Epidemiology of
59 Hepatocellular Carcinoma
Hashem B. El‐Serag
Department of Medicine, Baylor College of Medicine and Michael E. DeBakey Veterans Affairs Medical
Center, Houston, TX, USA
TRENDS IN HEPATOCELLULAR
CARCINOMA
Global epidemiology
Liver cancer, of which hepatocellular carcinoma (HCC) is the
dominant variety, represents the fourth leading cause of cancer
deaths worldwide. Globally, it ranks sixth in cancer incidence
and second in the absolute years of life lost. The incidence and
mortality of liver cancer vary by region. The age‐standardized
incidence rates of liver cancer are highest in Asia Pacific, East
Asia, and central sub‐Saharan Africa and lowest in southern
Latin America and tropical Latin America. Liver cancer ranks
first in cancer deaths in Egypt and Thailand, whereas it ranks
14th in Ukraine and Poland [1].
The geographic map of the incidence and mortality of HCC
has changed over time. Regions that traditionally have lower
incidence of HCC, such as North America and certain areas of
Europe, have seen increased incidence, and regions that are tra-
ditionally high risk, such as Japan and China, have shown declin-
ing rates. This observation is likely due to changes in exposure to
HCC risk factors, including chronic hepatitis C virus (HCV) or
hepatitis B virus (HBV) infection, heavy alcohol consumption,
diabetes, and non‐alcoholic fatty liver disease (NAFLD) [2, 3].
In low‐risk countries, increases in the rates of obesity, diabetes,
and NAFLD threaten gains in reducing the incidence of HCC,
whereas in high‐risk countries, aggressive HBV vaccination and
or aflatoxin‐reduction programs and the use of antivirals to treat
hepatitis B and C infections have reduced HCC incidence [2, 4].
Environment could play a role in regional and temporal varia-
tions in HCC incidence. This hypothesis is built in part on rates
of HCC in migrant populations. Migrants moving from low‐risk
African, Asian, or South American countries to Western Europe
The Liver: Biology and Pathobiology, Sixth Edition. Edited by Irwin M. Arias, Harvey J. Alter, James L. Boyer, David E. Cohen, David A. Shafritz,
Snorri S. Thorgeirsson, and Allan W. Wolkoff.
© 2020 John Wiley & Sons Ltd. Published 2020 by John Wiley & Sons Ltd.
had increased risk of HCC compared with their originating
­countries [5]. Among Chinese expats, HCC risk decreased com-
pared with that of Chinese population; however, the risk was still
higher than that of the host country. Even within similar geo-
graphic regions there can be wide variations, such as the 75.5%
difference in age‐standardized incidence rate observed between
persons from Bhopal and Dindigul, India and from Qidong City,
China [2]. The environmental factors contributing to these differ-
ences in HCC risk have yet to be clearly identified.
Sex differences in rates of HCC
In general, HCC is more prevalent in men than women
(Figure 59.1). For men, liver cancer was the most common can-
cer diagnosis in 11 countries and cause of cancer death in 40
countries. By contrast, Mongolia was the only country in which
liver cancer was the most common cancer diagnosis for women,
and liver cancer was the most common cause of cancer death for
women in only five countries [1]. Typically, the rate of liver can-
cer is two to three times higher in men than women [6]. There are
some exceptions; several countries have HCC rates in women
that approach those of men, but the risk factors associated with
the increased incidence in women have yet to be identified [4].
Notably, there is no correlation between gender disparity and the
level of HCC risk of the geographical region [2].
There are several hypotheses, including differences in behaviors,
alcohol consumption, immune responses, and epigenetics [7–9],
regarding the source of this disparity. One particularly strong
hypothesis involves differences in endogenous sex hormones. A
prospective cohort study of more than 9000 men in Taiwan found
that the relative risk of HCC increased between 50% and 400% for
men in upper tertile of testosterone level compared with the middle
and lowest tertiles [10, 11]. Several studies of CAG repeats in exon
 59: Epidemiology of Hepatocellular Carcinoma 759

Male:Female ratio
Thailand 2.7:1
China 3.4:1
Japan 3.0:1
Philippines 2.9:1
Singapore 3.8:1
Italy 3.0:1
France 5.5:1
Switzerland 4.8:1
Uganda 1.3:1
Spain 3.6:1
Croatia 2.8:1
Germany 2.6:1
Austria 3.1:1
United States 3.2:1
Brazil 2.3:1
Czech Republic 2.5:1
Slovenia 3.4:1
Slovakia 2.7:1
Latvia 3.1:1
Costa Rica 1.6:1
New Zealand 2.7:1
Finland 2.5:1
Australia 2.9:1
Russia 2.6:1
Poland 2.0:1
United Kingdom 2.2:1
Denmark 2.6:1
Colombia 1.3:1
India 2.4:1
Ecuador 1.3:1
Canada 2.7:1
Estonia 2.1:1
Sweden 2.0:1
Iceland 2.5:1
Malta 2.6:1
Israel 2.4:1
Norway 2.2:1
The Netherlands 2.6:1

30 20 10 0 10 20
Male Female
Age-Adjusted Rate Age-Adjusted Rate

Figure 59.1 Age‐adjusted incidence rates of hepatocellular carcinoma in men and women separately. The men:women incidence ratios are also
shown. Data from [1].

1 of the androgen receptor and its role in HCC have been conducted.
In one study, men with chronic HBV infection who had fewer
CAG repeats (≤20) and increased testosterone levels had a fourfold
increase in HCC risk compared with men with more repeats [12]. A
similar study was performed in women both with and without
chronic HBV. Those with two androgen receptor alleles with more
than 23 repeats had a higher risk of HCC compared with those who
had two short alleles or a short and long allele, and the risk was
increased further when the woman was an HBV carrier [9].
Transgenic mouse studies investigating the role of the androgen
receptor in HBV infections demonstrated that increased androgen
pathway signaling can increase HBV gene transcription [13], indi-
cating that the combination of chronic HBV infection, a substantial
risk factor for HCC, and sex hormone levels could contribute to the
apparent gender disparity in the incidence of HCC.
United States trends in incidence
In the United States, the number of cancer‐related deaths attrib-
uted to HCC is rising rapidly. One study of the United States
Cancer Statistics Registry reported the age‐adjusted incidence
rate increased by 2.3/100 000 persons between 2000 and 2012.
When broken down by year, these changes in incidence
increased approximately 4.5% between 2000 and 2009 and
began plateauing in 2010 [14]. The Centers for Disease Control
have reported similar increases in mortality through 2015.
Further investigation of the registry showed that the populations
experiencing the greatest increase in incidence were men aged
55–64 years and in individuals of Hispanic, African American,
and white ethnicity [15].
Notably, the overall age‐adjusted incidence rates for HCC
have skyrocketed among persons of Hispanic ethnicity, sur-
passing even that of persons of Asian race (Figure 59.2). The
trend is amplified among the Hispanic population born in the
United States. The higher rates of HCC in this population have
been attributed to a higher incidence of HCV [16] as well as
increased rates of alcoholic liver disease, NAFLD, metabolic
syndrome, and diabetes [17, 18], all of which are risk factors
for developing HCC. Among Hispanic patients with chronic
HCV or NAFLD, the risk of progression to cirrhosis and HCC
is higher. This observation has been attributed in part to a
genetic predisposition to cirrhosis, such as that associated with
the phospholipase domain‐containing 3 gene (PNPLA3)
­polymorphism (discussed later) [19].
760
16
14
Age-adjusted rate per 100,000
12
10
8 Black
6
0
00
01
02
03
20
20
20
20
Figure 59.2 Yearly age‐adjusted incidence rates of hepatocellular carcinoma in the United States between 2000 and 2012, broken down by race
and ethnicity. API, Asian Pacific Islanders; AI/AN, American Indian or Alaska Native. Modified from [14].
RISK FACTORS FOR HCC
Hepatitis B virus
HBV is a double‐stranded DNA virus that preferentially infects
hepatocytes. Infections can be acute or chronic, the latter being
a risk factor for HCC. The risk of the infection turning chronic
increases with earlier age at infection. Among adults who are
infected via sexual contact, needle stick, or transfusion, fewer
than 10% develop chronic infections, whereas among infants
infected by vertical transmission from HBV‐infected mothers,
80–90% develop chronic infections [20].
With chronic infections, HBV integrates into the host genome.
This integration is a precursor to hepatocarcinogenesis. HBV
induces chronic necroinflammatory disease, a continuous cycle
of hepatocyte necrosis and regeneration, which promotes muta-
tions in liver cells and leads to HCC [20, 21]. When evaluating
HCC tissue from individuals with chronic HBV, HBV DNA is
integrated into the genome in nearly all cases [2]. Worldwide,
chronic HBV accounts for 50% of HCC cases [20]. However,
this percentage varies by country. In areas with endemic HBV
infections, such as Asia and sub‐Saharan Africa, HBV accounts
for more than 70% of HCC cases [22]. By contrast, HBV only
accounts for 10–15% of HCC cases in the United States [23].
It is estimated that 350–400 million individuals have a
chronic HBV infection – approximately 5% of the global popu-
lation [24]. In the United States, approximately 0.33% of the
population are thought to have chronic HBV based on data from
the National Health and Nutrition Examination Surveys between
1988 and 1994. Those analyses showed that there was a higher
prevalence of chronic HBV carriers among men compared with
women and among non‐Hispanic blacks compared with non‐
Hispanic whites and Mexican Americans [25].
Most individuals with chronic HBV have inactive infections.
However, 10–30% develop active infections. Cirrhosis develops
in approximately 1–2% of those with chronic active infections.
Among those with cirrhosis, 1–6% per year will progress to
HCC. The time between infection and HCC development is esti-
mated to be in the range of 30–50 years [20].
THE LIVER: RISK FACTORS FOR HCC
Hispanic
White
API
AI/AN
04
05
06
07
08
09
10
11
12
20
20
20
20
20
20
20
20
20
Year
Relative risk of HCC from HBV
The relative risk of HCC from HBV is consistently quite high.
One meta‐analysis looked at case–control and prospective
studies evaluating individuals positive for HBsAg, a marker
of HBV infection. When individuals who were HBsAg posi-
tive were compared with those who were HBsAg negative, the
authors found that the lifetime relative risk of HCC was 15–20
[26]. When evaluating case–control studies from across the
globe, the estimated odds ratios of developing HCC ranged
from 5 to 65 among individuals with chronic HBV. This
observation is supported by prospective studies of HBV carri-
ers, who had relative risks for HCC of 5–103 compared with
noncarriers [2].
Absolute risk of HCC
The World Health Organization estimates that the lifetime
risk of developing HCC in individuals carrying HBV ranges
from 10 to 25% [2]. Based on cohort studies, the incidence of
HCC in patients with HBV seems to vary based on the level
of cirrhosis. Those with inactive disease had an HCC inci-
dence of 0.02–0.2 per 100 person‐years, those with active
chronic infections but no cirrhosis had an incidence of
0.3–0.6 per 100 person‐years, and those with compensated
cirrhosis had an incidence of 2.2–3.7 per 100 person‐years
[27, 28]. Much of our information on the risk of HCC among
individuals with HBV comes from areas where HBV is
endemic and the individuals evaluated were infected in
infancy or early childhood [29]. In a multicenter study from
the United States, where most individuals are infected later in
life, the annual incidence was estimated to be 0.42%. However,
more than 50% of the evaluated cohort were Asian Pacific
Islanders [30]. Another recent study evaluated a cohort of
more than 8000 primarily male patients with chronic HBV
infections identified from the United States Veterans Health
Administration (VHA) database between 2001 and 2013.
Among that cohort, the annual incidence rate of HCC was
0.65% for American Pacific Islanders, 0.57% for whites, and
0.40% for African Americans [31].
 59: Epidemiology of Hepatocellular Carcinoma
Determinants of risk associated with HBV
Increased risk
Numerous risk factors for HCC have been identified for indi-
viduals with chronic HBV infections. Demographics (e.g. male
sex, older age, Asian or African ancestry, family history of
HCC), clinical features (e.g. cirrhosis), viral factors (e.g. high
HBV replication levels, HBV genotype, infection duration,
coinfection), and environmental exposures (e.g. aflatoxin expo-
sure, alcohol and tobacco use) all contribute to the development
of HCC [27].
With respect to demographics, a 90 000‐participant prospec-
tive cohort study showed that male patients with chronic HBV
have a higher risk of both cirrhosis and HCC than female
patients [32]. Age has been shown to play a role in HCC risk,
both in general and based on race. Studies conducted in East
Asia showed a marked increased risk of HCC beyond 40 years
of age [31]. Studies in South Africa from the 1970s and 1980s
reported that African black patients with chronic HBV could
develop HCC at less than 40 years of age [33, 34], and these
data were confirmed in a recent study evaluating HCC in mul-
tiple African countries [35]. Data from the VHA cohort
described above showed that HCC risk increased with age. In
that cohort, adjusted hazard ratios for HCC were 1.97 for indi-
viduals 40–49 years of age, 3.00 for those 50–59 years of age,
and 4.02 for those older than 60 years of age compared with
individuals younger than 40 years of age. Notably, the risk of
HCC was extremely low in individuals younger than 40 years
of age, including those who were African American [31], indi-
cating that in the United States, African American race may not
be as high a risk factor for early HCC in the absence of other
risk factors.
Cirrhosis is the primary clinical risk factor for HCC. In
patients with chronic HBV, 70–90% of HCC cases arise from
cirrhotic liver [23]. As mentioned earlier, the incidence of HCC
in patients with HBV increases substantially with the progres-
sion of cirrhosis. This observation was supported by the results
of the VHA cohort study, which found an adjusted hazard ratio
of 3.69 for patients with cirrhosis compared with those without
cirrhosis [31].
Several viral factors have been shown to increase the risk of
HCC. The effects of viral load have been investigated in a pro-
spective cohort of HBsAg‐positive participants in a Taiwanese
study. The authors found a proportional increase in the inci-
dence of cirrhosis and HCC with increasing serum levels of
HBV DNA [36]. HBV genotype also factors into HCC risk.
In studies of Asian populations, the association between geno-
type and severe liver disease, cirrhosis, and HCC is greater for
genotype C than genotype B. Among studies out of North
America and Western Europe, the incidences of severe liver dis-
ease and HCC were greater for genotype D than genotype A
[37]. Population‐based studies have shown that the risk of HCC
associated with genotype C is higher than that of genotypes A2,
Ba, Bj, and D [38]. When looking deeper into the viral genetics,
studies have shown that specific mutations in the basal core pro-
motor and precore region affect the incidence of HCC. In the
case of the former, mutations at T1762 and A1764 have been
shown to increase incidence [39]. In the case of the latter, infec-
tion with the G1896A mutation is associated with decreased
incidence [40]. In addition to the virus itself, coinfection with
761
other viruses, such as HCV and HIV, can have substantial effects
on risk. The extent of the effect is somewhat controversial. With
respect to HCV coinfection, older meta‐analyses support an
additive effect on HCC risk [41, 42]. Studies conducted more
recently, including those in countries where coinfection is
uncommon, have reported sub‐additive effects on HCV [26].
Previous studies have noted a negative correlation between lev-
els of HBsAg and anti‐HCV antibody in serum, indicating viral
interference [42, 43]. This observation could account for the
sub‐additive effects observed.
Environmental factors that increase risk include both behav-
ioral factors (alcohol and tobacco) and exogenous exposures.
Alcohol is hepatotoxic but in itself is not mutagenic. Heavy
alcohol consumption can compound damages already incurred
from chronic HBV infection and is thought to have a greater
than additive effect on the development of HCC [44]. For exam-
ple, a population cohort study in Korea noted that the relative
risk of HCC increased significantly with increasing daily alco-
hol intake [45]. The effect of cigarette use is smaller, but a sig-
nificant positive interaction has been found between smoking
and the risk of HCC in individuals with HBV [46, 47]. One
known exogenous environmental risk factor for HCC is afla-
toxin B1, a mycotoxin generated by Aspergillus sp. that is found
in food items stored under warm, damp conditions. Aflatoxin is
known to mutate the p53 tumor suppressor, and this mutation is
often found in HCC tumors from individuals with HBV infec-
tions who live in aflatoxin‐endemic regions [8]. When evaluat-
ing the risk of HCC based on aflatoxin exposure and HBV
infection, the HCC risk for aflatoxin exposure alone is fourfold
greater, for chronic HBV carriers it is sevenfold greater, and for
aflatoxin and HBV combined it is 60‐fold greater than unex-
posed individuals, indicating a synergistic association between
the two [2].
All of these risk factors have been translated into scoring sys-
tems to identify individuals with chronic HBV for HCC surveil-
lance. The American Association for the Study of Liver Disease
devised a surveillance system based on cirrhosis, family history
of HCC, age, and race. Specifically, the guidelines recommend
surveillance for all patients with cirrhosis, for Asian men older
than 40 years and Asian women older than 50 years in the
absence of cirrhosis, and at younger ages for Africans and
African Americans [48, 49]. Several other scoring systems
developed for Asian patients with HBV infections have been
validated and yielded high 3‐ to 10‐year negative predictive val-
ues for HCC development. These scoring systems are based on
age, sex, cirrhosis, viral load, HBsAg status, and alanine ami-
notransferase levels [50–53]. The REACH‐B score is highly
effective at identifying at‐risk patients who are not cirrhotic.
The GAG‐HC and CU‐HCC scoring systems incorporate cir-
rhosis and HBV core promoter mutations into the calculations
and could potentially be applicable for non‐Asian populations
[3]. However, these scoring systems are not adequate for pre-
dicting HCC risk in patients with HBV who are successfully
undergoing antiviral therapy [54, 55]. Among patients with
HBV on nucleoside analog therapy, age, sex, cirrhosis, liver
stiffness, platelet count, and diabetes are known HCC risk fac-
tors [56–58]. Notably, pretreatment viral load, HBsAg status
and quantity, and aminotransferase level are not predictive of
HCC risk for patients treated with nucleoside analogs [36, 59,
60]. To address the unmet need for an HCC risk scoring system
762 THE LIVER: RISK FACTORS FOR HCC
in this population, the Cirrhosis, Age, Male sex, Diabetes (CAMD)
score was developed. The model was based on data from Taiwanese
patients in the national healthcare database who received entecavir
or tenofovir to treat chronic HBV and was externally validated
using data extracted from the Hong Kong national healthcare data-
base [61]. This system has a high level of accuracy and has been
validated in Caucasian and Asian populations [62].
Decreased risk
The most effective way to decrease the risk of HCC associated
with HBV infection is to not get the infection in the first place.
The development of an HBV vaccine has made excellent strides
toward reducing HBV infection rates in endemic areas, which
could reduce the incidence of HCC long term [63]. A large ran-
domized controlled trial in China found that HBV vaccination
reduced the risk of developing primary liver cancer by 84% over
25 years [3]. This effect is starting to be seen in other areas
where vaccination programs have been implemented [63]. The
30‐year report following the implementation of a universal
HBV vaccination program in Taiwan found that sex‐adjusted
HCC incidence declined 80% and sex‐adjusted HCC mortality
declined 92% in cohorts born after the vaccination program
began compared with those born before it began [64].
Vaccination programs have been implemented in most Asian
and Eastern European countries, Spain, and many sub‐Saharan
countries. Many of the countries that implemented their pro-
grams in the 1980s, such as China, Singapore, and Spain are
seeing reductions in the prevalence of HBsAg that are similar to
those seen in Taiwan, and the HCC incidence in these countries
is expected to decrease at similar rates [2, 63]. Many of the
countries that have implemented vaccination programs are
places where aflatoxin exposure is also endemic. Aflatoxin
abatement programs have the potential to further decrease HCC
risk. One such program was implemented in Qidong, China, an
area with one of the highest rates of liver cancer. This program
was initiated at approximately the same time as the government
began a slow rollout of an HBV vaccination program. In cohorts
with reduced aflatoxin exposure and minimal vaccination
­penetrance, the liver cancer mortality decreased by 45% and age‐
specific liver cancer incidence decreased 1.2‐ to 4‐fold. In
cohorts where reduced aflatoxin exposure was combined with
higher vaccine penetrance, the age‐specific liver cancer inci-
dence decreased 14‐fold, indicating that a combination of afla-
toxin reduction and HBV vaccination has the potential to make
meaningful reductions in HCC incidence in these areas [65, 66].
Although HBV vaccination can prevent future cases of HCC,
the primary intervention in patients with HBV is antiviral treat-
ment. Randomized controlled trials have provided evidence that
antiviral treatment can achieve sustained reductions in HBV
DNA levels as well as improve liver function and histology, but
the evidence that these agents meaningfully affect long‐term clin-
ical outcomes or risk of HCC is limited [3]. The primary drugs
used to treat chronic HBV infection are nucleoside a­nalogs
(NAs). The five NAs with regulatory agency approval – ­lamivudine,
telbivudine, adefovir, entecavir, and tenofovir disoproxil – can
suppress HBV DNA levels in nearly all patients [67]. Lamivudine
treatment is associated with reduced progression to cirrhosis,
lower Child–Pugh scores, and a 50% reduction in the rate of HCC
[68]. However, because lamivudine is associated with drug resist-
ance, the first‐line therapies are currently entecavir and tenofovir
disoproxil [67]. Increasing evidence suggests that NA treatment
can reduce but not eliminate the medium‐term risk of HCC [56,
69–71]. A meta‐analysis evaluating cohort studies and clinical tri-
als that investigated NAs, primarily lamivudine, and HCC risk
found that HCC incidence was significantly lower in NA‐treated
patients compared with untreated controls. Furthermore, patients
with lamivudine‐resistant HBV had a significantly higher risk of
HCC compared with NA‐naïve patients, and patients with lami-
vudine‐resistant HBV who achieved virological response follow-
ing rescue therapy did not have a significant reduction in HCC
risk. Collectively, these data suggest that long‐term viral suppres-
sion is critical for HCC risk reduction [71]. In a randomized
controlled trial investigating lamivudine versus placebo in
­
Taiwanese patients with chronic HBV and cirrhosis or advanced
fibrosis, HCC incidence was significantly lower in the lamivudine
group. However, this trial was terminated early due to the signifi-
cant response (median treatment duration, 32.4 months) [68].
There are fewer studies evaluating risk reduction in the newer
NAs. A retrospective nationwide study out of Taiwan identified 21
595 matched patients with chronic HBV who either received NA
therapy (lamivudine or entecavir) or were untreated. Among
patients who received entecavir, the 7‐year HCC incidence was
significantly lower than in untreated patients (7.3% vs. 22.7%,
respectively) [72]. A Japanese study comparing entecavir‐treated
patients with a matched historical control of untreated patients
found significantly lower 5‐year HCC incidence rates for the ente-
cavir‐treated group (3.7% vs. 13.7%, respectively) [73]. A study
investigating entecavir or tenofovir treatment in Caucasian patients
with chronic HBV found that 5‐year HCC risk reduced in patients
with cirrhosis following treatment, but the overall risk was still
higher than that in patients without cirrhosis. They also found that
all cases of HCC in their cohort developed in patients who began
NA treatment after the age of 50 years [7]. In a multinational
European cohort study of clinical outcomes of patients with
chronic HBV treated with entecavir, patients who had a virologic
response were 71% less likely to develop hepatic decompensation
or HCC or to die than those who did not have a response, but this
effect was only significant in patients with cirrhosis. However, this
study had a small sample size and short follow‐up, so strong con-
clusions cannot be drawn from these data [74].
In addition to NAs, interferons can be used to treat HBV,
although they are less used due to side‐effects and associated
patient compliance. Several meta‐analyses have evaluated the
effect of interferon treatment on HCC risk in patients with
chronic HBV, and they suggest that interferon treatment reduces
HCC incidence in those patients who can sustain a virological
response [75–77]. Overall, the data support that patients with
chronic HBV who receive treatment have a lower incidence of
HCC. However, these treatments do not eliminate the virus, so
continuous treatment is likely needed to sustain the effect until
new treatments capable of viral eradication are developed [3].
Hepatitis C virus
HCV is a positive‐sense RNA virus that primarily infects liver
tissues [20]. There are several HCV genotypes and subtypes
with different ethnic and geographic distributions [27, 78].
 59: Epidemiology of Hepatocellular Carcinoma
An estimated 75–85% of HCV infections become chronic based
on the continued presence of HCV RNA, an HCV biomarker,
in serum [16].
The association between chronic HCV infection and HCC
has been firmly established [20]. Unlike HBV, which integrates
in the genome to initiate tumorigenesis, HCV does not integrate
into the genome and is unlikely to initiate tumorigenesis itself.
Because as much as 90% of HCV‐associated HCC cases are
preceded by cirrhosis, it is likely that HCV promotes tumori-
genesis through the repetitive killing of hepatocytes by HCV
and the subsequent cellular regeneration that leads to cirrhosis.
HCV infection can also alter lipid metabolism, leading to liver
steatosis [79]. When considering the burden of HCV in HCC
incidence, estimates vary based on geography, largely due to the
geographic differences in prevalence [22]. It is estimated that
HCV accounts for approximately 20% of HCC cases worldwide
[8] and 40–50% of new HCC cases in the United States [23].
A model based on the population of HCV‐infected individuals
in the United States estimated that the number of HCV‐associ-
ated HCC cases increased by 130% when comparing the cases
occurring between 1990 and 1999 with those occurring between
2000 and 2009. The model projected that the number of cases
would increase an additional 50% for cases occurring between
2010 and 2019 [80]. Similar trends were seen in a cohort of
veterans diagnosed with HCV. In that study, the prevalence of
HCC increased 19‐fold between 1996 and 2006 [81]. This
observation could be due to the high prevalence of HCV
infection found in persons born between 1945 and 1965 [4].
Accordingly, the numbers of HCV‐associated HCC are antici-
pated to continue to rise and to peak in 2020 [63].
Relative and absolute risk of HCC from HCV
The estimates of relative risk of HCC in persons with HCV com-
pared with those who are uninfected vary in cohort studies between
10 and 20 [23, 41, 63, 82–84]. HCV‐related HCC cases typically
arise from patients with advanced fibrosis or cirrhosis [82, 83].
The annual incidence of HCC in patients with HCC‐induced cir-
rhosis ranges from 0.5 to 10% [85, 86]. At 25–30 years post infec-
tion, the incidence of cirrhosis ranges from 15 to 35% [87, 88].
Determinants of risk associated with HCV
Increased risk
There are several known risk factors for HCC in patients with
HCV, including sex, race, HCV genotype, coinfections with
HBV or HIV, insulin resistance, obesity, diabetes, and alcohol
consumption [27, 85, 86, 89]. When compared with non‐
Hispanic white patients, Hispanic patients have a higher risk of
cirrhosis and HCC development and African American patients
have a lower risk. The detection of HCV RNA in serum, which
indicates viremia, is a strong risk factor for HCC. Some studies
reported correlations between viral load and HCC; however,
other studies were unable to reproduce this correlation [3].
The HCV genotype represents a substantial risk factor for HCC
in patients with HCV. A meta‐analysis of studies investigating gen-
otype 1b as a risk factor for HCC found that patients infected with
genotype 1b had a 78% greater risk of HCC than those infected
with other genotypes and a 60% greater risk among patients who
763
also had cirrhosis [90]. However, genotype 3 has been consistently
and strongly associated with a higher risk of both cirrhosis and
HCC in studies based in the United States [86]. Patients with geno-
type 3 infections also have the highest risk of cirrhosis and HCC,
with incidence rates of 30 per 1000 person‐years and 7.9 per 1000
person‐years, respectively [86, 91]. Genotype 1 infections tend to
respond well to antiviral treatments compared with other genotypes
[8], whereas genotype 3 is more difficult to treat, so genotype 3 is
considered the greater risk [86, 91].
Patients with HCV/HIV coinfections have been shown to
progress to cirrhosis and decompensated liver disease faster
than those with an HCV mono‐infection. Further, the risk
increases as immunosuppression increases, indicating that
uncontrolled HIV infection exacerbates the pathological dam-
age caused by HCV [92, 93].
Patients with HCV who are insulin resistant have a higher
risk of hepatic steatosis, advanced fibrosis, and HCC. Notably,
several retrospective and prospective studies showed that
patients with HCV have an approximately 68% increased inci-
dence of diabetes compared with uninfected persons [94]; how-
ever, there is little evidence of a synergistic effect between HCV
and diabetes with respect to HCC risk [94, 95]. The implications
of insulin resistance and diabetes in hepatocellular carcinoma
risk are discussed in detail later.
Environmental factors can also affect the risk of HCC. Studies
have demonstrated a synergistic effect between heavy alcohol
consumption and HCV infection [44, 96]. Patients with HCV
who are also heavy drinkers have a twofold increased risk of
HCC compared with persons who are heavy drinkers alone [44].
A similar relationship has been identified between cigarette
smoking and HCC risk in subgroups of patients with HCV [46].
There is some evidence of a synergistic effect between HCV
and aflatoxin on HCC risk, but the scope of this issue is limited
because HCV infections are less common in aflatoxin‐endemic
areas [2, 97].
Decreased risk
As mentioned above, the cohort of persons born between 1945
and 1965 who have a high prevalence of HCV infections have
contributed to the rise in HCV‐related HCC [4, 63]. The main
factor that will likely decrease HCC incidence in this cohort is
sustained virologic response (SVR) achieved via directly acting
antiviral (DAA) treatments [98]. SVR is the primary modifier of
HCC risk among patients with HCV. SVR has been shown to
slow the progression of liver disease and reduce cirrhosis and
HCC risk [95]. A meta‐analysis of interferon‐based therapies,
the predecessor to DAAs, found that SVR following treatment
reduced the risk of HCC 76% at all stages of liver disease com-
pared with non‐responders. A similar reduction was found when
analyzing only those patients with cirrhosis. Although the risk
was reduced in patients with SVR, the rates did not revert to
baseline levels, especially for patients with cirrhosis. These data
indicate that virus eradication with antiviral treatment is an
important part of managing HCC risk [99]. Interferon‐based
treatments were eventually phased out because of their medio-
cre SVR rates and disabling side‐effects. By contrast, DAAs
achieve greater than 90% SVR rates and have comparatively
few side‐effects [100]. DAAs have been shown to be at least
764 THE LIVER: RISK FACTORS FOR HCC

equivalent to interferon with respect to HCC risk. A systematic
review comparing the two treatment regimens found no differ-
ences between treatments in both HCC occurrence and recur-
rence risk following treatment [101].
Studies overwhelmingly show that de novo HCC risk is
reduced by 50–80% in patients who achieve SVR following
DAA treatment [102–104]. However, HCC risk remains
relatively high for these patient populations and others, includ-
ing patients with diabetes and those who achieved SVR at an
older age, those who have high α‐fetoprotein levels, and those
with low platelet counts [95, 105–107] (Figure 59.3).
Accordingly, these patient populations are likely to require con-
tinued HCC surveillance over time [108]. A study by Kanwal
et al. [108] found that the risk of HCC reduced 76% in patients

With cirrhosis
Overall
Age
Younger than 65
65 year and older
Race
White
African American
Hispanics
Diabetes
No
Yes
Alcohol use
No
Yes
Drug use
No
Yes
Previous HCV treatment
No
Yes

Without cirrhosis
Overall
Age
Younger than 65
65 year and older
Race
White
African American
Hispanics
Diabetes
No
Yes
Alcohol use
No
Yes
Drug use
No
Yes
Previous HCV treatment
No
Yes
FIB-4
<1.45
1.45-3.25
>3.25

0.1 0.2 0.4 0.6 0.8 1.0 1.2 1.4 1.6 1.8 2.0 2.2 2.4 2.6 2.8 5.0
Incidence rate (per 100 person year)

Figure 59.3 The cumulative incidence and determinates of hepatocellular carcinoma following directly acting antiviral (DAA)‐related sustained
virologic response (SVR) among Veterans Administration (VA) patients with hepatitis C virus (HCV). The incidence rates are shown according to
several demographic and clinical features for patients with and without cirrhosis at baseline. Modified from [108] with permission of Elsevier.
 59: Epidemiology of Hepatocellular Carcinoma
who achieved SVR following DAA treatment. Among patients
who achieved SVR, the annual incidence of HCC was 0.9%, and
the highest rate of 1.0–2.2% was seen among patients who had
cirrhosis [108]. These incidence rates are at or below the thresh-
old for cost‐effective HCC surveillance [48, 49, 108]. Another
consideration is the whether the performance can be translated
into real‐world settings. The high efficacy and reduced side‐
effects seen with DAA regimens is likely to result in high effec-
tiveness in real‐world settings [3]. One notable feature of DAA
treatment is that it has been shown to achieve SVR in patients
with advanced cirrhosis, those who were heavy drinkers, and
those with HIV coinfection, all of which independently increase
HCC risk [102–104].
However, the impact of DAAs will depend largely on the
identification of individuals with chronic HCV infections, many
of whom are asymptomatic and do not realize they are infected,
and the accessibility and penetration of DAA treatment in diag-
nosed patients [109]. In the United States, an estimated 45–70%
of persons infected with HCV are unaware of their infection
status [110]. Further, in the United States and Europe, fewer
than 20% of patients with HCV obtain treatment, either because
they have not been screened for HCV or because of treatment
costs [111]. A modelling study investigated the reduction in the
number of HCC cases that would occur over a 10‐year period at
current treatment rates and if half or all persons with HCV were
treated. The study estimated that the number of HCC cases
would reduce by 5% at the current treatment rate, by 30% if half
were treated, and by 60% if all were treated [80]. To achieve
these gains, more of the population needs to be screened, and
those with HCV need to be diagnosed and treated [63]. In an
effort to reduce the incidence of HCV‐associated liver disease
and HCC in the United States, the Centers for Disease Control
implemented a screening initiative that recommends testing all
people born between 1945 and 1965 for HCV [112]. However,
the success of the initiative hinges on patient consent, buy‐in by
physicians, and the ability of patients to afford the expensive
treatments [113]. Overall, DAAs have the potential to substan-
tially reduce HCV‐associated HCC risk if the barriers to identi-
fication of persons with HCV and the subsequent access to
treatment can be addressed.
Alcoholic liver disease
Studies have consistently shown an association between heavy
alcohol consumption and risk of HCC [114–116]. The defini-
tion of heavy alcohol consumption and the duration of heavy
drinking that puts individuals at risk varies highly between stud-
ies, with values ranging from 240 to 560 g/week and from
greater than 1 year to greater than 5 years, respectively. Some
studies do not even include a definition of the duration of
heavy drinking [96]. It is also unclear if alcohol is carcinogenic
or if carcinogenesis is secondary to cirrhosis development.
Regardless of the outstanding questions, alcohol consumption
contributes to liver disease and therefore contributes to HCC
[23]. Generally, there are some disparities seen between studies
conducted in areas with a low rate of HCC and those in areas
with a high rate of HCC. In the former, studies tend to show cor-
relations between alcohol consumption and HCC; in the latter,
studies tend to be less conclusive. This observation could be
765
because of differences in mean alcohol consumption and inter-
actions with other risk factors [2].
Relative and absolute risk of HCC from heavy
alcohol consumption
Heavy alcohol consumption is estimated to have an increased
relative risk for HCC of 1.5‐ to 3‐fold [114]. A meta‐analysis of
studies investigating associations between alcohol intake and
liver cancer found a relative risk of liver cancer to be 1.16 for
heavy drinking (i.e. more than three drinks per day). There was
a linear relationship between risk and the amount of alcohol
consumed, with the risk increasing by 46% with a daily con-
sumption of 50 g ethanol and by 66% with a daily consumption
of 100 g [117].
Determinants of risk
Approximately 13–23% of cases of HCC can be linked to heavy
alcohol consumption [118, 119]. In a cohort study of patients
with HCC who attended United States Veterans Administration
(VA) hospitals, the cases of HCC associated with heavy alcohol
consumption decreased from 21.9% to 15.7% between 2005
and 2010 [18]. The risk of HCC from heavy alcohol consump-
tion varies by race and gender. The population‐attributable frac-
tion was 25.6% for white, 30.1% for Hispanic, and 18.5% for
black populations [118]. Similarly, the odds ratios of HCC were
9.5 for Hispanic and 3.6 for black populations [119]. For gen-
der, the odds ratios were estimated to be 4.41–7.5 for males and
3.34–6.4 for females [118, 119]. Other comorbid conditions,
such as HBV or HCV coinfection and obesity are likely risk
factors as well [120].
The only known way to decrease the risk of HCC associated
with heavy alcohol consumption is to cease drinking. A meta‐
analysis investigating the effects of alcohol cessation on HCC
risk estimated that the risk of HCC declined by 6–7% per year,
although the authors noted the estimate is uncertain due to het-
erogeneity among studies. Based on their estimate, they calcu-
lated that it would take 23 years of abstinence (95% confidence
interval 14, 70 years) to reach the same risk of HCC as those
who never drank alcohol [121].
Metabolic syndrome, diabetes, and obesity
Metabolic syndrome is a cluster of risk factors related to insulin
resistance, obesity, cardiovascular disease, blood pressure, and
glucose metabolism. Metabolic syndrome itself has been linked
to several cancers [122], and several risk factors associated with
metabolic syndrome independently increase the risk of HCC
[123]. Increasing evidence suggests that metabolic derange-
ments associated with metabolic syndrome could be an etiologic
factor for HCC in the absence of cirrhosis [124]. The mechanism
underlying the role of metabolic syndrome is unclear. However,
the changes in lipid metabolism associated with the syndrome
could contribute to steatosis, NAFLD, and non‐alcoholic steato-
hepatitis (NASH), all of which are precursors to HCC [2, 23].
With the prevalence of metabolic syndrome as well as obesity
and diabetes, major contributors to metabolic syndrome, rising
dramatically in the United States, the prevalence of related can-
cers, including HCC, is increasing [5, 125, 126].
766 THE LIVER: RISK FACTORS FOR HCC
HCC risk associated with diabetes
Type 2 diabetes was estimated to increase risk of HCC two‐ to
threefold in a meta‐analysis of case–control and cohort studies.
This analysis included various study designs from several
­geographic populations, and the results from included studies
consistently showed positive correlations [94]. These numbers
were corroborated in other systematic reviews [127, 128].
However, there are several outstanding questions that muddy
data interpretation. First, it is unclear if the liver damage caused
by diabetes is the source of the HCC risk or if the diabetes inde-
pendently increases risk beyond that associated with liver dam-
age. Second, there are cases in which diabetes is caused by
chronic liver disease prior to the development of HCC (reverse
causality); the effects of these cases on risk of HCC are unknown
[23]. A recent meta‐analysis investigated cohort studies that
only evaluated patients with chronic liver to reduce the inclu-
sion of reverse causality cases. This analysis found that risk of
HCC increased 1.5‐ to 2‐fold in patients with diabetes [129].
Collectively, these data support that type 2 diabetes indepen-
dently increases the risk of HCC [94, 129].
The treatment of type 2 diabetes with metformin has been
shown to decrease the risk of HCC, whereas treatment with
insulin or sulfonylurea can increase the risk of HCC [130].
Further, the duration of diabetes may be associated with an
incremental increase in the risk of HCC [131]. Flemming et al.
devised a predictive HCC risk model for patients who are
­cirrhotic based on the National Liver Transplantation Waitlist
database. The model evaluated diabetes status in addition to age,
race, cirrhotic etiology, sex, and liver dysfunction severity to
predict 1‐year HCC risk [132].
HCC risk associated with obesity
Most, but not all, studies have reported modest increases in rela-
tive risk of HCC in persons with obesity. A systematic review of
studies investigating associations between body mass index
(BMI) and HCC found positive associations in seven cohort
studies, with relative risks ranging from 1.4 to 4.1, no associa-
tion in two cohort studies, and an inverse association for one
subgroup in one cohort study [133]. A meta‐analysis of observa-
tional studies evaluating excess body weight and liver cancer
risk found that persons who were overweight (25–30 kg m−2)
and obese (>30 kg m−2) had increases in liver cancer risk of 17%
and 89%, respectively [134]. A case–control study investigated
the effect of obesity in early adulthood (i.e. mid‐20s to mid‐40s)
on HCC risk in patients with HCC matched with healthy con-
trols. This study found that persons who were obese in early
adulthood had an estimated odds ratio for HCC of 2.6 for all
participants. The estimated odds ratios for men and women
were 2.3 and 3.6, respectively [135]. A cohort study evaluating
the effect of abdominal obesity and weight gain on HCC risk
found a threefold higher risk of HCC in participants in the high-
est tertile of waist‐to‐hip and waist‐to‐height ratio compared
with those in the lowest tertile. Similarly, participants in the
highest tertile of weight gain had a 2.48‐fold higher risk of HCC
compared with those in the lowest tertile [136]. Similar to type
2 diabetes, the mechanisms by which obesity increases the risk
of liver disease are unknown. Obesity could induce physiologi-
cal changes or changes on the molecular level that lead to HCC,
or chronic liver disease could induce metabolic changes that
lead to obesity [23]. Further studies are needed to clarify
these mechanisms.
HCC risk associated with metabolic syndrome
One meta‐analysis evaluated cohort and case–control studies
investigating the association between metabolic syndrome and
HCC risk, and included four studies with a total of 829 651
participants. The estimated relative risk of HCC in participants
with metabolic syndrome was 1.81 compared with healthy par-
ticipants [137].
Determinants of risk
Increased risk
When compared with the relative risks associated with viral
hepatitis infections, the risks associated with type 2 diabetes,
obesity, and metabolic syndrome are quite low. However, in
more developed countries, the prevalence of these conditions is
much higher than that of viral hepatitis [2]. In 2008, approxi-
mately 6.4% of the global population was estimated to have dia-
betes. Further, in developing countries, the rate at which diabetes
prevalence is increasing far exceeds that in developed countries.
Based on projection models, the prevalence of diabetes is
­estimated to increase by 69% in developing countries and by
20% in developed countries [138]. Parallel trends have been
observed for the prevalence of obesity based on increases in
BMI [139]. Given these trends, it is likely that the number of
HCC cases related to metabolic syndrome, type 2 diabetes, and
obesity will increase in the future [2].
Several factors have been identified that affect HCC risk in
persons with obesity. As mentioned earlier, waist‐to‐hip ratio, a
measure of abdominal obesity, increases the risk of HCC [136].
The visceral adipose tissue associated with obesity alters the
levels of cytokines in the body, making obesity a low‐grade
inflammatory disorder. These alterations in cytokine levels are
thought to contribute to HCC tumorigenesis and progression
and are likely to represent a risk factor for HCC [140]. Obesity
can lead to NAFLD and the subsequent development of NASH,
which increases the risk of HCC [141]. Another potential risk
factor is viral hepatitis infection. In the study of obesity in early
adulthood described earlier, an independent synergistic interac-
tion on HCC risk was observed between obesity and viral hepa-
titis infection [135].
Decreased risk
One of the features associated with metabolic syndrome is
abnormal cholesterol and triglycerides levels [142]. Statins are a
class of drugs primarily used to lower cholesterol to prevent car-
diovascular disease [2, 143]. Increasing evidence suggests that
statins could be potential anticancer agents based on their ability
to inhibit angiogenesis and metastasis and enhance apoptosis
[144, 145]. Population studies out of Taiwan have reported HCC
risk reductions of 47–56% with statin treatment [146, 147]. In
similar studies of Taiwanese patients with HBV and HCV, HCC
risk decreased up to 66–67% in those treated with statins
­compared with those not taking statins, and a dose–response
relationship was observed [148, 149]. A similar Taiwanese
 59: Epidemiology of Hepatocellular Carcinoma
study investigating the effects of individual statin medications
found that simvastatin, lovastatin, and atorvastatin reduced
HCC risk by 30–48% [150]. These associations were not
observed in early studies conducted in Denmark and the United
States, areas with low rates of HCC [151, 152]. However, more
recent studies out of the United States and Sweden found sig-
nificant inverse associations between statin use and HCC risk in
the general population [153–155] and in subgroups, such as
men with diabetes [156] and men with HCV infection [157].
Two meta‐analyses conducted in parallel found similar results,
with a relative risk of 0.58 [158] and an adjusted odds ratio of
0.63 [159] for statin users compared with non‐statin users.
Notably, the meta‐analysis including three randomized clinical
trials found no significant benefit (adjusted odds ratio, 0.95)
when only the trials were analyzed [159]; however, none of the
trials had sufficient power to detect changes in HCC develop-
ment, so this finding may be somewhat misleading [63, 106].
With respect to type 2 diabetes, use of the antidiabetic medi-
cation metformin could be used to reduce HCC risk. Metformin
is a first‐line treatment for type 2 diabetes used to reduce serum
glucose and insulin levels [2]. Three meta‐analyses investigat-
ing the effects of metformin on cancer risk were performed in
parallel. One meta‐analysis evaluated observational studies and
randomized trials looking at the effects of metformin and other
hypoglycemic drugs on cancer. Meta‐analysis of the nine
studies investigating liver cancer uncovered odds ratios of
0.34 when metformin was compared with no metformin, 0.09
when metformin was compared with other drugs, and 0.56 when
­metformin was compared with sulfonylureas [160]. Another
meta‐analysis evaluated seven studies looking at the effect of
metformin use on HCC. This analysis found a relative risk of
0.24 when metformin use was compared with non‐users [161].
The third meta‐analysis evaluated studies investigating the
effect of metformin and other diabetes treatment on the risk of
HCC. This analysis revealed an odds ratio of 0.50 for metformin
use, 1.62 for sulfonylurea use, and 2.61 for insulin use. No
effect was seen for thiazolidinedione use [130]. However, the
results of these meta‐analyses should be interpreted cautiously,
largely because metformin is prescribed early in disease pro-
gression whereas the others are prescribed after metformin
­failure once the disease has progressed. This difference can lead
to an overestimation of risk reduction by metformin [2]. An
alternate interpretation of the data is that lack of glycemic con-
trol for long periods and more severe disease could increase the
risk of HCC [23].
Non‐alcoholic fatty liver disease
NAFLD is caused by the accumulation of excess triglycerides in
the liver. This accumulation occurs in the absence of heavy alco-
hol consumption and leads to steatosis. One consistent feature
of nearly all NAFLD cases is insulin resistance, a risk factor
associated with metabolic syndrome. Accordingly, NAFLD is
thought to be a hepatic manifestation of metabolic syndrome
[162]. Worldwide, NAFLD is becoming a leading cause of
chronic liver disease [163]. The prevalence of NAFLD in the
United States has doubled over the last two decades up to 30%
in some segments of the adult general population [164–166].
Among patients with NAFLD, 20–30% are estimated to develop
767
NASH and concomitant necroinflammation and fibrosis, which
progresses to cirrhosis in 10–20% of cases [162, 167]. NAFLD
is now a leading cause of cirrhosis, and 30–40% of new HCC
cases are associated with metabolic disorders [118, 119, 164–
166]. NASH is the second‐leading etiology for liver transplants
related to HCC in the United States [168]. The increasing num-
ber of HCC cases due to NASH‐related cirrhosis could offset
the reductions in HCV‐related HCC expected after 2020 [63].
One pressing threat to reductions in HCC incidence is the fact
that patients are often unaware they have NASH‐related cirrho-
sis because the cirrhosis can be well compensated for years.
These asymptomatic patients go undiagnosed, all the while, the
risk of developing HCC remains [23]. Additionally, a small pro-
portion of patients with NAFLD and/or NASH develop HCC in
the absence of cirrhosis [169].
Relative and absolute risk of HCC from NAFLD
Both the etiology and presence of cirrhosis affect HCC risk.
A systematic analysis of studies investigating the links between
NAFLD or NASH and HCC risk found that the HCC risk of the
included studies varied from 0 to 38% with follow‐ups of 5–10
years, with most studies having small‐ to medium‐sized cohorts
from tertiary care settings. The authors found that NAFLD or
NASH patients lacking cirrhosis had minimal HCC risk. By
contrast, patients with NASH‐related cirrhosis had incidences
ranging from 2.4 to 12.8%. However, the appropriateness of
performing subgroup analysis and extrapolating these data to
the general population is limited due to the nature of the included
studies. Notably, HCC risk was found to be substantially lower
for patients with NASH‐related cirrhosis compared with patients
with HCV‐associated cirrhosis [170]. A large cohort study
including 296 707 patients with NAFLD and an equal number
of matched controls without NAFLD from 130 VHA facilities
found that patients with NAFLD had a higher annual HCC risk
than controls (hazard ratio 7.62) [171]. These data support an
association between HCC risk and NAFLD.
Determinants of HCC risk for NAFLD
Increased risk
Most of the existing epidemiological studies of NAFLD and
HCC risk lacked the sample size to perform adequate subgroup
analyses and identify high‐risk groups, or the power to arrive at
accurate estimates [170]. An exception is the VHA cohort study,
where the HCC risk for patients with NAFLD ranged from 1.6
to 23.7 per 1000 person‐years, with the highest risk among older
Hispanic patients with cirrhosis. However, the authors also
found that approximately 20% of patients with NAFLD and
HCC had no evidence of cirrhosis [171]. Some case–control
studies found that the prevalence of diabetes and obesity were
higher for patients with NAFLD‐related HCC compared with
patients with other chronic liver diseases [170]. A subgroup
analysis from a meta‐analysis investigating the associations of
PNPLA3 polymorphisms with liver fibrosis, HCC risk, and
HCC prognosis found that patients with NASH‐associated cir-
rhosis and the PNPLA3 polymorphism had a higher risk of
developing HCC than those who lacked the polymorphism
(odds ratio 1.67), indicating that there could be a genetic com-
ponent to NASH‐associated HCC development [172].
768 THE LIVER: ACKNOWLEDGMENTS
Decreased risk
Weight loss can reduce NASH severity [173]; however, to date,
no studies have directly addressed whether treatment of NAFLD
or NASH can reduce the risk of HCC. One study found that
bariatric surgery reduced the risk of HCC in persons who are
obese and have the PNPLA3 polymorphism [174], but more
studies are needed to clarify the effect in the context of NAFLD
and NASH.
HCC in the absence of cirrhosis
While most HCC develops in the presence of cirrhosis, a subset
of cases can occur in the absence of cirrhosis. In the case of
HBV‐related HCC, approximately 10–30% of cases arise in the
absence of cirrhosis [175, 176]. HCC in the absence of cirrhosis
is an even rarer occurrence in patients with HCV, with one study
finding only 3% of HCC cases lacking cirrhosis [175]. A study
of HCC risk in patients with HCV who were taking peginter-
feron maintenance therapy found that the few HCC cases devel-
oping in the absence of cirrhosis did so in the presence of
advanced fibrosis [177]. In general, HCV‐associated HCC
occurring in the absence of cirrhosis tends to affect those with
bridging hepatic fibrosis [3]. By contrast, NAFLD‐ and NASH‐
related HCC can develop with little to no fibrosis [178, 179].
NAFLD‐related HCC represents the largest proportion of HCC
cases occurring in the absence of advanced fibrosis or cirrhosis
[169]. Because HCC surveillance is centered around cirrhosis,
these cases tend to be caught later. Patients with alcohol‐ or
HCV‐related HCC are significantly more likely to have received
HCC surveillance within three years before their HCC diagnosis
than those with NAFLD‐related HCC. Similarly, patients with
NAFLD are less likely to receive HCC‐specific treatments than
those with HCV‐related HCC [169]. Given the available data,
HCC screening in patients with NAFLD‐related advanced fibro-
sis and cirrhosis may be warranted, particularly among Hispanic
patients and patients with metabolic syndrome.
Autoimmune hepatitis
Autoimmune hepatitis is an autoimmune disorder in which a T
cell‐mediated immune response to liver autoantigens erodes
hepatic tissues, leading to fibrosis and cirrhosis [180, 181].
Patients can have an array of presentations from asymptomatic
to severe acute hepatitis, and in some cases can progress to ful-
minant hepatic failure [182, 183]. Among patients with autoim-
mune hepatitis, approximately 30% present with cirrhosis at the
time of diagnosis [184, 185]. Some studies have linked autoim-
mune hepatitis with HCC risk, but the magnitude of that risk
varies [186–189]. One meta‐analysis evaluated 25 cohort stud-
ies investigating HCC risk and risk factors among patients with
autoimmune hepatitis. The pooled incidence of HCC among all
patients with autoimmune hepatitis was 3.06 per 1000 patient‐
years, and among those who had cirrhosis at diagnosis was
10.07 per 1000 patient‐years. Further, 98.9% of patients with
autoimmune hepatitis who developed HCC had cirrhosis before
or at the time of diagnosis. However, the risk of HCC was still
lower for patients with autoimmune hepatitis than for those with
viral hepatitis. Given the high incidence of HCC in patients with
autoimmune hepatitis and cirrhosis, HCC surveillance in those
patients who progress to cirrhosis may be warranted [190].
CONTRIBUTION OF RISK FACTORS
TO THE BURDEN OF HCC
Cirrhosis is by and large the most significant risk factor and the
foundation for most HCC surveillance programs. Because
patients with compensated cirrhosis can have their condition go
undetected for years, HCC surveillance is often underused [3].
When looking at the contribution of risk factors on HCC bur-
den, we must consider the population‐attributable fraction, a
combination measure of the prevalence of a condition and the
risk estimate. This measure provides the estimated proportion of
disease cases that can be eliminated by addressing the risk fac-
tor. For example, in the United States, viral hepatitis infections
are much rarer than NAFLD. Despite their higher HCC risk esti-
mates, the population‐attributable fraction of HBV and HCV
are lower than that of NAFLD [118]. As of 2013, the popula-
tion‐attributable fractions for obesity and diabetes were 36.6%,
for HCV was 22.4% and for HBV was 6.3% in the United States
[118]. Because the prevalence of obesity and diabetes is on the
rise in developed and developing countries [138, 139], we antic-
ipate that the population‐attributable fractions of obesity,
­diabetes, metabolic syndrome, and NAFLD will increase in the
coming years. Notably, despite the lower population‐attributable
fraction, HCV is still the leading cause of HCC and the leading
etiology in patients with HCC undergoing liver transplants.
However, NAFLD is the fastest growing cause of HCC, with the
number of NASH‐associated liver transplants increasing by
11.8‐fold between 2002 and 2016 [191]. In the VHA cohort
investigating temporal trends in NAFLD‐related HCC, the pro-
portion of NAFLD‐related HCC cases remained relatively
unchanged between 2005 and 2010, whereas that of HCV‐
related HCC cases increased significantly [18]. The differences
seen between population‐attributable fraction and epidemiolog-
ical reports are likely due to the lag between changes in the risk
factors of a population and the time of HCC development, which
can take decades to manifest [192, 193]. Generally, the popula-
tion‐attributable fraction is used to identify the targets for
­prevention programs [3]. The temporal lag associated with HCC
population‐attributable fraction can give clinicians and public
health workers the opportunity to identify candidates for HCC
surveillance, including those who do not fit within traditional
risk‐assessment models, and intervene with risk factors pro-
jected to cause a higher proportion of HCC cases, essentially
changing the trajectory of disease over time.
ACKNOWLEDGMENTS
GRANT SUPPORT: This material is based upon work sup-
ported by Cancer Prevention & Research Institute of Texas
grant (RP150587). The work is also supported in part by the
Center for Gastrointestinal Development, Infection and Injury
(NIDDK P30 DK 56338).
 59: Epidemiology of Hepatocellular Carcinoma 769

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