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Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23 Page 7 of 22

Table 2. Principal recent studies show the association between fibrosis biomarkers and indirect and direct evidence of increased CVD risk and mortality among NAFLD patients

Author
(ref.) Series, method Findings Comment
Cross-
sectional
[58]
Kim et al. 11,154 participants in whom NAFLD was defined 3.2% of participants had NFS > 0.676, indicative of advanced fibrosis While US-diagnosed NAFLD is not associated
using US evidence of steatosis in the absence of The presence of NAFLD was not a risk factor for increased mortality. Conversely, mortality with increased mortality, advanced fibrosis,
competing liver diseases were followed for a increased paralleling advancing fibrosis scores such that those at a high probability of advanced assessed with noninvasive fibrosis markers,
median of 14.5 years fibrosis had a 69% increase in mortality (for NFS: HR 1.69; for APRI: HR 1.85; for FIB-4: HR 1.66) significantly predicts mortality, mainly owing to
Liver fibrosis presence and severity were vs. controls without fibrosis, after adjustment for age, sex, race-ethnicity, education, income, CVD, independent of confounders
evaluated through NFS, APRI, and FIB-4 diabetes, hypertension, history of CVD, lipid-lowering medication, smoking status, waist
circumference, alcohol, caffeine consumption, total cholesterol, HDL-C, transferrin saturation,
and CRP
Such increases in mortality were almost entirely accounted for by CVD (for NFS: HR 3.46; for
APRI: HR 2.53; for FIB-4: HR 2.68)
[59]
Song et al. 665 NAFLD subjects free of heart disease were MVA identified age, BMI, and eGFR as significantly predicted CACS > 100 Widely used blood biomarkers of liver fibrosis
enrolled NFS, FIB-4 score, and APRI were significantly associated with a CAC score > 100 after adjusting: can identify NAFLD patients with high CVD risk
NFS, FIB-4 score, Forn’s index, and the APRI were for age and sex (model 1) and age, sex, BMI, and eGFR (model 2)
used to evaluate the severity of hepatic fibrosis Predictive accuracy could be improved with integrated scores combining noninvasive biomarkers
of hepatic fibrosis with other parameters
Ballestri 157 HCV, 16 HBV, and 107 NAFLD consecutive Regardless of liver disease etiology, biomarkers of hepatic fibrosis performed better in predicting In NAFLD (and chronic viral hepatitis),
[45]
et al. patients were enrolled advanced rather than significant liver fibrosis biomarkers of hepatic fibrosis can exclude
The following liver fibrosis biomarkers were In NAFLD patients: advanced fibrosis and are associated with CVR
employed for capturing significant/advanced Forns index and HFS performed best in predicting advanced fibrosis scores
hepatic fibrosis: ARR; APRI; FIB-4; Forns index; Lower cut-offs of hepatic fibrosis biomarkers had high NPVs for advanced fibrosis
BARD; and HFS FIB-4, Forns index, NFS, and HFS were positively correlated with SCORE and FR risk scores
CVR was assessed using the following scoring
systems: SCORE, Progetto CUORE, or the FR
scoring systems
Schonmann Historical data on 8511 individuals, 3292 with Individuals with advanced fibrosis had higher CVD risk after adjustment for sociodemographic Fib-4, being independently associated with
[60]
et al. inconclusive fibrosis and 195 with advanced characteristics, the SCORE, use of statins and aspirin (HR 1.63). The association persisted in both CVD, offers the opportunity for using markers
fibrosis (FIB-4 ≥ 2.67), were retrieved from a females and males of liver fibrosis in CVD risk assessment in
computerized medical database When age-specific cut-offs were utilized, a significant dose-response association between primary care
Hepatic fibrosis was assessed with the FIB-4 inconclusive and advanced fibrosis and CVD was found (HR 1.15 and 1.60, respectively)
score, and the association with CVD was adjusted
for SCORE
[61]
Han et al. In 9444 KNHNES participants, liver fibrosis was The quartiles of ASCVD risk scores were positively correlated to MAFLD and FIB-4 defined- MAFLD per se carries a substantial ASCVD
assessed with FIB-4 and NFS significant liver fibrosis (P for trend < 0.001) risk, further worsened by concomitant
A high ASCVD risk was defined as a 10-year Compared to MAFLD-free controls, individuals with both MAFLD and FIB-4 defined-significant significant liver fibrosis. This, in turn, is
ASCVD risk score > 10% liver fibrosis had a greater ASCVD risk (OR = 2.40; P < 0.001) (adjusted for sex, age, exercise, associated with sarcopenia
smoking, alcohol consumption, ASCVD history, SBP, fasting blood glucose, BMI, HOMA-IR, CKD,
LDL-C, and muscle mass)
The impact of MAFLD on a high probability of ASCVD risk was greater than that of significant
liver fibrosis (OR = 4.72 for MAFLD vs. OR = 1.88 for FIB-4 defined-significant liver fibrosis; all P
< 0.001) (adjusted for sex, age, exercise, current smoking, alcohol consumption, ASCVD history,
CKD, LDL-C, and muscle mass)