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potentially risky conditions such as alcohol intake, tobacco aminotransferase. Interestingly, this positive effect of
habit, overweight, diabetes, aflatoxin consumption and oral caffeine is mainly relevant in heavy drinkers. [12,13] Notably,
contraceptives use, should be considered. [3] coffee consumption would be inversely related to the hazard
of cirrhosis, which is the main risk factor of HCC. [14,15]
Barcelona-Clinic Liver Cancer (BCLC) staging system is a
widely used set of criteria to guide management of patients Although some authors [16,17] suggested a not statistically
with HCC. It takes into account tumor stage, liver functional significant association between coffee consumption and risk
status, physical status and cancer-related symptoms. of HCC, many other studies reported positive results.
[4]
Surgical treatment of HCC is a potentially curative approach,
[18]
including liver transplantation (LT) and liver resection. LT In an Italian case-control study (including 250 HCC), coffee
is the best treatment option for patients fitting the “Milan intake showed a significant protective role against HCC. In
criteria” since it removes both neoplasm and underlying all patients, ten-year coffee intake was associated with a
liver disease. For patients with single tumor < 2 cm, with decreased risk of HCC with a dose-effect relation (double
a Child-Turcotte-Pugh class A, without clinically significant with 3-4 cups/day respect to 1-2 cups/day).
portal hypertension and with normal bilirubin, liver resection
[19]
represents a feasible strategy. Ablation with ethanol or In a further Italian study (185 HCC), patients drinking≥4
[4]
acetic acid or thermal, is another potentially curative option. cups/day (no decaffeinated) had a lesser risk of HCC
It is practicable in patients with single, small tumors not respect to the others.
candidates for surgery. Many HCC cases are diagnosed in
[4]
[20]
stage B of BCLC algorithm, for which the standard of care Tanaka et al. developed a Japanese case-control study (209
is the transcatheter arterial chemoembolization (TACE). HCC) showing that coffee consumption during the last 1-2
[4]
Lastly, sorafenib is the unique universally approved systemic years, was associated with a decreased risk of HCC. Another
palliative drug for BCLC C patients. [4] Japanese case-control study including 73 HCC, analyzed the
[21]
role of coffee in patients with hepatitis C. Coffee drinking
In the European and in the North-American guidelines, ≥1 cup/day significantly reduced the risk of HCC compared
[5]
[6]
no natural product is mentioned neither for the prophylaxis to the abstinence. The same data were found for hepatitis B
[22]
nor for the treatment of HCC. On the contrary, in the Asian- chronic carriers with a risk reduction of 30-80%.
[7]
Pacific ones, natural products are cited for both primary and
secondary prophylaxis. Two large Japanese prospective studies [23,24] including
hepatitis B, C and sieronegative subjects, reported that
Literature data are available regarding the coffee-derived drinkers of ≥ 5 cups/day had a lower dose-dependent HCC
substances as prevention tools in high-risk populations, risk respect to abstinent patients.
the possible prevention or adjuvant effect of many kinds of
Traditional Chinese Medicine (TCM), and possible utility of The relationship between coffee and risk of HCC was
[25]
cannabinoids as antineoplastic drugs. studied also by Johnson et al. through a large prospective
study including 63,257 patients. The authors reported that
Hereby, we sought to review the current knowledge on subjects consuming ≥ 3 cups/day experienced a 44% of HCC
the role of some natural products in the prevention and risk reduction.
treatment of HCC. The research included published articles
[26]
(peer reviewed original articles, review articles and meta- Hu et al. firstly analyzed the possible association between
analyses). The search terms included “natural products and coffee consumption, serum gamma-glutamyltransferase and
hepatocellular carcinoma”, “natural products and liver”, HCC. The study cohorts included 60,323 patients without
“hepatocellular carcinoma treatment options”, “coffee cancer. During a median follow-up period of 19.3 years, 128
and HCC”, “Traditional Chinese Medicine and HCC”, and participants developed HCC. According to the author’s data,
“cannabinoids and HCC”. a combination of very low coffee consumption and high level
of serum GGT was associated with nearly nine-fold increased
COFFEE risk of HCC.

Many data are available about the dose-dependent protective In 2007, Bravi et al. performed a meta-analysis based on 10
[27]
effect of coffee respect to the development of liver disease studies (both European and Asian) and a total of 2,260 HCC
and HCC. Both in vitro and in vivo studies showed that several cases. Authors reported a 41% of reduction in HCC risk among
[8]
coffee compounds such as diterpenes, cafestol and kahweol, coffee drinkers compared to non-drinkers. In the same year,
may act on some enzymes involved in carcinogenesis. [9,10] Larsson et al. published another meta-analysis with similar
[28]
Diterpenes, cafestol and kahweol seem to modify the conclusions. In 2013, Bravi et al. conducted a further
[29]
xenotoxic metabolism via induction of glutathione-S- meta-analysis including more recent studies. According to
transferase and inhibition of N-acetyltransferase. Caffeine the authors, coffee drinkers had a decrease of 40% in the
[11]
and antioxidant substances from coffee beans, may improve risk of HCC compared to abstinent patients. Moreover, high
some liver enzymes, such as γ-glutamyltransferase and coffee drinkers showed more than 50% of risk drop. Notably,
72 Hepatoma Research | Volume 2 | March 9, 2016