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Page 10 of 22 Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23

CAD severity was assessed with the number of risk of CVEs and CV mortality
diseased vessels, Gensini, Syntax, and Jeopardy At Cox MVA, NFS and FIB-4 were independently associated with CVEs [HR (95%CI): 1.150
scores (1.063-1.244), P < 0.001 and 1.128 (1.026-1.240), P = 0.012] (adjusted for sex, BMI, current
Outcome: predictive values of NFS and FIB-4 for smoking, T2D, hypertension, family history of CAD, left ventricular ejection fraction, creatinine,
CAD severity, CAC, and CVEs TG, LDL-C, HDL-C and baseline statin use)
[73]
Zupo et al. 1929 elderly patients were recruited in a The eight-year risk of death was almost two-fold among individuals in the highest-risk FIB-4 In clinical practice, FIB-4 may help to identify
population study in southern Italy, followed for score group, even after controlling for possible confounding factors (age, sex, smoking, individuals at risk of higher mortality
eight years education, alcohol consumption, and multimorbidity)
Based on the FIB-4 score, patients were assigned FIB-4 scores were associated with a steeper mortality curve than the APRI scores
to three liver fibrosis risk groups (low,
intermediate, and high)
For comparison purposes, the APRI score was
also calculated in secondary analyses
[74]
Zupo et al. 1929 elderly individuals Compared to non-frail elderly individuals, liver frailty subjects were significantly older, with lower Compared to non-frail controls, the liver frailty
Cardiovascular Health Study criteria were education and higher multimorbidity phenotype - defined based on simple measures
employed to classify physical frailty At Cox MVA, a two-fold increased overall mortality risk (HR 2.09) was found after adjusting for primarily available in a primary care setting - is
Mean observation time from a maximum of 56.87 confounding factors (age, sex, education, and alcohol consumption) associated with a two-fold increased risk of
± 22.41 to a minimum of 48.49 ± 18.69 months overall mortality in a patient population from
Physical frailty + FIB-4 above 2.67 is defined as southern Italy
“liver frailty”
Physical frailty, high-risk liver fibrosis, and liver
frailty subjects were compared to non-frail
controls
Proportional Cox regression tested each
category’s adjusted association between liver
frailty and all-cause mortality

Vieira 81,108 patients with (a) NAFLD, (b) NASH, or (c) After adjusting for established CVR factors, FIB-4 ≥ 2.67 remained the strongest independent FIB-4 ranks as the most accurate predictive
Barbosa at risk of NASH. Median follow-up: 3 years predictor of MACE overall (aHR 1.80) and was significantly associated with MI (aHR 1.46), factor of MACE, irrespective of traditional CVR
[75]
et al. Outcome: MACE (i.e., MI, hospitalization for hospitalization for unstable angina (aHR 1.24), hospitalization for HF (aHR 2.09), CABG (aHR factors and hepatic diagnosis at the baseline
unstable angina or HF, and coronary 1.65), and PCI (aHR 1.72)
revascularization)

AF: Atrial fibrillation; aHR : adjusted hazard ratio; APRI: aspartate aminotransferase to platelet ratio index; ARR: aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio; ASCVD atherosclerotic
cardiovascular disease; AUROC: area under the receiver operating charcateristics curve; BARD: BMI, AAR, Diabetes; BMI: body mass index; CAC: coronary artery calcification; CABG: coronary artery bypass graft;
CAD: coronary artery disease; CI: confidence intervals; CKD: chronic kidney disease; CRP: C reactive protein; CVD: cardiovascular disease; CVEs: cardiovascular events; CVR: cardiovascular risk; eGFR: estimated
glomerular filtration rate; ES: effect size; FIB-4: fibrosis-4 score; FR: Framingham risk; FRS: Framingham risk score; GPR: gamma-glutamyltransferase-to-platelet ratio; HbA1c: glycosylated hemoglobin; HBV: hepatitis
B virus; HCV: hepatitis C virus; HDL-C: high-density lipoprotein cholesterol; HF: heart failure; HFpEF: heart failure with preserved ejection fraction; HFS: Hepamet fibrosis score; aHR: adjusted HR; HR: hazard ratio;
hsCRP: high specificity C reactive protein; LDL-C: low-density lipoprotein cholesterol; KNHNES: Korea National Health and Nutrition Examination Survey; MACE: major cardiovascular events; MetS: metabolic
syndrome; MI: myocardial infarction; MVA: multivariate analysis; NAFLD: nonalcoholic fatty liver disease; NFS: NAFLD fibrosis score; NPV: negative predictive value; NASH: nonalcoholic steatohepatitis; NYHA: New
York Heart Association; PCI: percutaneous coronary intervention; PRA: proportional regression analysis; SCORE: European Systematic Coronary Risk Evaluation calculator; SBP, systolic blood pressure; SD, standard
deviation; T2D: type 2 diabetes; TG: triglycerides; US: ultrasonography; WFA+ -M2BP: Wisteria floribunda agglutinin- positive Mac-2 binding protein.

VCTE, ARFI, and SSI have shown good accuracy for noninvasively assessing the degree of fibrosis in patients with biopsy-proven NAFLD, although fewer
studies are available for SSI, and more data are requested regarding the best cut-off points for ARFI and SSI [52,82-85] . However, VCTE and SWE techniques are