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Page 16 of 22 Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23

[118]
circulating free fatty acids, and risky lipidomic features . While tending to underestimate the specific
pathogenic role of NAFLD, this theory highlights the common involvement of MetS and NAFLD in
accelerating atherogenesis.

Other views maintain that the liver is not an innocent bystander and that fibrosing NASH is directly linked
with the development of CVD events through increased intrahepatic synthesis of biological mediators such
as prothrombogenic factors, fetuin-A, and specific lipidomic profiles typical of unstable coronary
plaques . This theory is illustrated in Figure 2 (reprinted, with permission) .
[118]
[118]
Clinical implications
The studies in the present review sustain the theory that noninvasive assessment of hepatic fibrosis can be
successfully achieved with algorithms based on anthropometry and laboratory parameters; and with
elastometry techniques based on either ultrasonography or MR. The next step could be to combine these
[119]
techniques in a two-step strategy. To this end, Tamaki et al. conducted a multicenter study of 806 biopsy-
proven NAFLD patients to ascertain the accuracy of a diagnosis based on a two-step procedure featuring
FIB-4 and MRE. First, individuals exhibiting FIB-4 lower than 1.3 were considered negative irrespective of
MRE. Next, if FIB-4 was equal/above 1.3, patients were defined as negative when MRE was lower than 3.6
and positive if MRE was equal/more than 3.6 kPa. The study aimed to compare the diagnostic accuracy of a
two-step strategy to MRE alone. The authors found that the AUROC of MRE alone and the two-step
strategy were 0.840 and 0.853 in the training cohort (P = 0.4) and 0.867 and 0.834 in the validation cohort
(P = 0.2), respectively, suggesting that the two methods had a comparable diagnostic accuracy. In the overall
population, the NPV and PPV of MRE for advanced fibrosis were 92.2% and 73.7%, respectively, whereas
the NPV for the first and second step and PPV for the second step were 90.9%, 84.4%, and 77.0%,
respectively. The authors conclude that the two-step diagnostic strategy is not different from MRE and
might help to avoid overusing MRE, reduce healthcare expenditures, and could be used to screen large
[119]
population samples .

In this evolving scenario, it is becoming increasingly apparent that noninvasive assessment of fibrosis might
serve a dual purpose in various clinical settings, notably primary care. On the one hand, it may better
stratify those at high risk of fibrosing liver disease; on the other hand, it may simultaneously allow the
identification of increased CVR. This finding is critical for personalized and precision medicine approaches
that are eagerly awaited for metabolic disorders and NAFLD [120-123] . For example, personalized diagnostic
and follow-up schedules might be envisaged for these individuals based on noninvasive fibrosis scores.
Importantly, these patients may simultaneously be offered innovative anti-fibrotic agents or drugs
[124]
targeting hepatic fibrosis and atherogenesis .
[125]
CONCLUSIONS
While the pathomechanisms associating hepatic fibrosis with CVR and cardiovascular outcomes remain
under investigation, accumulating epidemiological and clinical data strongly support that liver fibrosis
assessed noninvasively is a risk factor for MACE and mortality. This notion can potentially revolutionize
clinical practice in the NAFLD arena and CVR assessment. Further investigation is required to focus on the
therapeutic implication of “killing two birds with one stone” using anti-fibrotic agents that combat
atherogenesis.