Causes of and Prevention Strategies for
Giuseppe Cabibbo,aMarcello Maida,aChiara Genco,aMichela Antonucci,b
and Calogero Cammàa
Hepatocellular carcinoma (HCC) is a challenging malignancy of global importance. It is associated
with a high rate of mortality and its prevalence in the United States and in Western Europe is
increasing. Cirrhosis is the strongest and the most common known risk factor for HCC, usually due
to hepatitis C virus (HCV) and hepatitis B virus (HBV) infections. However, different lines of
evidence identify in non-alcoholic fatty liver disease (NAFLD) a possible relevant risk factor for
occurrence of HCC. Given the continuing increase in the prevalence of obesity and diabetes, the
incidence of non-alcoholic steatohepatitis–related HCC may also be expected to increase, and a
potential role of behavior treatment and/or insulin-sensitizing drugs can be envisaged. Vaccination
against HBV is the most efficient primary prevention measure currently available to reduce the HCC
incidence and mortality in high-incidence areas, while data on the role of interferon (IFN) and
nucleos(t)ide analogues (NUC) are still controversial. The pooling of data from the literature
suggests a slight preventive effect of antiviral therapy on HCC development in patients with
HCV-related cirrhosis, but the preventive effect is limited to sustained virological responders.
Semin Oncol 39:374-383 © 2012 Elsevier Inc. All rights reserved.
cancer-related death worldwide.1The geographic dis-
tribution of HCC is highly uneven: three areas with
different incidence rates (low, intermediate, and high)
have been recognized. This variability of HCC inci-
dence suggests the influence of one or more environ-
mental risk factor that are most prevalent in the areas of
higher incidence but not in areas where the incidence
of HCC is lower. North America and Western Europe
are generally considered to be low-incidence regions
(incidence 2.6–9.8 per 100,000 population),2but in
these regions the incidence of HCC is rising.3–7Men are
generally more susceptible than women to HCC. Male
predominance is, however, more obvious in the pop-
ulation at high risk for the tumor (mean male-to-female
epatocellular carcinoma (HCC) is a challenging
malignancy of global importance. It is the sixth
most common cancer, and the third cause of
ratio, 3.7:1.0) than in those populations at low or in-
termediate risk (2.4:1.0).1HCC is associated with a high
rate of mortality and its prognosis remains dismal, in
particular when diagnosis is made at an advanced stage,
when patients are symptomatic with a variable degree
of liver function impairment.8
In oncology, cancer prevention may be categorized
as primary or secondary. Primary prevention refers to
the identification of genetic, biologic, and environmen-
tal factors that play an etiologic or pathogenetic role, in
order to impair their effects on tumor development and
halt progression of cancer and ultimately death. The
objective of primary prevention is to prohibit or to halt
effective contact of a carcinogenic agent with a suscep-
tible target in the human body. Secondary prevention
refers to identification of existing pre-neoplastic and
early neoplastic lesions in order to treat them thor-
oughly and expeditiously. Since the stage of cancer
dictates the therapeutic choice, early detection is a
primary objective. The goal of cancer screening is to
reduce mortality through a reduction in incidence of
Although early diagnosis and effective treatments
are paramount in controlling the death rate of patients
with HCC, the importance of cancer prevention has
gradually emerged because advanced (ie, large or lo-
cally invasive) HCC is difficult to cure. Since the basic
mechanism of all cancer development results from ac-
aSezione di Gastroenterologia, DIBIMIS, University of Palermo, Pal-
bDipartimento di Oncologia, Divisione di Chirurgia Generale ed Onco-
logica, University of Palermo, Palermo, Italy.
Conflicts of interest: none.
Address correspondence to Professor Calogero Cammà, Sezione di Gas-
troenterologia, Dipartimento Biomedico di Medicina Interna e Spe-
cialistica, University of Palermo, Piazza delle Cliniche 2, 90127 Pal-
ermo, Italy. E-mail: email@example.com
0270-9295/ - see front matter
© 2012 Elsevier Inc. All rights reserved.
Seminars in Oncology, Vol 39, No 4, August 2012, pp 374-383
cumulation of epigenetic and genetic alterations in
cells, the current concept of multistage carcinogenesis
has promoted chemo-prevention to the stage of a new
medical science.11Therefore, HCC (chemo)-prevention
remains a major issue in the long-term management of
cirrhotic patients, especially where chronic HCV or
hepatitis B virus (HBV) infection is the leading cause of
chronic liver disease (up to 80% of cases in the Medi-
A prevention program for HCC should fulfill the
following prerequisites: (1) identification of the risk
factors for HCC; (2) determination of the pathogenetic
mechanisms of liver carcinogenesis, as well as of the
genetic markers that identify the early events in the
carcinogenetic process and, possibly, availability of an-
imal tumor models; and, finally, (3) evaluation of the
available data from epidemiologic and clinical studies
on candidate (chemo)-preventive agents.
HEPATITIS B AND C VIRUSES
Since treating an entire population with pharmaco-
logic agents to prevent cancer is not the goal of pre-
vention, intensive screening and prevention programs
should be confined to patients at high risk of develop-
ing HCC. Clinically defined high-risk groups are well
known.13However, the accuracy and the reliability of
recognized clinical, virologic, histologic, and molecular
risk factors for neoplastic transformation are still insuf-
ficient; thus, accurate risk prediction of developing
cancer in individual patients remains an elusive goal.
HCC development is closely related to chronic in-
flammation of the liver due to hepatitis viral infections,
and most commonly arises in a cirrhotic liver.12The
annual incidence of HCC reaches approximately 2% to
7% in HBV or HCV cirrhosis.14In Europe and the United
States, an estimated 20% to 40% of patients with
chronic HBV or HCV infection develop cirrhosis within
15 to 30 years, and many of these will develop HCC;
this risk is increased if HBV/HCV co-infection is pres-
ent.15These projections are important because approx-
imately 170 million people are infected with HCV and
400 million individuals harbor a chronic HBV infection.
According to a consensus report of the National
Institutes of Health, the annual probability of a new
diagnosis of liver cancer among patients with chronic
HBV is 0.5%, and among patients with cirrhosis is 2.4%.
Studies on natural history of HBV infection conclusively
show that the risk of HCC development increases with
age, with the persistence of abnormal amino-trans-
ferases and with higher necro-inflammation on liver
biopsy. Data on the incidence of HCC emerging from
longitudinal studies with prolonged follow-up must be
considered with caution due to the selection and in-
creased surveillance for cases with more severe dis-
ease. There is evidence, from a long-term prospective
study by Villa et al16in a homogeneous cohort of
inactive HBV carriers, that this condition by itself is not
associated with a higher risk of HCC in Caucasian
subjects. The authors concluded that over a 30-year
period, chronic HBV carrier blood donors from North-
ern Italy did not develop clinically significant liver dis-
ease, HCC, or other liver-related morbidity or mortality
at a higher rate than uninfected controls. An unknown
number of subjects in the general population harbor
occult HBV infection, that is, the presence of HBV
genomes in the liver in the absence of detectable
amounts of HBsAg and even of any other marker of
HBV infection in the blood.17This condition is found in
more than 50% of subjects with chronic HCV infection
in highly endemic areas, possibly due to the common
pathways of spread of HBV and HCV. In this context,
occult HBV infection may be related to a high risk of
carcinogenesis in HCV cirrhosis.18In a study19investi-
gating the prevalence and molecular status of occult
HBV in 107 patients with HCC and 192 patients with
chronic hepatitis, all HCV-RNA–positive and HBsAg–
negative in serum, occult HBV-DNA was detected in
the liver of 68 cases of HCC (63.5%) and in 63 patients
with chronic hepatitis (32.8%) (P ?.0001; odds ratio
[OR], 3.6; 95% confidence interval [CI], 2.2–5.9). The
association of occult HBV with HCC was significant
irrespective of age and sex. However, further prospec-
tive studies are needed to substantiate this association.
Cirrhosis per se is a precancerous condition, but the
magnitude of the oncogenic risk varies widely with
etiology, that is, high with HBV and HCV and low with
Chronic ingestion of large amounts of alcohol in-
creases risk of developing cirrhosis and the subsequent
development of HCC. In one study, alcoholic liver
disease accounted for 32% of all HCCs.21Less common
risk factors for the development of HCC include afla-
toxin exposure, genetic hemochromatosis, and alfa1-
However, even after the exclusion of all of these
causes and of other rare risk factors, approximately
15% to 50% of HCC cases occur in a context of cryp-
togenic cirrhosis (CC), suggesting the determinant role
of other pathogenetic factors.22In accord with these
data, different lines of evidence have identified nonal-
coholic fatty liver disease (NAFLD) as the main cause of
HCC on CC worldwide.23NAFLD is a pathological con-
dition whose prevalence in the general population av-
erages 20% to 30%.24,25It is considered the hepatic
manifestation of insulin resistance,26and is therefore
strongly associated with other clinical expressions of
insulin resistance, such as metabolic syndrome and its
features, namely, obesity, type 2 diabetes, dyslipidemia,
and hypertension.27Many reports have described
HCC development in patients with CC secondary to
Causes and prevention strategies 375
NAFLD.28?36However, the more significant data on the
association between NAFLD and HCC on CC have
emerged from both prospective/cohort studies and in-
direct evidence. In fact, different cross-sectional retro-
spective studies have found many risk factors for
NAFLD in patients with HCC on CC, and a number of
reports have shown an independent link between risk
factors for NAFLD—especially obesity and diabetes—
and HCC occurrence, despite the underlying presence
of HBV and/or HCV infection.
The mechanism linking NAFLD to HCC is not com-
pletely understood. The pathogenetic key of NAFLD is
insulin resistance, which both directly and indirectly,
by inducing steatosis and oxidative stress, leads to
progression of the disease. Insulin resistance via in-
creased levels of insulin and insulin-like growth factor
(IGF), oxidative stress via increased production of re-
active oxygen species and lipid peroxides, and adipo-
kine/cytokine interplay via increased levels of tumor
necrosis factor-?, interleukin-6, and leptin and reduced
levels of adiponectin, may favor HCC development
among different mechanisms. These can stimulate he-
patic stellate cells, favor DNA damage with occurrence
of mutations in oncosuppressors and/or oncogenes,
and activate proliferative signaling pathways. All of
these mechanisms can lead to non-alcoholic steato-
hepatitis and its evolution in cirrhosis and HCC.23
Various lines of evidence, including a systematic
review and a meta-analysis,37have suggested that obe-
sity is linked to excess risk for many cancers, such as
HCC. Calle et al38specifically reported that in a large
prospective study encompassing more than 900,000
individuals in the United States followed for a 16-year
period, liver cancer mortality rates were 1.68 times
higher in women and 4.52 times higher in men with a
body mass index ?35 compared to those with a normal
body mass index. Other population-based cohort and
follow-up studies performed in Sweden,39,40the United
States,41Denmark,42and Korea43confirmed a higher
rate of HCC diagnosis in obese patients, with an in-
creased relative risk ranging from 1.5- to 3.6-fold. Fi-
nally, a recent meta-analysis44summarizing the evi-
dence from cohort studies found increased HCC risks
of 17% for overweight people and 90% for obese sub-
jects compared with normal-weight subjects.
Diabetes, another frequent feature in patients with
NAFLD, also has been reported as an independent risk
factor for HCC in both prospective and cross-sectional
studies. Different case-control studies,45?51comparing
patients with newly diagnosed HCC to healthy con-
trols, found an independent association between dia-
betes and HCC, with an increased risk of HCC ranging
from 1.5- to 4.3-fold. These data, arising from studies
performed in the United States,45?49Italy,50and
Greece,51confirmed HCV, HBV, alcohol, tobacco, and
body mass index as risk factors for HCC. However, they
also identified in diabetes an independent risk factor
for HCC, showing a synergistic effect with alcohol
intake and viral infection. The largest of these studies,
by Davila et al45in a cohort of 2,061 HCC patients,
showed a threefold increase in HCC risk in diabetic
patients, also confirming these data in the subgroup of
subjects without known risk factors for HCC (HCV,
HBV, alcoholic liver disease, and hemochromatosis).
However, a potential bias in case-control studies is
discerning the correct temporalrelationship between
exposure (diabetes) and outcome (HCC).
Vaccination and Counseling
In the setting of primary prevention the epidemio-
logic data available point to vaccination against HBV as
the most efficient primary prevention measure cur-
rently available to reduce HCC incidence and mortality
in high-incidence areas. Eradication of HBV by vaccina-
tion has reduced the incidence of HCC in children in
Taiwan,52becoming the most radical way to prevent
HCC associated with chronic HBV.
Since vaccination against HCV is yet unavailable and
there is only a low probability of a vaccine against HCV
being developed in the near future, other preventive
methods are required to reduce the burden of HCV-
related liver disease. Counseling is needed for primary
prevention of new infection by rigorous implementa-
tion of infection control practice to prevent nosoco-
mial and iatrogenic HCV transmission and secondary
prevention of HCV transmission from infected persons
to other persons.12However, the impact of any preven-
tion program on HCV spread is relatively low because
the majority of the infected patients are not under
medical care. Although screening of the whole popu-
lation is not recommended, it is important to test for
HCV in all persons with risk factors for HCV infection.
A strategy aiming to prevent chronic liver disease of
any etiology (alcohol, obesity, others) may be required
to prevent HCC in low- and intermediate-incidence
areas, and hence, worldwide. The incidence of HCC
might be further reduced by eliminating aflatoxin from
the food supply in areas of the world where agricul-
tural products are stored under conditions that favor
the growth of Aspergillus flavus and Aspergillus para-
siticus. A recent case-control study conducted in Sudan
clearly demonstrated that reduction of aflatoxin con-
tamination of foods may be a useful public health
strategy in HCC prevention.53Only well-recognized
risk factors for HCC are discussed here. Other risk
factors, like anabolic or sex steroids, smoking habits,
and perhaps plant-derived or chemical agents, have not
been considered because their impact on HCC epide-
miology is doubtful or very small, and available data are
sparse and somewhat conflicting.
376 G. Cabibbo et al
Interferon for HBV Cirrhosis
IFN has been the mainstay of therapy for chronic
HBV since the early 1980s. Since then, several random-
ized controlled trials (RCTs) and cohort studies have
been published. The results of these trials remain in-
consistent about the natural history of HBV disease,
because the overall assessment of treatment effect on
true disease end points (ie, progression to cirrhosis, to
HCC, and death) cannot usually be assessed in short-
term trials.54A major issue of concern is the fact that
RCTs of IFN for chronic HBV have been performed
mostly in patients without advanced fibrosis or cirrho-
sis. The transferability of these results to the whole
spectrum of subjects with chronic liver disease due to
HBV is thus questionable.
All potentially relevant papers were initially classi-
fied into two subsets (1: controlled trials; 2: cohort
Subset 1: Controlled Trials
The rate of HCC in treated and untreated patients
with HBV cirrhosis was reported in 11 studies, includ-
ing 2,560 patients.55?65IFN seemingly decreased the
rate of HCC occurrence in all but one trial, and a
significant difference was observed in three studies.
The pooled estimate of the preventive effect of treat-
ment was significantly in favor of IFN (rate difference:
?0.04; 95% CI, ?0.01 to ?0.07). A remarkable heter-
ogeneity was detected among studies (heterogeneity
39.12 with 10 df; P ?.0001).66
Since the trials showed significant inconsistency,
subgroup analyses were performed in relation to the
ethnic origin of patients (European v Oriental studies).
Consistent results were observed only when assessing
data pooled from European reports: in this subgroup,
no preventive effect of HCC was found.
Subset 2: Cohort Studies
It has been suggested from long-term cohort studies
that IFN treatment may have a protective effect against
HCC development in patients with chronic HBV infec-
tion. We reviewed the clinical course and outcome
of patients enrolled in long-term follow-up stud-
ies.61,62,65,67?75The 12 studies (11 prospective and one
retrospective) included a total of 1,952 patients, of
which 1,187 were not receiving active treatment.
Length of follow-up ranged from 2.1 to 8.9 years. Meta-
analysis of longitudinal studies with prolonged fol-
low-up showed no significant differences in the rate of
HCC between treated patients (1.9%; 95% CI, 0.8%–
3.0%) and controls (3.16%; 95% CI, 1.8%–4.5%).
All data dealing with HCC development coming
from studies with prolonged follow-up must be inter-
preted with caution, because possible biases can lead
to erroneous estimates: (1) data collected from both
prospective and retrospective studies conducted in ter-
tiary care centers with limited generalizability; (2) lack
of randomization reducing the internal and the external
validity of the studies; (3) heterogeneity of patients
enrolled, both in respect to clinical and demographic
features and to possible cofactors; (4) slow and pro-
longed course of the disease not allowing an inception
cohort; (5) few clinically relevant events, relatively
small sample size, and duration of follow-up less than 8
to 10 years; (6) high mortality from nonhepatic causes;
(7) selection and increased surveillance for cases with
more severe disease and unfavorable course; (8) pro-
gressive shift over the years of the global spectrum of
the disease due to intervening factors (eg, new diag-
nostic tests and screening programs; new treatments).
In conclusion, there is no sound evidence from
controlled trials and prospective cohort studies to sup-
port a recommendation for widespread use of IFN to
prevent HCC in these patients.
Even though these observations were not applicable
to studies in Asia, the trend for lower HCC incidence in
cirrhotic patients treated with IFN was recently con-
firmed by two other meta-analyses,76,77in which six
studies demonstrated a prevalence of HCC of 11.6% in
treated patients versus 21.5% in controls (relative risk:
0.53; 95% CI, 0.36–0.78) and an overall pooled risk
reduction of HCC in treated patients of 34%.
Nucleos(t)ide Analogues for HBV Cirrhosis
It has been argued that long-term suppression of
HBV replication could reduce hepatocyte turnover and
lessen the risk of dysplasia and cancer.78In 2004, a
large RCT79showed a decrease in the incidence of HCC
in patients with HBV-related advanced liver disease
treated with lamivudine compared to untreated con-
trols. In the wake of this study, further controlled trials
and retrospective or prospective cohort studies80?84
were performed, mostly in patients with advanced liver
disease. These studies collected cohorts of HBeAg–
positive and –negative patients and showed a marked
degree of heterogeneity, making it difficult to assess the
actual level of benefit obtained by nucleos(t)ide ana-
logues (NUC) treatment.
We have pooled the available literature data to eval-
uate whether NUC treatment reduces the incidence of
HCC in patients with HBV-related chronic liver disease.
The effects of NUC on cancer incidence were assessed
in six studies: two RCTs79,83and four nonrandomized or
cohort studies.80?82,84The six studies included 2,394
patients: 1,372 received NUC therapy (1,116 as lami-
vudine monotherapy and 206 as lamivudine and adefo-
vir combination therapy) and 1,022 were untreated
controls. Since in the cohort study a control arm of
untreated patients was not included, we indirectly
compared the rate of HCC development in the treat-
ment arm to the mean control rate pooled from all
Causes and prevention strategies 377
other studies. The percentage of males ranged from
73% to 85%. The sample size of each study varied
greatly, ranging from 754 to 105 patients. Mean patient
age ranged from 34 to 50 years. The proportion of
patients with cirrhosis differed greatly among studies,
ranging from 0%82to 100%.83Similarly, great variability
was observed among trials in the HBeAg status, ranging
from 0%81to 100%.82A large variability of NUC sched-
ules between trials was found in the length of treat-
ment (range, 19–96 months) and in the treatment
follow-up (range, 2.7–8.2 years). NUC treatment seem-
ingly decreased HCC rate in all six evaluable studies,
with a significant difference being observed in three.
The pooled estimate of the treatment effect by random
effect model analyses was significantly in favor of a
preventive effectiveness of NUC (relative risk, 0.26;
95% CI, 0.12–0.48). We found a remarkable statistical
quantitative heterogeneity among the studies, in the
difference of the magnitude of the preventative effect
of the treatment on the risk of cancer development.
Large differences were observed in the baseline risk of
HCC among the different studies: HCC rate in the
untreated group ranged from 2.4% to 32.4%. The re-
sults of this meta-analysis demonstrate that the hetero-
geneity in the magnitude of the preventive effect of
NUC on the risk of cancer is the most impressive
feature of these studies. Regarding HBV-related chronic
infection, the pooled data suggested a preventive effect
of NUC on HCC development in patients without cir-
rhosis and in subjects with HBeAg-positive infection.
The benefit on HCC prevention was observed in stud-
ies from Asia. As with all meta-analyses, a methodolog-
ical issue of the meta-analysis described above, is the
potential limitation of the generalizability of its results
to new populations and settings, particularly in west-
ern populations and in real clinical practice.
Interferon for HCV Cirrhosis
The role of IFN in preventing HCC in HCV-related
cirrhosis is controversial. It has been argued that long-
term suppression of viral replication could reduce he-
patocyte turnover and lessen the risk of dysplasia and
cancer. In 1995, a small RCT showed a decrease in the
incidence of HCC in patients with HCV cirrhosis
treated with IFN-alpha, compared with untreated con-
trols.85In the wake of this study, several controlled
trials86?104were performed. Three meta-analyses on
aggregate data66,105,106evaluated whether IFN reduces
the incidence of HCC in patients with HCV-related
cirrhosis. In the last published,66IFN seemingly de-
creased HCC rate in all but one of 20 studies included
in the meta-analysis, a significant difference being ob-
served in 13 studies. The rate difference (RD) between
IFN-treated patients and controls of each trial ranged
from ?33.3% to ?3.9%. The pooled estimate of the
treatment effect was significantly in favor of a preven-
tive effectiveness of IFN (RD, ?12.2%; 95% CI, ?8.4%
to ?16.1%; P ?.00001). A remarkable heterogeneity
among the studies (P ?.0001) was found. The most
prominent heterogeneity was in the difference of mag-
nitude of the treatment effect on the risk of cancer
(“quantitative heterogeneity”). Large differences were
observed in the baseline risk of HCC among the differ-
ent trials: the HCC rate in the untreated group ranged
from 6.8% to 73%. The available evidence from meta-
analyses is sufficient to conclude that IFN may prevent
or delay the development of HCC in patients with
HCV-related cirrhosis. However, the magnitude of the
overall effect is low and the observed benefit might be
due to spurious associations. The preventive effect is
stronger among sustained responders to IFN, which
intrinsically represent a small proportion of all cirrhotic
After the meta-analyses, three observational cohort
studies, two prospective studies conducted in Japan107
and in Taiwan108and one retrospective study con-
ducted in Italy109clearly have confirmed that the effi-
cacy of IFN in the chemoprevention of HCC is exclu-
sively linked to the achievement of a sustained viral
eradication, while no benefit in reducing HCC devel-
opment was observed in non-responder patients. Re-
cently, the effectiveness of long-term maintenance
therapy with pegylated-IFN at low dose in non-re-
sponder patients with advanced fibrosis or HCV-related
cirrhosis was evaluated by three RCTs: the HALT-C
trial,110the Epic-3 trial,111and the COPILOT trial.112
Patients in these studies were quite homogeneous in
terms of recruitment criteria, stage of liver disease at
entry, follow-up, and treatments. The outcomes as-
sessed were death, hepatic decompensation as defined
by Child-Pugh score progression, HCC, and, for non-
cirrhotic patients, an increase in hepatic fibrosis. Not
surprisingly, in all three RCTs the clinical outcomes
were similar in the treatment and control groups. The
three studies show that the natural history of cirrhosis
was not significantly affected by low-dose PEG-IFN
maintenance treatment as both overall, event-free sur-
vival and HCC development, did not differ between
treated and untreated patients. So, no benefit of main-
tenance therapy in reducing the progression of fibrosis,
hepatic decompensation, or mortality, or in preventing
the development of HCC was observed, despite the
improvement of inflammatory markers (alanine amino-
transferase and necroinflammatory histologic findings)
and the reduction of viral load. It seems reasonable,
therefore, to recommend caution when treating cir-
rhotic patients to reduce the risk of cancer with long-
term maintenance IFN regimens.
Insulin-Sensitizing Drugs for NAFLD
In the light of all of the above-cited evidence of the
cross-talk between mechanisms leading to NAFLD and
378 G. Cabibbo et al
pathogenesis of HCC, it is interesting to speculate that
the behavioral treatment and/or use of drugs able to
improve NAFLD also may have some application in
HCC. In the previous section we showed that the key
mechanisms in NAFLD pathogenesis, namely, insulin
resistance, oxidative stress, and deregulated adipokine/
cytokine interplay, are able to induce DNA alterations
and proliferative pathways also found in HCC. At the
moment, other than behavioral therapy,113the only
pharmacological treatments that have demonstrated, in
different independent studies, the ability to improve
biochemical, metabolic, and histological parameters in
NAFLD patients concern the use of insulin-sensitizer
drugs such as thiazolidinediones (peroxisome prolifera-
tor-activated receptor-gamma [PPAR?] agonists)114?116
and metformin.117Interestingly, various studies suggest
that these drugs also have potential antineoplastic ef-
fects. Thiazolidinediones, by interaction with nuclear
receptors, namely, PPAR?, exert anti-inflammatory and
insulin-sensitizer actions.118In addition, a recent pa-
per119showed PPAR? hypoexpression in human HCC,
suggesting a potential protective role of these recep-
tors. In line with these data, some experimental models
have observed an antiproliferative and proapoptotic
effect of thiazolinediones119,120that could also exert
their antineoplastic action via induction of adiponec-
tin.121,122However, other studies have shown contrast-
ing results,123,124underscoring the need for further re-
search. Recent evidence also has pointed out that
metformin, a widely used antidiabetic drug that acts via
activation of adenosine monophosphate–activated pro-
tein kinase (AMPK), may reduce the risk of can-
cer,125,126suggesting also a tumor-specific antineoplas-
tic effect of metformin that could suggest its potential
role in the management of specific type of cancer in
nondiabetic individuals. Accordingly, data from exper-
imental studies has shown that metformin exerts an
antineoplastic effect directly, by blockage of cell cycle
inhibiting cyclin D1 expression and pRb phoshoryla-
tion, and indirectly, not only by activating the AMPK
pathway, that is able to inhibit the mammalian target of
rapamycin (mTOR) proliferative cascade,127,128but also
by interacting with CD8?T cells and therefore with the
immune response.125It is noteworthy to underline also
that in contrast to the antineoplastic effect of met-
formin different lines of evidences showed an in-
creased cancer risk in diabetic patients on insulin ther-
apy.125These data have been interpreted considering
the stimulatory effect of exogenous insulin on insulin/
IGF1 axis, that, as cited in the previous section, have
the potential to support self-sufficiency in growth sig-
nals, resistance to apoptosis, being able to offer an
adaptive advantage to cancer foci. So, the potential
utility of insulin-sensitizing drugs or behavior therapy
in HCC should be tested in large prospective studies on
patients with NAFLD and/or insulin resistance as an
instrument for preventing HCC occurrence.
The accuracy and the reliability of well-recognized
clinical, virologic, histologic, and molecular risk factors
for HCC are still insufficient; thus, accurate risk predic-
tion of developing cancer in individual patients remains
an elusive goal. Future directions in chemoprevention
of HCC will include the development of molecular risk
models and of new chemopreventive agents.
HBV continues to be the major HCC risk factor
worldwide, although its importance will most likely
decrease during coming decades due to the widespread
use of the HBV vaccine in newborns in HBV endemic
and HCC high-incidence areas.
HCV has been the dominant viral cause in HCC in
North America, some Western countries, and Japan.
Growing evidence suggests that NAFLD is a new,
relevant, and increasing risk factor for HCC develop-
ment. Indeed, despite the fact that few NAFLD patients
develop liver cirrhosis with its complications over
many years, the rapid increase in predisposing factors
for NAFLD, namely, obesity, insulin resistance, and
diabetes, explains the emerging increase in NAFLD
prevalence in the general population, and the conse-
quent increase in the incidence of HCC due to NAFLD.
Obesity and diabetes are increasing at a fast pace
throughout the world, and these conditions would
plausibly account for more HCC cases in future. So,
reduction of excess energy intake in early life, avoid-
ance of obesity in adult life, and increased physical
activity throughout life are desirable and could have a
relevant impact in reduction of HCC burden, especially
in developed countries. Moreover, recent data are quite
interesting in suggesting a potential approach (behav-
ior treatment and/or insulin-sensitizing drugs) aimed at
prevention of the occurrence of HCC in patients with
NAFLD and/or insulin resistance, even if large-scale
prospective studies are needed.
A strategy aiming at preventing chronic liver disease
of any etiology (HCV infection, alcohol, obesity, oth-
ers) may be required to prevent HCC in low- and
intermediate-incidence areas, and hence, worldwide.
In the setting of chemoprevention, pooling of the lit-
erature data suggest a slight preventive effect of IFN on
HCC development in patients with HCV-related cirrho-
sis. The magnitude of this effect is low, and the ob-
served benefit might be due to spurious associations.
The preventive effect is more evident among sustained
responders to IFN. There is no sound evidence to
support a recommendation for widespread use of IFN
to prevent HCC in HBV-related cirrhosis. Despite the
many methodological problems of the studies, which
hamper an accurate evaluation of the anti-HCC activity
of both IFN and NUC, successful suppression of HBV
does not seem to prevent, although it delays, the onset
of HCC in HBV patients.
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