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Page 6 of 22 Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23

this finding are that these noninvasive tests are biased by the different characteristics of the groups studied
but are linked to T2D per se, which carries modifications of the levels of some noninvasive biomarkers of
[48]
fibrosis .

Collectively, these studies support the notion that combining serum biomarkers and biomarkers based on
imaging techniques offers increased accuracy in the noninvasive assessment of significant hepatic fibrosis
among those with NASH. Whether such combined indices also predict CVR more accurately than currently
available biomarkers and techniques remains to be ascertained.

Prediction of CVD and mortality
A consistent body of research has documented that biopsy-proven liver fibrosis is robustly associated with
[55]
overall and liver-related mortality . Noninvasive fibrosis scores, including AAR, FIB-4, and NFS, identify
[56]
individuals prone to the risk of progressive fibrosis . Therefore, the logical question is whether (and to
what extent) the same predictive power is retained by noninvasive biomarkers.

In their seminal study, Perazzo et al. prospectively followed 2312 patients with T2D or dyslipidemia for 5-15
years and found that advanced fibrosis, defined by a FibroTest > 0.48, were significantly associated with
overall mortality[hazard ratio (HR) 1.95, 95% confidence interval (CI) 1.12-3.41], advancing to fibrosis at
baseline (HR 0.92, CI: 1.04-3.55), and worsening to advanced fibrosis over time (HR 4.8, CI: 1.5-14.9) .
[57]
Moreover, among patients with an increased CVR (defined by a Framingham risk score ≥ 20%), advanced
fibrosis predicted cardiovascular events (HR 2.24, CI: 1.16-4.33) . After this pioneering study, many others
[57]
confirmed that indirect biomarkers of fibrosis are associated with cardiovascular events and mortality, as
summarized in Table 2 .
[45]
Sonoelastography techniques
Diagnosis of liver fibrosis
Several ultrasound-based elastographic techniques have been implemented for the noninvasive assessment
of liver fibrosis, including VCTE and shear wave elastography (SWE) techniques, divided into point-SWE
(pSWE) such as acoustic radiation force impulse (ARFI) elastography and two-dimensional-SWE (2D-
SWE) such as supersonic shear imaging (SSI) [76,77] .

VCTE is the most widely used technique for the noninvasive staging of liver fibrosis in chronic liver disease
and is evaluated using a dedicated tool called FibroScan . VCTE uses a single hand-held probe that
[78]
measures the velocity of low-amplitude shear waves by ultrasound, providing a point-of-care LSM. VCTE
does not produce real-time sonographic images of the liver; however, the device is also equipped with a
controlled attenuation parameter (CAP), a sensitive noninvasive method for diagnosing hepatic steatosis.
Fibroscan enables simultaneous quantification of fibrosis and steatosis. To exclude significant/advanced
fibrosis, an optimal cut-off threshold of 8 kPa has been proposed for the sequential use of noninvasive tests
for risk stratification in NAFLD patients .
[78]
Conversely, ARFI and SSI are fully integrated into conventional ultrasound machines and, therefore, can be
performed during routine abdominal ultrasound examinations. SWE techniques to generate shear waves
utilize ultrasound impulses of high frequency; the operator is required to identify a region of interest and
[79]
acquire a series of LSMs . ARFI and SSI have shown reliable intra- and inter-observer measurement
agreements . Moreover, ARFI and SSI can selectively analyze specific liver points, including heterogeneous
[80]
[81]
liver fibrosis or focal liver lesions .