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Onzi et al. Hepatoma Res 2019;5:7 I http://dx.doi.org/10.20517/2394-5079.2018.114 Page 3 of 7

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Figure 1. Hepatocellular carcinoma demonstrated in magnetic resonance of the abdomen. Yellow arrow - larger nodule (5.7 cm); red
arrow - smaller nodule (1.9 cm)

cardiovascular disease [2,12] . The main risk factors involved in the occurrence of HCC in cirrhotic patients
[13]
due to NASH are male gender, age over 70 years-old, diabetes and hypertension . It was estimated that
[14]
the presence of NAFLD-associated HCC is 7.6-fold greater than in a same sex and age control group .
Nevertheless, the impact of hepatitis C virus (HCV) in HCC is still greater than that of NAFLD - the risk for
HCC in cirrhotic patients with HCV is three times greater than that of patients with NAFLD . Considering
[15]
only studies strictly including patients with or without cirrhosis, the reported incidence of HCC in NAFLD
patients with cirrhosis was between 6.7% and 15% at 5-10 years, whereas the incidence in NAFLD patients
[16]
without cirrhosis was 2.7% at 10 years and 23 per 100,000 person-years .

[17]
The prevalence of NAFLD has become similar in the West and the East . Obesity, which has been
mostly a health problem of the Western world, has emerged rapidly in Asia, due to globalization and rapid
[18]
urbanization, which lead to a change of dietary patterns to those of the West . In China, the number
of obese people has increased from below 0.1 million in 1975 to over 43.2 million in 2014, accounting
for 16.3% of obese people worldwide. In India, the number of obese people increased from 0.4 million to
[19]
9.8 million during the same period . This will increase the prevalence of NAFLD in Asia, which will
in turn increase the cases of HCC not only from the increasing prevalence of NAFLD but also from the
anticipated decreasing burden of HBV and HCV infections. It is a fact that primary, secondary and tertiary
preventive strategies for HCC due to NAFLD are lacking. NAFLD has been estimated to contribute to 10%-
12% of HCC cases in Western populations and 1%-6% of HCC cases in Asian populations. The increasing
burden of NAFLD-related HCC over time has been demonstrated in studies from both Western and Asian
populations . For example, in a Sri Lanka cohort, the most common cause of HCC was NAFLD-related
[20]
[21]
cirrhosis . Hence the global incidence of NAFDL is increasing rapidly, its impact on HCC incidence may be
explosive [22,23] .

Although HCC is more frequent in the presence of cirrhosis, several studies have shown that hepatic
carcinogenesis may also develop in the context of NASH or NAFL, without association with advanced
fibrosis [1-3,7,24] . A 2.5-fold increased risk of developing HCC in patients with NAFLD without cirrhosis was
[1]
observed when compared to other etiologies of chronic liver disease . This is particularly concerning, since
[14]
in a recent study 20% of NAFLD-related HCC occurred in the absence of cirrhosis . The patient with non-
[3,7]
cirrhotic NASH presenting HCC is older, male, and meets one or more criteria for metabolic syndrome .
The pathogenesis of HCC related to NAFLD is different, once metabolic syndrome and obesity manifest
several exclusive mechanisms that favor the occurrence of tumors: increased release of free fatty acids, of
multiple proinflammatory cytokines, and the reduction of activity of anti-inflammatory agents such as