03	370.71±88.19	0.146
ALT (U/L)	29.11(19.47, 48.56)	26.59(19.65, 37.22)	25.46(17.77, 34.49)^+	0.010
AST (U/L)	22.31(18.40, 31.14)	21.72(18.15, 27.22)	21.83(17.57, 27.83)	0.749
ALB (g/L)	43.85±3.16	43.23±3.36*	42.81±3.25*	0.029
TB (umol/L)	12.31(9.46, 16.17)	12.72(9.84, 16.54)	12.20(9.50, 15.47)	0.647
TC (mg/dl)	4.81±0.91	4.92±1.07	4.74±1.24 ^+	0.049
TG (mg/dl)	1.73(1.25, 2.36)	1.73(1.25, 2.40)	1.56(1.17, 2.28)	0.396
HDL-C (mg/dl)	1.12±0.24	1.14±0.27	1.11±0.25	0.273
LDL-C (mg/dl)	2.62±0.69	2.64±0.78	2.57±0.92	0.465
Apo A (mg/dl)	1.38±0.20	1.39±0.21	1.35±0.21 ^+	0.021
Apo B (mg/dl)	0.94±0.20	0.96±0.23	0.94±0.25	0.366
FIB-4 score	1.06±0.78	1.28±0.75*	1.45±0.89*^+	<0.001
NFS	−1.92±1.24	−1.33±1.58*	−0.93±2.13*^+	<0.001
APRI	0.23(0.19, 0.34)	0.24(0.19, 0.32)	0.24(0.19, 0.34)	0.883
CAC scores	0(0, 0)	0(0, 35.9)*	241.0(86.7, 510.0)*^+	<0.001
0	212(99.1%)	463(50.1%)*	11(5.3%)*^+	<0.001
0–100	1(0.5%)	338(36.5%)*	46(22.2%)*^+	<0.001
>100	1(0.5%)	124(13.4%)*	150(72.5%)*^+	<0.001

Notes: *p<0.05 vs Normal group; ⁺p<0.05 vs Non-obstructive group.

Abbreviations: CAD, coronary artery disease; BMI, body mass index; HTN, hypertension; T2DM, type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; eGFR, estimated glomerular filtration rate; UA, uric acid; ALT, alanine aminotransferase; AST, aspartate aminotransferase; ALB, albumin; TB, total bilirubin; TC, total cholesterol, TG, triglyceride; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein; Apo A, apolipoproteins A; Apo B, apolipoproteins B; FIB-4, fibrosis 4; NFS, nonalcoholic fatty liver disease fibrosis score; APRI, aspartate aminotransferase-to-platelet ratio index; CAC scores, coronary artery calcium scores.

Figure 1 The percentage of liver fibrosis risk divided by the FIB-4 score in the normal, non-obstructive, and CAD groups. The percentage of high FIB-4 score were significantly higher in the CAD group than in the other two groups (p<0.01).

Abbreviations: FIB-4, fibrosis 4; CAD, coronary artery disease.

Figure 2 The percentage of liver fibrosis risk divided by the NFS in the normal, non-obstructive, and CAD groups. The percentage of high NFS were significantly higher in the CAD group than in the other two groups (p<0.01).

Abbreviations: NFS, nonalcoholic fatty liver disease fibrosis score; CAD, coronary artery disease.

Table 2 Factors Associated with CAD in Subjects with MAFLD: Logistic Regression

Variable	Univariate		Multivariate
	OR (95% CI)	p-value	OR (95% CI)	p-value
Age (years)	1.047 (1.032–1.062)	<0.001
Male	0.558 (0.412–0.755)	<0.001
BMI (kg/m^2)	0.986 (0.941–1.033)	0.555
Systolic pressure (mmHg)	1.011 (1.004–1.018)	0.003
Diastolic pressure (mmHg)	1.001 (0.989–1.012)	0.897
HTN	1.587 (1.142–2.206)	0.006
T2DM	2.064 (1.495–2.850)	<0.001
Carotid atherosclerosis	4.268 (3.071–5.931)	<0.001	2.058 (1.350–3.138)	<0.001
Fasting glucose (mmol/L)	1.071 (1.022–1.123)	0.004
HbA1c (100%)	1.255 (1.131–1.393)	<0.001
Platelet (×109/L)	0.999 (0.997–1.002)	0.568
Creatinine (umol/L)	1.017 (1.007–1.027)	<0.001	1.020 (1.005–1.035)	0.010
eGFR	0.993 (0.986–1.000)	0.058
UA (umol/L)	1.001 (0.999–1.003)	0.299
ALB (g/L)	0.961 (0.919–1.005)	0.083
TB (umol/L)	0.997 (0.973–1.022)	0.810
TC (mg/dl)	0.864 (0.750–0.994)	0.041
TG (mg/dl)	0.945 (0.848–1.053)	0.305
HDL-C (mg/dl)	0.680 (0.384–1.204)	0.186
LDL-C (mg/dl)	0.890 (0.735–1.077)	0.229
Apo A (mg/dl)	0.387 (0.184–0.813)	0.012
Apo B (mg/dl)	0.726 (0.374–1.410)	0.344
FIB-4 score	1.345 (1.142–1.583)	<0.001
NFS	1.191 (1.080–1.313)	<0.001
APRI	1.471 (0.936–2.311)	0.094
CAC scores	1.007 (1.006–1.009)	<0.001	1.007 (1.005–1.008)	<0.001

Abbreviations: CAD, coronary artery disease; MAFLD, metabolic dysfunction-associated fatty liver disease; BMI, body mass index; HTN, hypertension; T2DM, type 2 diabetes mellitus; HbA1c, glycosylated hemoglobin; eGFR, estimated glomerular filtration rate; UA, uric acid; ALB, albumin; TB, total bilirubin; TC, total cholesterol, TG, triglyceride; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein; Apo A, apolipoproteins A; Apo B, apolipoproteins B; FIB-4, fibrosis 4; NFS, nonalcoholic fatty liver disease fibrosis score; APRI, aspartate aminotransferase-to-platelet ratio index; CAC scores, coronary artery calcium scores; OR, odds ratio; CI, confidential interval.

Table 3 Associations of Noninvasive Fibrosis Scores with CAD in Subjects with MAFLD: Logistic Regression

Variable	OR (95% CI)	p-value
FIB-4 score
Unadjusted	1.345 (1.142–1.583)	<0.001
Model 1	1.388 (1.176–1.639)	<0.001
Model 2	1.238 (1.042–1.471)	0.015
Model 3	1.229 (1.031–1.464)	0.021
NFS
Unadjusted	1.191 (1.080–1.313)	<0.001
Model 1	1.218 (1.101–1.348)	<0.001
Model 2	1.114 (1.023–1.214)	0.013
Model 3	1.108 (1.018–1.207)	0.018

Notes: Model 1: adjusted for gender; Model 2: adjusted for gender and presence of hypertension, DM, and carotid atherosclerosis; Model 3: adjusted items in Model 2 plus for total cholesterol and creatinine.

Abbreviations: CAD, coronary artery disease; MAFLD, metabolic dysfunction-associated fatty liver disease; FIB-4, fibrosis 4; NFS, nonalcoholic fatty liver disease fibrosis score; OR, odds ratio; CI, confidential interval.

Table 4 Correlation of Liver Fibrosis Scores with Clinical Parameters: Correlation Analysis

Variables	FIB-4 Score		NFS
	r	P	r	P
BMI	−0.141	<0.01	0.087	<0.01
Systolic pressure	−0.007	0.801	0.013	0.645
Diastolic pressure	−0.167	<0.01	−0.157	<0.01
Fasting glucose	0.013	0.621	0.406	<0.01
HbA1c	0.086	0.002	0.345	<0.01
TC	−0.071	0.009	−0.119	<0.01
TG	−0.131	<0.01	−0.113	<0.01
HDL-C	0.063	0.020	0.029	0.281
LDL-C	−0.089	<0.01	−0.109	<0.01
CAC scores	0.285	<0.01	0.245	<0.01

Abbreviations: FIB-4, fibrosis 4; NFS, nonalcoholic fatty liver disease fibrosis score; BMI, body mass index; HbA1c, glycosylated hemoglobin; TC, total cholesterol, TG, triglyceride; HDL-C, high-density lipoprotein; LDL-C, low-density lipoprotein; CAC scores, coronary artery calcium scores.