Southern Europe as an example of interaction between various environmental factors. A systematic review of the epidemiologic evidence.

Hepatitis B virus (HBV), hepatitis C virus (HCV) and
alcohol consumption are major causes of hepatocellular
carcinoma (HCC) worldwide. We performed a systematic
review of epidemiologic studies carried out on HCC aetiology
in Southern Europe, an area with an intermediate–
high prevalence of these agents as well as of putative
risk factors such as tobacco smoking, diabetes and
obesity. To retrieve the articles, we performed a Medline
search for titles and abstracts of articles. After the
Medline search, we reviewed the papers and reference lists
to identify additional articles. A synergism between HCV
infection and HBV infection, overt (hepatitis B virus
antigen (HbsAg) positivity) or occult (HBsAg negativity
with presence of HBV DNA in liver or serum), is
suggested by the results of some studies. The pattern of
the risk for HCC due to alcohol intake shows a continuous
dose–effect curve without a definite threshold, although
most studies found that HCC risk increased only for
alcohol consumption above 40–60 g of ethanol per day.
Some evidence supports a positive interaction of alcohol
intake probably with HCV infection and possibly with
HBV infection. A few studies found that coffee has a
protective effect on HCC risk due to various risk factors.
Some data also support a role of tobacco smoking,
diabetes and obesity as single agents or preferably cofactors
in causing HCC. In countries with a relatively high
alcohol consumption and intermediate levels of HCV and
HBV infections (1–3% of population infected by each
virus), such as Mediterranean countries, the three main
risk factors together account for about 85% of the total
HCC cases, leaving little space to other known risk
factors, such as haemochromatosis, and to new, still
unrecognised, factors as independent causes of HCC.