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Page 4 of 22 Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23

hyaluronic acid (HA) as a biomarker of liver disease, the role of HA in the pathophysiology of liver disease
is less well-characterized, representing grounds for continued investigation of the role of HA in hepatic
fibrogenesis and related downstream effects [28-30] .

NONINVASIVE PREDICTORS OF LIVER FIBROSIS
Liver histology is the standard in evaluating liver fibrosis; however, this procedure has some limitations,
such as invasiveness. Moreover, it carries the risk of complications. Finally, it is limited by sampling errors
and intra- and inter-observer variability [14,31] . Owing to these drawbacks, research on diagnostic tools for
accurately and noninvasively staging fibrosis is ongoing, and several fibrosis assessment tools have been
developed to avoid liver biopsy in a subset of patients .
[32]
Given that imaging techniques tend to be available only among referral centers owing to substantial costs,
general clinical scoring systems and combined assessment of laboratory biomarkers for liver fibrosis
[32]
determination will be discussed first .
Serum liver biomarkers
Diagnosis of liver fibrosis with noninvasive biomarkers
The so-called “direct” fibrosis biomarkers (including ELF, FibroTest, FibroMeter NAFLD, Hepascore,
ADAPT, FIBC3, ABC3D, and others) are not universally available. Moreover, some are patented and incur a
fee. These tests are discussed in detail elsewhere and are beyond the scope of this review [33-35] .

Several “indirect” biomarkers of fibrosis, based on a combination of anthropometric and serum variables,
are freely available globally for clinical practice. They are listed in Table 1, which also illustrates the
diagnostic accuracies [36-44] .

Ballestri et al. evaluated various liver fibrosis biomarkers to identify significant/advanced fibrosis[AST: ALT
ratio (AAR); AST-to-platelet ratio Index (APRI), fibrosis-4 (FIB-4) index, Forns index, BMI, AAR, Diabetes
(BARD) score, and Hepamet fibrosis score (HFS)] in their series of 157 hepatitis C virus (HCV), 16 hepatitis
B virus (HBV), and 107 NAFLD consecutive patients . These individuals used the following scoring
[45]
systems to estimate CVR: SCORE, Progetto CUORE, or the Framingham risk scoring systems. Data showed
that biomarkers of hepatic fibrosis had a higher diagnostic performance in patients with advanced fibrosis
(compared to those with significant fibrosis). The Forns Index and HFS showed the best performance for
NAFLD in identifying advanced fibrosis. By lowering their cut-off values, these fibrosis biomarkers
exhibited high negative predictive values (NPVs) for advanced-stage fibrosis. Interestingly, FIB-4, Forns
index, NFS, and HFS were positively correlated with SCORE and Framingham risk scores. Collectively,
these findings support the notion that biomarkers of liver fibrosis can exclude advanced fibrosis while
[45]
positively correlating with CVR scores . A more recent study by Brandman et al., conducted on 1483
individuals with biopsy-proven NAFLD recruited in the USA or the UK, found that two scores most
accurately identified cirrhotic patients: FIB-4 and NFS[area under the receiver operating characteristic curve
[46]
(AUROC) 0.84-0.86)] .
It remains uncertain which of the various noninvasive fibrosis tests is best in clinical practice, and the choice
depends on the cut-off used. Confirming this notion, Sun et al. performed a meta-analysis of four studies
with 1038 adult patients and found that FIB-4 at a cut-off threshold of 1.30 was more accurate than a cut-off
of 3.25, NFS and BARD; however, FIB-4 has a limited capacity to predict advanced fibrosis in patients with
NAFLD . The limitations inherent in these noninvasive fibrosis biomarkers should not be neglected. For
[47]
example, Boursier et al. evaluated 1051 biopsy-proven NAFLD patients in whom serum blood fibrosis