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Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23 Page 11 of 22

more accurate for detecting advanced fibrosis/cirrhosis (F3-F4 stages) than for mild-moderate (F1-F2)
fibrosis [77,86] . The diagnostic performance of various elastographic techniques for detecting liver fibrosis
stages (considering hepatic histology as the reference) among NAFLD individuals as reported in the most
recent and most significant meta-analysis of 70 studies[53 VCTE, 11 pSWE, four 2DSWE, 11 MRE] are
shown in Table 3 . According to this meta-analysis, the diagnostic performance of SSI was worse than
[87]
reported in a previous meta-analysis of individual patient data, which were not included in the present
meta-analysis .
[85]

VCTE can also be used in clinical practice in cirrhotic patients to rule out significant portal hypertension
with esophageal varices needing treatment, thus sparing unnecessary screening endoscopy examinations
3 [88]
(e.g., NAFLD criteria: LSM < 30/25 kPa for the M/XL probe and platelet count > 110.000 mm ) .

Sonoelastographic techniques present several limitations in clinical use. VCTE and SWE techniques may be
unsuccessful or provide inaccurate measurements in obese patients and those with prominent subcutaneous
adipose tissue. This issue was overcome by developing the XL probe to perform VCTE among obese and
overweight individuals . Moreover, LSMs using VCTE and SWE are influenced by liver inflammation,
[80]
congestion, extra-hepatic cholestasis, and the postprandial state, which can increase liver stiffness and
elevate the measurements, independent of fibrosis [77,80,86] . SWE-based techniques, at variance with VCTE, are
less influenced by the retention of intraabdominal fluid and should be preferred in patients with ascites [80,89] .

MRE has shown a higher accuracy than VCTE and SWE for detecting even the lowest fibrosis stages in
NAFLD patients; moreover, the diagnostic performance of MRE is not influenced by obesity and other
confounders [80,90] . Finally, MRE has shown a modest ability to discriminate simple steatosis (i.e., NAFL)
from NASH [78,91] . However, this technique is expensive, and its availability in clinical practice is limited .
[80]

Prediction of CVD and mortality
Solid evidence supports an independent association between NAFLD and CVD, primarily coronary heart
disease (CHD); however, the nexus of hepatic fibrosis and CVD is less clear [92,93] .

Observational and longitudinal studies evaluating the association between liver fibrosis severity assessed by
transient elastography (mostly VCTE) and CVD/mortality outcomes in general populations and NAFLD
and T2D patients are reported in Table 4. A recent large observational study from the Framingham Heart
Study cohort (30% NAFLD prevalence) showed that hepatic fibrosis defined with VCTE was associated with
CVR factors such as metabolic syndrome (MetS) and its components irrespective of CAP values and other
[99]
confounding factors . In a community-based study (with a prevalence of NAFLD 31%), steatosis and
severity of fibrosis by VCTE were independently associated with a higher CV risk by the Atherosclerotic
Cardiovascular Disease risk score from AHA/ACC determining the ten-year risk of heart disease or
[100]
stroke . Consistently, a higher LSM significantly correlated with a higher risk of coronary artery
calcifications in NAFLD patients and with CHD assessed by computed tomography or coronary
[101]
angiography in subjects with suspected CHD, independent of NAFLD status . Another study on patients
[95]
with T2D showed that advanced liver fibrosis by MRE found severe coronary artery calcifications in the
whole study population and NAFLD patients on univariate analysis; however, the limited sample size
precluded performing an extensive multivariable analysis to adjust for potential confounders . At variance
[109]
with these findings, a study found that NAFLD (but not NAFLD with advanced fibrosis) independently
predicted clinically relevant CHD .
[94]