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Page 6 of 15 Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16

[72]
the opposite effect however, in which a diagnosis of dyslipidemia was protective against HCC . One
potential reason for these conflicting reports is the definitions used to identify patients (i.e. ICDs versus lipid
measurements versus medication use). These data must be interpreted in the context of statin use, which has
more recently been shown to have chemoprotective effects against fibrosis progression and HCC [14,15] .

Statins
Early animal studies showed that statins, which inhibit the 3-hydroxy-3-methylglutaryl coenzyme A
reductase (HMG-CoA reductase), cause hepatotoxicy. The level of hepatic injury did not translate to humans
clinical trials however, and mostly caused asymptomatic abnormal aminotransferases that would resolve with
[73]
time . Over the years, research and subsequently clinical practice has changed to favor the use of statins in
NAFLD and NASH patients for the cardiovascular protective effects, which are closely linked to NAFLD [74,75] .
Independent of its association with cardiometabolic disease, plasma lipidomic studies in NAFLD and
NASH patients have also shown that lipid dysregulation is important in NAFLD pathogenesis, where levels
of palmitoleic and oleic acids are increased [76-78] . These plasma levels were reflective of an increase in the
activity of certain lipid enzymes, such as stearoyl-CoA desaturase 1 (SCD1), the rate limiting enzyme in
monounsaturated fatty acids [77,78] , which is now being targeted in phase 3 clinical trials for the treatment
of NAFLD [76,79,80] . Plasma (whole body) and liver lipid compositions also do not always correlate such that
[78]
understanding lipid dysregulation becomes even more complex .
Over the years studies have showed the benefits of statins for patients with cirrhosis. In a retrospective
cohort analysis conducted within the VA from 2008-2016 that included 21,921 patients on statins and
[14]
51,023 controls without statins, Kaplan et al. demonstrated that for every year of statin exposure, the
associated adjusted HR was 0.92 (95%CI: 0.89-0.94) for mortality. This was seen in all etiologies of cirrhosis
including NAFLD and NASH, which comprised 23% of the cohort. These benefits of statins have also been
[15]
reported in HCC. In another retrospective cohort within the VA from 2002-2016, Thrift et al. reported
that after a diagnosis of HCC, statin users had a decreased risk of cancer-specific death with an adjusted
HR of 0.85 (95%CI: 0.77-0.93). Their sub-group analysis of NAFLD-associated HCCs did not demonstrate
a decrease in cancer-specific (adjusted HR = 1.80, 95%CI: 0.59-1.08) or all-cause (adjusted HR = 0.90,
95%CI: 0.73-1.10) mortalities. The benefits were evident in the group of patients with cirrhosis however,
for both cancer-specific (adjusted HR = 0.80, 95%CI: 0.68-0.94) and all-cause (adjusted HR = 0.88, 95%CI:
[15]
0.79-0.98) mortalities, respectively, suggesting a fibrosis or cirrhosis-specific effect . A nested case-control
study conducted from 2002-2013 in the Republic of Korea also demonstrated a benefit from statin use with a
[81]
reduced risk of HCC development (adjusted OR = 0.44, 95%CI: 0.33-0.58) . Several meta-analyses have also
confirmed these findings across different study populations, health care systems and etiologies of HCC [82-84] .
The anti-fibrotic and chemoprotective effects of statins are thought to be potentially independent of their
lipid-lowering mechanisms and through other pleiotropic effects mediated by the mevalonate pathway [85,86] .
Among the statins, those that are lipophilic (atorvastatin and simvastatin) have been linked to reduced HCC
incidence and mortality outcomes compared to hydrophilic statins (pravastatin and rosuvastatin) in patients
[17]
with chronic hepatitis B or C-related HCC . To the best of our knowledge, the differentiating effects of the
type of statin used in NAFLD and NAFLD-associated HCC have not been studied.

Aspirin
Chronic inflammation is a known risk factor for fibrosis. Non-steroidal anti-inflammatory drugs, including
aspirin, have been associated with having chemoprotective effects in other malignancies including colorectal,
breast, prostate and other gastrointestinal cancers [87,88] . Early in vitro studies demonstrated that aspirin had
[90]
[89]
chemoprotective effects against HCC . Sahasrabuddhe et al. assessed the association between aspirin use
in a prospectively collected data of 300,504 patients in the National Institutes of Health-AARP Diet and Health
Study cohort, where patients had used aspirin over the previous 12 months (73% used aspirin). Of the 250
patients who developed HCC, those on aspirin had decreased risk for both HCC (adjusted relative risk = 0.49,