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Page 8 of 15 Benhammou et al. Hepatoma Res 2020;6:35 I http://dx.doi.org/10.20517/2394-5079.2020.16

[93]
hepatocytes, which subsequently leads to activation of TLR4 and pro-fibrotic pathways . Overexpression
of TLRs leads to overproduction of chemokine ligand (CCL) 3, CCL4, CCL5 and interleukin (IL) 4,
proinflammatory proteins known to be elevated in the presence of HCC, with IL-8 known specifically to be a
hepatocarcinogen [109] .

Beyond modification of intestinal microbiota and overstimulation of the host’s innate immune system,
dysbiosis has also been shown to disrupt bile acid regulation, where under physiological conditions,
the microbiome metabolizes primary bile acids to secondary bile acids that are recirculated through the
enterohepatic circulation [110] . When comparing patients with NAFLD to healthy controls and those with
simple steatosis, Mouzaki et al. [100] discovered that NAFLD patients had higher fecal levels of primary
bile acids, specifically colic acid, chenodeoxycholic acid and lithocholic acid. Others have also shown,
using animal models, that elevated levels of lithocholic acid may be carcinogenic [100,102] . Bile acid dysbiosis
in patients with cirrhosis is also well illustrated by Jacobs et al. [111] using duodenal aspirate analyses.
Although NASH only comprised 13% of the cohort of patients with cirrhosis, the study identified microbial
differences based on the etiology of the cirrhosis, cirrhosis complications (specifically patients with hepatic
encephalopathy) and ethnic differences where Hispanics were found to have lower levels of two conjugated
forms of ursodeoycholic acid. This is especially interesting given the ethnic differences previously described
in Hispanics and the observation that ursodeoycholic acid may have anti-carcinogenic effects on HCC [112-114] .

The role of gut dysbiosis in creating a pro-carcinogenic environment is further supported by animal studies.
Specifically, in mice models, researchers have shown that the administration of antibiotics/probiotics
disrupts the development of new HCC lesions. The replacement of the pro-inflammatory gut milieu, either
with sterilization or bacterial replacement, highlights once again the role of the gut-hepatic axis in HCC
development, and brings to light the potential role of therapeutics in patients at high risk of HCC [115-117] .

Overall, gut dysbiosis has been repeatedly shown to promote metabolic diseases and accelerate the
progression of fatty liver disease. There is now increasing evidence however, that the gut microbiome
acts as an independent risk factor for HCC development. By promoting an environment that espouses
intestinal permeability, hepatic inflammation and bile acid dysregulation, the gut microbiome creates a pro-
carcinogenic environment that may allow for the development of HCC, potentially by working as an epigenetic
regulator of gene expression. Most studies in the literature are currently limited to animal models, and of
those involving human subjects, samples sizes are often limited by their understandably strict inclusion
criteria. Thus, further studies are needed to elucidate the intricate relationship between gut dysbiosis and
HCC. Although far from clinical application, this also opens up new avenues for biomarker discovery and
potentially, therapies.

CIRRHOSIS VS. NON-CIRRHOSIS
As highlighted above, work remains to be done to further understand the prevalence, causes and outcomes
of NAFLD-associated HCC given its complexities with many environmental contributors. Complicating the
presentation of NAFLD-associated HCC is that it can occur in a non-cirrhosis background, which causes a
clinical dilemma to providers given the lack of current screening guidelines for this patient population. It is
estimated that the prevalence of NASH-associated HCC in patients without cirrhosis to be 38% based on a
[11]
recent meta-analysis , which differs based on the population, country and how the study was conducted. In
Japan, where patients can also have “lean” NAFLD, studies have reported that NASH-related HCC can occur
without cirrhosis in 38%-49% of cases [118-120] . A multi-center prospective study conducted in Spain reported a
[12]
prevalence of 50% of HCC in NAFLD patients without cirrhosis . Similarly, a retrospective study in France
assessing the prevalence of non-cirrhosis HCC in a cohort of 323 HCCs over a 20-year span (of which 12%
were due to NAFLD) determined that 63% of the cases occurred in the absence of bridging fibrosis/cirrhosis,
although this was biased towards patients without advanced liver disease who could undergo hepatic