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Page 2 of 22 Ballestri et al. Metab Target Organ Damage 2023;3:1 https://dx.doi.org/10.20517/mtod.2022.23

techniques associated with ultrasonography or magnetic resonance. Our literature review identified numerous
studies demonstrating that biomarkers of fibrosis (the most common being FIB-4) and elastographic techniques
predict overall mortality and major cardiovascular events among NAFLD patients. The mechanisms accounting for
this association are briefly reviewed. In addition to assessing hepatic fibrosis at baseline, during follow-up, and after
therapeutic interventions in NAFLD patients, noninvasive assessment of hepatic fibrosis may predict
cardiovascular events and overall mortality in these patients.

Keywords: Biomarkers, elastometry, fibroscan, ultrasound, biopsy, cardiovascular risk, natural course,
steatohepatitis

INTRODUCTION
Liver fibrosis is associated with pathogenically diverse triggers and describes the excess accumulation of
[1,2]
extracellular matrix (ECM) components that result from persistent liver injury . Evolutionarily,
fibrogenesis maintains tissue integrity by encapsulating an offending agent and limiting tissue damage;
however, given sufficient time and whenever the fibrotic response exceeds a physiological amount, fibrosis
[3]
impairs liver regeneration and jeopardizes hepatic function . This notion accounts for increasing healthcare
[4]
expenditures associated with advanced liver fibrosis stages .
Irrespective of the specific pathogenic type of inciting hepatic insult (e.g., viral, alcoholic, metabolic,
autoimmune, cholestatic, drug-induced, or inherited), repeated bouts of hepatitis, hepatocyte damage, and
wound-healing fibrosing response, if left untreated, result in progressive hepatic fibrosis and cirrhosis .
[5,6]
Cirrhosis is a fully de-structured liver histology characterized by accumulating large quantities of connective
scar tissue and nodular architecture resulting in portal hypertension, progressive liver failure, or
hepatocellular carcinoma . Fibrosis is the sole histologic feature of nonalcoholic steatohepatitis (NASH)
[7]
that predicts significant clinical outcomes such as cirrhosis, liver failure, and hepatocellular carcinoma [8-10] .
Nevertheless, the major overall cause of mortality in patients with NASH is cardiovascular disease (CVD),
especially in patients who do not yet have advanced cirrhosis, while significant hepatic-related morbidity
[11]
and mortality are strictly associated with NASH-cirrhosis . Seen from another perspective, but consistently
with these notions, Mantovani et al. performed a meta-analysis of 5,802,226 adults in 36 published
longitudinal studies over a median follow-up of 6.5 years and found that NAFLD was associated with a
moderately increased risk of fatal or non-fatal CVD events . However, this risk markedly increased across
[12]
[12]
the severity of NAFLD, especially the fibrosis stage, irrespective of confounding metabolic factors .
While the diagnosis of cirrhosis may be clinically apparent in more advanced cases, earlier forms of the
[7]
disease may require liver histology assessment . Liver biopsy, however, is an invasive procedure with
inherent sampling issues and observer variability and cannot be proposed other than for selected NAFLD
patients, particularly in therapeutic trials [13,14] . On the one hand, hepatic fibrosis is a major determining
factor of outcomes in chronic liver disease of all etiologies (NAFLD included); on the other hand, liver
biopsy cannot be proposed extensively. The present study, therefore, focuses on the role of biomarkers and
imaging techniques in diagnosing liver fibrosis and prognostication of the cardiovascular risk (CVR), which
is inherent in advanced NAFLD forms.

CELLULAR AND MOLECULAR PATHOPHYSIOLOGY OF HEPATIC FIBROSIS
Mechanistically, fibrogenesis occurs when stressed or damaged hepatocytes release substances such as
reactive oxygen species and activate macrophages and lymphocytes to generate several types of cytokines,
including transforming growth factor-β and platelet-derived growth factor . Collectively, these cytokines
[15]