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Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23 Page 9 of 22

Combined primary endpoints: all CV death, multivariable adjustment (sex, race, NYHA class, smoking, SBP, serum sodium, blood urea and clinical outcomes related to HF events
aborted cardiac arrest, and hospitalization for HF nitrogen, prior CVD, previous hospitalization for HF and ongoing spironolactone)
Cox MVA was used to test the association
between the risk of fibrosis severity and the
combined primary endpoint
Parikh Nested case-cohort study within the REGARDS 572 incident ischemic strokes were registered during follow-up. No significant association was In women (but not men), there may be an
[67]
et al. cohort: black and white participants aged ≥ 45 found between liver fibrosis and ischemic stroke globally with FIB-4 and NFS. Nevertheless, such association between advanced hepatic fibrosis
years recruited between 2003 and 2007 and an association was found in women alone using FIB-4 and enhanced ischemic stroke risk
followed up for ischemic stroke (median duration
5.4 years)
FIB-4 and NFS were calculated using baseline
data for stroke cases and a random cohort sample
Cox proportional hazards models were used to
estimate the HR of stroke after adjusting for
potential confounders. Sex differences were
assessed
[68]
Oh et al. 4163 subjects from the Korean Genome and During follow-up, 643 subjects (15.4%) died. FIB-4, NFS, and APRI were consistently higher in In Koreans, noninvasive assessment of fibrosis
Epidemiology Study were followed biannually deceased subjects regardless of baseline glucose metabolism status correlates with overall and hepato-specific
over a 15.6 median period FIB-4 and NFS exhibited acceptable discrimination power for mortality, with AUROC values of mortality
Cox proportional hazards regression was used to 0.686 and 0.666, respectively. HRs for FIB-4 and NFS were 1.41 and 1.43, respectively (adjusted
gauge the HRs of either NAFLD or indexes of for age, sex, smoking, BMI, and HbA1c)
hepatic fibrosis in the global patient population FIB-4 and NFS were significantly associated with liver-specific mortality but not CV mortality
and subsets identified with BMI and The association between mortality with fibrosis indices was more marked among subjects with
2
glucometabolic status BMI < 25 kg/m
Delgado The impact of NAFLD noninvasive fibrosis indices Modeling the common NAFLD and fibrosis scores, FIB-4 and NFS, as splines revealed significant Noninvasive indices of fibrosing NAFLD do not
[69]
et al. was evaluated in a large cohort of German associations with all-cause and CV mortality when Cox regression models were only adjusted for offer additional data in assessing CVD events
patients (3316 subjects) referred to coronary CVR factors that were not already included in the calculation of the scores among angiography-proven CAD
angiography between 1997 and 2000. Median Stratifying the scores into quartiles yielded HRs for all-cause and CV mortality for the fourth
follow-up of 9.8 years (range 0.1-11.3) quartile versus the first quartile of 2.28 and 2.11 for FIB-4 and 3.21 and 3.12 for NFS
However, an independent association of FIB-4 or NFS with overall or CV mortality was not
observed in the prospective CAD cohort after full adjustment for age, sex, BMI, T2D,
hypertension, smoking, LDL-C, HDL-C, medication, and alcohol intake
Tamaki 3512 subjects were enrolled in this prospective FRS ≥ 20% was found in 17.5% CVD risk was associated with liver fibrosis and
[70]
et al. study between April 2019 and November 2020 Advanced fibrosis (FIB-4 ≥ 2.67, NFS ≥ 0.675, and WFA+ -M2BP ≥ 1.0) and the presence of fatty steatosis irrespective of CVR copathologies
Liver fibrosis was assessed noninvasively with liver was significantly associated with high CVD risk independent of metabolic confounding suggesting that these hepatic conditions may
FIB-4, NFS, and WFA+ -M2BP, and fatty liver was factors (T2D, dyslipidemia, and hypertension) help disclose individuals at a high CVR
diagnosed with US. (OR 2.53-9.62)
FRS ≥ 20% identified an elevated risk of CVD Advanced fibrosis and steatosis were associated with the most elevated CVD risk. Next were
individuals with advanced hepatic fibrosis in the absence of steatosis
[71]
Akuta et al. Retrospective investigation of the incidence and MVA FIB-4 ≥ 2.7 strongly predicted the three disease outcomes, independently of CKD, PNPLA3 Data have shown that the FIB-4 index ≥ 2.67
noninvasive predictors of CVDs, extra-hepatic rs738409, BMI, hypertension, and extra-hepatic malignancies (and PNPLA3 genotype) affects the incidence
cancer, and liver-related complications in 477 Moreover, the global occurrence of CVDs significantly differed among the various PNPLA3 of complications, particularly CVDs, among
Japanese patients with biopsy-proven NAFLD polymorphisms. These CVD risk factors could be attributed to CC PNPLA3 genotype, CKD, and Japanese NAFLD patients
followed for a median of 5.9 years FIB-4 ≥ 2.7
[72]
Jin et al. This study enrolled 5143 individuals with stable Both NFS and FIB-4 predicted CAC. All CAD severity parameters were significantly more NFS and FIB-4 were significantly associated
CAD demonstrated angiographically who were elevated among those with higher NFS scores with CAD severity, CAC, and CVEs
followed up for seven years At Kaplan-Meier analysis, patients with intermediate and high NFS and FIB-4 scores had a higher