Page 98 - Read Online

Liu et al. Hepatoma Res 2020;6:42 I http://dx.doi.org/10.20517/2394-5079.2020.25 Page 3 of 12

alcohol consumption was no longer independently associated with HCC in individuals with F0-F1 fibrosis
[21]
stage .

HCC is often diagnosed at a later Barcelona Clinic Liver Cancer (BCLC) stage in patients with ALD and
with a more severe underlying cirrhosis leading to a worse prognosis compared to other liver diseases [14,22] .
A previous study reported that patients with alcohol-related HCC are often younger and are more
frequently diagnosed with a multifocal or infiltrative/massive tumor compared to HCV-related HCC.
However, this apparent greater cancer aggressiveness disappeared after adjusting for confounding factors,
[23]
and prognosis was similar in ALD and HCV patients when stratified by BCLC stages . Moreover, a
recent study did not show significant differences in tumor characteristics between patients with AC- and
[24]
NAFLD-related HCC . Overall, the higher proportion of advanced BCLC stages observed in ALD/AC
patients might only reflect a lower compliance with surveillance programs, rather than a greater tumor
aggressiveness.

LIMITATIONS OF SCREENING STRATEGIES IN PATIENTS WITH AC-RELATED HCC
The American Association for the Study of Liver Diseases and European Association for the Study of the
Liver recommend HCC surveillance in all cirrhotic patients using ultrasound, with or without alpha-
fetoprotein determination, every 6 months [25,26] . This surveillance program has been shown to increase
overall survival and improve the quality-adjusted life expectancy [27,28] . However, this periodic surveillance
has been shown to be difficult to implement in daily clinical practice, ultimately leading to a significant
[29]
prevalence of HCC detected at a more advanced stage . Thus, more than 20% of HCC patients are also
[30]
diagnosed with an unsuspected cirrhosis . This phenomenon is even more pronounced in patients with
ALD because AC is underdiagnosed due to their poor compliance in cancer surveillance programs .
[30]
Therefore, risk factors identified for AC are potential candidates for susceptibility to HCC.
Due to the aforementioned limitations, there is an urgent need for new detection strategies and the
development of new highly sensitive, reliable, and easily accessible biomarkers that can either improve the
early detection of HCC in high-risk patients with AC or identify individuals at risk of progressive ALD
[31]
when liver fibrosis is incomplete and potentially reversible .

Individual variation in susceptibility to HCC is known, but there is limited information to predict who
among the patients is at high risk of progressing to HCC. A better understanding of the contributing
molecular, genetic and epigenetic factors is required to identify drivers of and therapeutic options for
hepatocarcinogenesis.

CONTRIBUTION OF GENETIC VARIANTS TO THE PREDICTION OF ALCOHOL-RELATED HCC
The association of genetic variants with the risk of alcohol-related HCC has been reported. Earlier studies
targeted genes with known functions, specifically genes known to operate in the pathogenesis of ALD and
[32]
recently proposed to be part of a “5-hit working model” of disease progression leading to HCC . These
candidate genes, involved in hepatic alcohol metabolism [alcohol dehydrogenase (ADH), acetaldehyde
dehydrogenase (ALDH), ethanol-induced cytochrome P450 (CYP2E1), CYP2E1-dependent microsomal
ethanol oxidizing system (MEOS)] and affecting downstream mechanisms including oxidative stress
[CYP2E1, glutathione S-transferase (GST), manganese superoxide dismutase (MnSOD), N-acetyltransferase
2, ectonucleotide pyrophosphatase/phosphodiesterase 1, homeostatic iron regulator (HFE)], endotoxin
release [CD14, toll-like receptor 4 (TLR4)], immune function (TNFα, IFNg, IL-10, IL-1B, CD14) and
fibrogenesis [TGFβ, angiotensin, leptin, metalloproteinases (MMPs), tissue inhibitors of MMPs (TIMPs)],
have been extensively reviewed for their association to alter risk of ALD/AC and ALD-related HCC [12,33-35] .
But results from most of these earlier studies could not be replicated or confirmed due to limitations in