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Rastogi. Hepatoma Res 2020;6:47 I http://dx.doi.org/10.20517/2394-5079.2020.35 Page 3 of 17

Although relatively less common, chronic HCV-infection is also a risk factor for the development of HCC
in non-cirrhotic livers [8,20,21] . HCV carcinogenesis is likely mediated by viral factors and the host immune
[7]
response . Oxidative stress in hepatocytes with sustained necro-inflammatory processes leads to cell
injury, repeated cell divisions leading to genetic alterations in stem cells, and cause transformation into
dysplastic and malignant phenotypes [16,22,23] . HCV does not integrate into the host genome, but its direct
hepatocarcinogenic potential is attributable to certain HCV gene products (core, NS3, NS4B and NS5A)
and has been reported in murine fibroblast culture studies. However, the carcinogenic potential of HCV is
[24]
much lower than HBV, and HCCs related to HCV mostly develop in cirrhotic livers . A study reported
the annual incidence of HCV-associated HCC to be 0.8% among non-cirrhotic patients, and 2%-8% among
[21]
cirrhotic patients .
Metabolic syndrome and alcohol related liver disease
[8]
Metabolic syndrome is the most frequent cause of HCCs in non-cirrhotic backgrounds . NAFLD, with
or without NASH, is the hepatic manifestation of metabolic syndrome and a common risk factor for HCC
[25]
[26]
development . 39%-49% of NAFLD-related HCC cases arise in non-cirrhotic livers . Amongst various
etiologic links, patients with NAFLD most frequently develop HCCs in non-cirrhotic backgrounds .
[27]
Alcohol related hepatocarcinogenicity is almost exclusively due to the development of cirrhosis [28,29] .
However, excessive alcohol intake in the setting of chronic HCV and diabetes mellitus may potentiate
oxidative stress and free radical damage. This can lead to rapid progression to HCC even in non-cirrhotic
livers [8,30] . As shown in one study, 15% of non-cirrhotic HCC patients had alcohol-HCV infection
[8]
synergism .

The aforementioned cause-effect relationships for HCC development can be due to direct carcinogenic
action. Nonetheless, the role of chronic liver inflammation leading to repeated cycles of cell injury and
[31]
regeneration, and subsequent genetic and epigenetic alterations in hepatocytes, is equally plausible .
Hepatocyte injury resulting from microbial or sterile etiologies activates resi dent liver immune cells
and later, facilitates the recruitment of nonresident immune cells to the liver, thereby mounting a strong
inflammatory response. Persistent inflammation as a result of hepatitis virus or microbial attack resulting
from breaches of the gut–liver axis lead to the production of proinflammatory cytokines such as IL-6,
TNF-α, IL-1 and IL-18 through inflammasome-independent or -dependent pathways. Activated
transcription factors make the hepatic milieu a fertile zone for cellular transformation . Tregs coupled to
[32]
the activation of Notch and TGF-β are involved in perpetuation of the in flammatory response and HCC
[33]
development in patients chronically infected with the HBV .

Other liver disorders and tumors
Inherited metabolic and congenital diseases, in particular hereditary hemochromatosis, α-1-antitrypsin
deficiency, Wilson disease, type I glycogen storage disease, porphyria, hypercitrullinemia, Alagille
[6]
syndrome, and congenital hepatic fibrosis have predisposition to developing HCC in non-cirrhotic livers .
Mild iron accumulation is found in background liver parenchyma in non-cirrhotic HCCs, indicating the
[34]
role of excess iron within hepatocytes as a genotoxic cocarcinogen factor .

Other genotoxic factors such as aflatoxin B1, produced by the fungus Aspergillus flavus, can contaminate
[35]
cereals, legumes, spices and fruits . It is metabolized by the P450 enzyme in the liver to generate an
epoxide, which binds to DNA and leads to the development of non-cirrhotic HCC via p53 mutation [35,36]
and also, amplifies the risk of HCC development among patients with HBV infection through this
[37]
mutation . Exposure to microcystins (metabolites of cyanobacterial blooms) through water and aquatic
food is also implicated in hepatocarcinogenesis . Chemical industrial carcinogens such as pesticides, vinyl
[38]
chloride, arsenic, tobacco combustion derivatives, and radioactive elements such as Thorotrast, can also
[6]
cause liver cancer .