Liver cancer: descriptive epidemiology and risk factors other than hbv and hcv infection
Liver cancer: Descriptive epidemiology and risk factorsother than HBV and HCV infection
Shu-Chun Chuang a, Carlo La Vecchia b,c, Paolo Boffetta a,*
a Lifestyle, Environment and Cancer Group, International Agency for Research on Cancer, 150 cours Albert Thomas, 69008 Lyon, Franceb Department of General Epidemiology, Mario Negri Institute of Pharmacological Research, Milan, Italyc Institute of Biostatistics and Biometry, University of Milan, Milan, Italy
The incidence of liver cancer is high in all low-resource regions of the world, with the
exception of Northern Africa and Western Asia. The estimated worldwide number of
new cases of liver cancer in 2002 is 600,000, of which 82% are from developing countries. Given the poor survival from this disease, the estimated number of deaths is similar to thatof new cases.
Hepatocellular carcinoma (HCC) is the main form of liver cancer. A part from chronic
infections with Hepatitis B and Hepatitis C viruses, which are the main causes of HCC, con-
tamination of foodstuff with aﬂatoxins, a group of mycotoxins produced by the fungi Asper-
gillus ﬂavus and Aspergillus parasiticus, is an important contributor to HCC burden in many
low-income country. Alcoholic cirrhosis is an important risk factor for HCC in populations
with low prevalence of HBV and HCV infection, and the association between tobacco smok-
ing and HCC is now established. Diabetes is also related to an excess risk of HCC and theincreased prevalence of overweight and obesity likely contributes to it.
The second most important type of liver cancer is cholangiocarcinoma, whose main
known cause is infestation with the liver ﬂukes, Opistorchis viverrini and Clonorchis sinensis,which is frequent in some areas in South-East Asia. Angiosarcoma is a rare form of livercancer whose occurence is linked to occupational exposure to vinyl chloride.
Ó 2008 Published by Elsevier Ireland Ltd.
common cause of cancer mortality . The estimatedworldwide number of new cases of liver cancer in 2002
The epidemiology of liver cancer is made complex by
is 600,000, of which 82% are from developing countries.
the large number of secondary tumours, which are difﬁcult
China alone accounts for 55% liver cancer death worldwide
to separate from primary liver cancers without histological
The incidence of liver cancer is high in all low-resource
veriﬁcation. The most common histological type of liver
regions of the world, with the exception of Western Asian
malignant neoplasm is hepatocellular carcinoma (HCC).
and Northern African countries other than Egypt. The high-
Other forms include: (i) childhood hepatoblastoma, and
est rates (above 40/100,000 in men and above 10/100,000
(ii) adult cholangiocarcinoma (originating from the intra-
in women) are recorded in Thailand, Japan, Korea, and cer-
hepatic biliary ducts) and (iii) angiosarcoma (from the
tain parts of China. In most high-resource countries, age-
intrahepatic blood vessels). Primary liver cancer is the
standardized rates are below 5/100,000 in men and 2.5/
sixth most common cancer in the world and the third most
100,000 in women. Intermediate rates (5–10/100,000 inmen) are observed in areas of Southern and Central EuropeThe 5-year survival rate was 8% in the United Statesduring 1988–2001 9% in Europe during 1995–1999
* Corresponding author. Tel.: +33 472738554; fax: +33 472738320.
and 5% in developing countries in 2002 .
0304-3835/$ - see front matter Ó 2008 Published by Elsevier Ireland Ltd. doi:10.1016/j.canlet.2008.10.040
S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14
Table 1Overall age-adjusted (world standard population) mortality rates from hepatocellular carcinoma (HCC) per 100,000 men and women in selected Europeancountries in 1990–1994 and 2000–2004 (unless mentioned in parentheses), and the corresponding change in rates.
Countries whose data did no allow distinction between HCC and other liver cancersEstonia
Number of deaths in the more recent year available.
Within Europe, male overall mortality from HCC in-
tion, alcohol drinking, tobacco smoking, and aﬂatoxin. The
creased in Austria, Germany, Switzerland, while decreased
suspected risk factors for liver cancer include diet, obesity,
in recent years in France and Italy, which showed upward
diabetes and insulin resistance, use of oral contraceptives,
trends up the mid 1990s In the early 2000s the
iron overload In the following, we will review risk fac-
highest HCC rates in men were in France (6.8), Italy (6.7)
tors other than infections with HBV and HCV, which are
and Switzerland (5.9), while the lowest ones were in Nor-
way (1.0), Ireland (0.8) and Sweden (0.7). In women, amoderate increase in HCC mortality was observed in Spain
and Switzerland, while mortality decreased in severalEuropean countries, particularly since the mid 1990s. In
Ecological studies have shown that the incidence of HCC
the early 2000s, female HCC mortality rates were highest
correlates not only with HBV and HCV infection, but also
in Italy (1.9/100,000), Switzerland (1.8) and Spain (1.5),
with contamination of foodstuff with aﬂatoxins, a group
and lowest in Greece, Ireland and Sweden (0.3) Inci-
of mycotoxins produced by the fungi Aspergillus ﬂavus
dence and mortality from liver cancer have been rising
and Aspergillus parasiticus, which cause liver cancer in
many species of experimental animals Contamination
The male to female ratio in liver cancer incidence is
originates mainly from improper storage of cereals, pea-
about 2.4 and the difference is stronger in high- incidence
nuts and other vegetables and is prevalent in particular
in Africa, South-East Asia and China. The investigation of
The epidemiology of liver cancer is linked to the inci-
the carcinogenic role of aﬂatoxins in humans has been
dence and mortality rates from liver cirrhosis, since a large
complicated by the inadequacy of traditional methods of
proportion of HCCs develop from cirrhotic liver . The im-
exposure assessment (e.g., questionnaires). During the last
proved survival and reduced mortality from cirrhosis, due
decades, however, prospective studies have shown a
to improvements in the prevention and treatment of this
strong association between biological markers of aﬂatoxin
condition, have in fact increased the possibility of develop-
exposure in serum or urine and risk of subsequent liver
ing HCC in cirrhotic patients. Of some importance are also
cancer. A carcinogenic role of aﬂatoxins, in particular of
the improvements in diagnosis, mainly due to widespread
aﬂatoxin B1 (AFB1), has therefore been conﬁrmed and
use of ultrasound and measurement of a-fetoprotein since
shown to be independent from – and to interact with –
the early 1980s, which led to more frequent detection of
that exerted by HBV infection AFB1 frequently induces
neoplastic liver in cirrhotic patients.
G:C to T:A transversions at the third base in codon 249 of
The established risk factors for hepatocellular carci-
P53. HBV alone does not affect the mutation rate while
noma include Hepatitis B or C viruses (HBV and HCV) infec-
the coexistence of AFB1 exposure was associated with in-
S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14
creased mutation prevalence . In area where HBV infec-
among HBV positive subjects , while another Japanese
tion is prevalent, AFB1 exposure is usually also a problem
study found a higher RR among HBV positive subjects
. HBV infected persons might be beneﬁted by eliminat-
and an Italian study reported an interaction between to-
bacco smoking and infection with HBV and HCV .
Alcohol drinking is associated with an increased risk of
Several data have been reported on a potentially favor-
liver cancer A meta-analysis has shown a dose re-
able effect of coffee on liver function and liver diseases,
sponse relationship between alcohol intake and liver can-
including liver cancer . Data on coffee and liver cancer
cer with relative risks (RRs) of 1.19 (95% CI = 1.12–1.27),
are based on at least 10 studies, 6 case–control (from
1.40 (95% CI = 1.25–1.56), and 1.81 (95% CI = 1.50–2.19)
Greece, Italy and Japan) and 4 cohort investigations (all
for 25, 50, and 100 g of alcohol intake per day, respectively
of these from Japan). Overall, the pooled relative risk (RR)
. It is believed that there is no ‘‘safety threshold” for the
was 0.54 (95% conﬁdence interval, CI, 0.39–0.76) for
case–control studies, and 0.64 (95% CI 0.56–0.74) for co-
The most probable mechanism of alcohol-related liver
hort studies Such an inverse relation may however
cancer is through the development of liver cirrhosis
be spurious, and due to the fact that subjects with a broad
. In a Swedish cohort study , the risk of liver can-
spectrum of digestive tract disorders, liver diseases or cir-
cer among alcoholisms was 2.3 (95% CI = 2.0–2.7). Among
rhosis may reduce their coffee consumption. Indeed, caf-
patients who were diagnosed with alcoholism and cirrho-
feine metabolism is impaired in patients with cirrhosis,
sis, the risk increased to 16.5 (95% CI = 12.7–21.2). In addi-
who could therefore reduce coffee intake in order to avoid
tion, HCV infection appeared to accelerate the course of
side effects of caffeine. Thus, bias due to reduction of coffee
alcoholic liver disease and to cause the development
drinking in unhealthy subjects cannot be excluded
of HCC at a younger age among drinkers than among
The inverse association between long-term coffee con-
non-drinkers . Donato et al. examined the associ-
sumption and type 2 diabetes was also suggested It
ation between alcohol intake and HCC among 464 cases
is interesting to investigate the main or joint effect of cof-
and 824 hospital controls. They found that for each level
fee drinking on the risk of liver cancer with or without the
of alcohol intake, the highest risks were observed among
subjects with HCV infection, followed by those with HBV
Green-yellow vegetables were associated with a reduc-
infection, and ﬁnally by those without hepatitis virus infec-
tion in liver cancer mortality among Japanese atomic-
tion, with parallelism between the curves. Furthermore,
bomb survivors (RR = 0.81, 95% CI = 0.67–0.97 for ‘‘2–4
synergistic interactions between alcohol intake and smok-
times per week” and RR = 0.75, 95% CI = 0.60–0.95 for ‘‘dai-
ing, obesity and diabetes had been observed The pop-
ly or almost daily” comparing to ‘‘once per week or less”, p
ulation attributable risks in Mediterranean area to liver
for trend = 0.0092) . However, no evidence has been
cancer were 28.8% for alcohol, 21.6% for HCV, and 16.2%
found in Greece that vegetable intake may reduce the risk
for HCV and alcohol combined . Alcoholic cirrhosis is
of HCC Nonetheless, a marginally inverse association
probably the most important risk factors for HCC in popu-
was implied between milk and dairy products and HCC risk
lations with low prevalence of HBV and HCV infection and
(OR = 0.70, 95% CI = 0.49–1.01). In another case–control
low exposure to aﬂatoxins, such as North America and
study in Italy, investigators observed protective effect from
milk and yoghurt (OR = 0.28, 95% CI = 0.13–0.61), white
The reduction in per capita alcohol consumption ob-
meats (OR = 0.44, 95% CI = 0.20–0.95), eggs (OR = 0.31,
served since the 1970s in various countries of southern
95% CI = 0.14–0.69), and fruits (OR = 0.48, 95% CI = 0.22–
Europe has likely contributed to the decrease in cirrhosis
1.05) In conclusion, there is limited suggestive pro-
incidence and mortality in those countries during the last
tective effect from fresh fruits; while the evidence for other
decade, with a consequent impact on HCC mortality, too.
dietary factors is not conclusive Most of the evidenceon diet and liver cancer is based on case–control studies,and the retrospective assessment of diet is particularly
problematic in studies involving chronically ill individualssuch as liver cancer patients.
Tobacco smoking is causally associated with liver can-
cer A meta-analysis on smoking and liver cancerconcluded an overall OR of 1.56 (95% CI = 1.29–1.87)
comparing current-smokers to never-smokers and of 1.49(95% CI = 1.06–2.10) comparing former smokers to never-
Obesity is now widely recognized as a signiﬁcant risk
smokers. The associations among current smokers ap-
for the development of many types of cancers. A meta-
peared to be consistent with the overall RR regardless of
analysis found that the relative risks (RR) for liver can-
region, study design, study sample size, and publication
cer were 1.17 (95% CI = 1.02–1.34) for those who were
overweight (BMI = 25–30) and 1.89 (95% CI = 1.51–2.36)
The synergistic interaction between tobacco smoking
for those who were obese (BMI P 30).
and HBV/HCV are inconsistent. A Taiwanese study found
Diabetes, a condition closely associated with obesity,
a higher RR of tobacco smoking among HBV negative than
has been proposed as a risk factor for both chronic liver
S.-C. Chuang et al. / Cancer Letters 286 (2009) 9–14
disease and HCC. A case–control study conducted in
CI = 1.07–2.38; excess: OR = 2.10, 95% CI = 1.25–3.52)
Italy found an odds ratio (OR) for liver cancer of 2.1 (95%
The effect of iron overload seems to be independent
CI = 1.4–3.2) after adjustment for age, sex, area of resi-
from development of cirrhosis and may interact with alco-
dence, alcohol and tobacco consumption, history of hepati-
hol and HBV/HCV infections. Most of the HH is associated
tis and liver cirrhosis, BMI, and family history of liver
with HFE gene mutation. HFE mutation seems to be associ-
ated with iron overload in patients with end-stage liver
It is well known that patients with various forms of liver
diseases and might accelerate hepatic ﬁbrosis in patients
disease can be predisposed to impaired glucose tolerance
with chronic hepatitis C infection . However, results
and suggested that the relationship between diabetes
from small studies considering HFE mutations in HCC pa-
and HCC is a result of HCV infection . However, a co-
tients are conﬂicting, showing either no increased HCC risk
hort study in high hepatitis virus infection area (Tai-
or a positive association of iron overload only in the
wan) found that the effect of type 2 diabetes was higher
presence of viral or alcohol induced liver damage or cirrho-
in those with HCV negative than in those with HCV posi-
(HR) = 2.08 (95% CI = 1.03–4.18) and 0.62 (95% CI = 0.22–
1.76) for HCV negative and positive, respectively). A popu-lation-based case–control study conducted in Los
Angeles, CA, USA on non-Asian population found an in-creased risk of HCC among diabetic patients free of HBV/
Hepatoblastoma is the most common childhood hepatic
HCV (OR = 3.2, 95% CI = 1.5–6.7) and an interaction with
tumor . It represented 1% of malignancies for children
HBV/HCV (ORint = 4.8, 95% CI = 2.7–6.9 on an additive
younger than 20 years old with a peak incidence of 11.2/
scale). Interaction with drinking (>4 drinks per day) was
1,000,000 during infancy . The etiology of hepatoblas-
also observed in the study (ORint = 4.2, 95% CI = 2.6–5.8
toma is still unknown. Current knowledge on the cause
include Beckwith–Wiedemann syndrome, hemohypertro-
The potential mechanism from obesity and diabetes to
phy, familial adenomatous polyposis, and Gardner’s syn-
HCC may be through fatty liver or non-alcoholic fatty liver
drome. Evidences for parental occupational exposures are
disease (non-alcoholic steatohepatitis, NASH) How-
ever, NASH is usually asymptomatic and difﬁcult to iden-tify until liver cancer or cirrhosis is established. The most
important issue now is the temporal ambiguity betweendiabetes and chronic liver diseases. Whether diabetes is a
Intrahepatic cholangiocarcinoma is the second most
result of cirrhosis, which in turn predisposes the subject
frequent type of liver cancer and accounts for about 3% of
to HCC, or an independent risk factor for HCC, is still under
gastrointestinal cancers worldwide In most regions
debate. In addition, the effect of duration and treatment of
of the world the incidence in the range 0.2–2/100,000;
diabetes on the risk of HCC might be worthwhile to
the incidence is much higher in areas where liver ﬂuke
infestation is common, such as North-East Thailand . During the last decades the incidence has increased in
many high-income countries; the reasons of this trendare not known Infestation with the liver ﬂukes, Opis-
Use of combined estrogen–progestogen oral contracep-
torchis viverrini and Clonorchis sinensis, is the main known
tives (OC) greatly increases the risk of liver adenomas, and
cause of this form of malignancy. Infection occurs via con-
is associated with the risk of HCC, although the absolute
sumption of improperly cooked ﬁsh. Liver cirrhosis,
risk is likely to be small and has been shown in populations
chronic HCV infection, heavy alcohol consumption ,
at low HBV risk . Case reports have associated use of
obesity, and gallstones were reported to be associated
anabolic steroids with development of liver cancer, but
with the malignancy. Other risk factors include inﬂamma-
the evidence is not conclusive at present. A recent meta-
tory bowl disease, primary sclerosing cholangitis, and a 1-
analysis was failed to link the use of oral contraception
antitrypsin deﬁciency . Exposure to thorotrast, a con-
and the risk of HCC due to the huge variation among stud-
trast medium containing radioactive thorium used for
ies Future investigations on the duration, intermit-
angiography in Europe and Japan during 1930–1955, re-
tency, recency of OC use, effect modiﬁcation by HBV/
sulted in an increase of cholangiocarcinoma and of liver
HCV, and other reproductive factors might help to improve
Hepatic angiosarcoma is a rare mesenchymal tumor of
An increase in iron storage in the body is a likely cause
the liver which usually presents in elderly men The
of HCC: the evidence comes from studies of patients with
estimated incidence was about 0.14–0.25/1,000,000 in
hemochromatosis (HH) or other disorders of iron metabo-
the USA . Workers exposed to vinyl chloride, a mono-
lism. Iron was observed to be associated with HCC in a
mer used in the chemical industry for production of the
group of patients in their end stage of liver diseases other
plastic polymer, polyvinyl chloride, experience an in-
than HH as well (none: reference; mild: OR = 1.59, 95%
creased risk of angiosarcoma. The identiﬁcation of clusters
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Por/ Ernesto Rios Juan Bautista Alberdi –el gran ausente del Congreso Constituyente de 1853- fue el corifeo argentino del liberalismo en boga en ese entonces, que imprimió a la Constitución su sesgo individualista, su fundamentación iluminista, y su estructuración como pieza central para “poner en manos ajenas el usufructo de nuestras riquezas y hasta el control intern