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Carvalho et al. Hepatoma Res 2020;6:6 I http://dx.doi.org/10.20517/2394-5079.2019.027 Page 3 of 6

cytokines [interleukin 6 (IL-6) and tumor necrosis factor (TNF-a)] and immunosuppressive cytokines [9,10]
(IL-10). The accumulation of these immunostimulating agents around the liver inflammation focus
induces mitochondrial imbalance in hepatocytes (increased oxygen uptake and increased production
of superoxide anions, hydroxyl radicals, and oxide), leading to the production of high levels of reactive
oxygen species (ROS) and a consequent increase in oxidative stress [11,12] .

In addition, hepatic mitochondria are also essential in hepatocyte survival as the mediator of apoptosis and
necrosis, controlling the balance between cell survival and death by regulating membrane permeability,
and activating the intrinsic pathway of apoptosis (cytochrome C protein release, apoptosis formation, and
[9]
caspase activation ). In addition, increased ROS production causes oxidative damage to mitochondrial
proteins (impairing ATP synthesis) and alters the induction of pore production from mitochondrial
transition permeability. These changes make the inner membrane permeable to small molecules that can
[13]
cause ischemia or reperfusion injury and DNA damage by activating the intrinsic apoptotic mechanism .
These mechanisms can induce recurrent cycles of cell damage, repair, and regeneration in hepatocytes,
leading to the formation of dysplastic nodular lesions, which are precursor lesions of HCC. Associated with
[14]
these changes are genetic and epigenetic changes that are directly related to tumor progression and HCC .
CAFFEINE AND HCC
Caffeine, one of the components of coffee, appears to play a central role in protecting against the
development of chronic liver disease and HCC. It reduces HCC cell proliferation, and it has been observed
[15]
that protection against HCC is lower for decaffeinated coffee .

Other substances, such as cafestol and kahweol, tirpenoid molecules present in coffee beans, increase the
activity of liver enzymes, which may improve metabolism and excretion of carcinogens [16,17] . However,
cafestol and kahweol are only present in minimal quantities in filtered coffee, and these coffee varieties
are popular in countries, such as Japan and Finland, where studies have shown inverse associations with
HCC [18,19] .

Specific coffee protection mechanisms may include inhibition of viral hepatitis activity and prevention of
diabetes mellitus type 2. In addition, coffee has a number of health benefits, including a lower incidence of
[20]
neurological diseases, various cancers, and reduced mortality from any cause .

AMOUNT OF COFFEE CONSUMPTION AND PROTECTIVE EFFECT ON HEPATOCARCINOGENESIS
Several studies report not only the protective effect of coffee use on the pathogenesis of HCC but also that
[21]
the protection is related to the amount of coffee ingested. Inoue et al. conducted a prospective cohort
of 116,686 Japanese individuals to assess the influence of coffee consumption on the risk of hepatocellular
carcinoma. Coffee proved to be a liver protective factor, with 51% lower risk of developing cancer by daily
consumers compared to those who never drank coffee. An inverse relationship was also noted between
consumption and incidence of this neoplasia, one or two cups per day (HR = 0.52), three or four cups per
day (HR = 0.48), and more than five cups per day (HR = 0.24).

[22]
The study by Johnson et al. analyzed 63,257 over-middle-aged Chinese individuals over approximately 5
years between 1993 and 1998. They that 18.5% of individuals did not drink coffee, 11.1% were light drinkers
and drank less than one cup per day, 36% were average consumers who drank between one and two cups
a day, and 34.4% were heavy drinkers and drank more than two cups of coffee a day. Of the 362 patients
diagnosed with HCC, an inverse relationship was found between coffee consumption and HCC risk, with
a lower risk for each increase in the number of coffee cups drunk (P = 0.05). Heavy consumers had a 44%
lower risk of HCC than those who did not drink coffee after adjusting for potential confounders.