DR. KATHERINE A.

MCGLYNN (Orcid ID : 0000-0003-2329-9933)

Accepted Article
Article type : Review

Corresponding Author Email ID: mcglynnk@mail.nih.gov

Epidemiology of Hepatocellular Carcinoma
Katherine A. McGlynn1, Jessica L. Petrick2, Hashem B. El-Serag3

1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD 20854
2Slone Epidemiology Center, Boston University, Boston, MA 02118
3Baylor College of Medicine, Houston, TX 77030

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differences between this version and the Version of Record. Please cite this article as doi:
10.1002/HEP.31288
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 International incidence, mortality, temporal trends
Accepted Article Primary liver cancer is the seventh most frequently occurring cancer in the world and the
second most common cause of cancer mortality (1). The highest incidence rates in the world are
found in Asia and Africa (Figure 1) (2). Mongolia has the highest incidence at 93.7 per 100,000, but
China has the greatest number of cases, due to both an elevated rate (18.3 per 100,000) and the
world’s largest population (1.4 billion persons) (1).
Globally, hepatocellular carcinoma (HCC) is the dominant type of liver cancer, accounting for
approximately 75% of the total (2). Incidence rates of HCC have been decreasing in some high-rate
areas but increasing in many low-rate areas (Figure 2) (3). In the interval between 1978 and 2012,
HCC incidence declined in many Asian countries and Italy, but increased in India, the Americas,
Oceania, and most European countries (3). In more recent years, however, the increase in some
countries, such as the US, has abated, as rates in various subgroups have plateaued or declined (4,
5).
Prognosis of HCC is poor in all regions of the world(6). As a result, incidence and mortality
rates are roughly equivalent. In 2018, the estimated global incidence rate of liver cancer per
100,000 person-years was 9.3 while the corresponding mortality rate was 8.5 (1).

Demographic characteristics
Age. In most populations, incidence rates of HCC and age are directly correlated until
approximately 75 years of age (2). The median age at diagnosis, however, is generally somewhat
younger. In the US, for example, the median age at diagnosis among men is between ages 60 and 64
years, while the median age among women is 65-69 years (7). By contrast, in Africa, there is a
significant difference in median age at diagnosis between Egypt (58 years) and other African
countries (46 years) (8).
Sex. In most countries, incidence rates among men are two to four-fold higher than rates
among women (2). For example, in the U.S., the 2016 age-adjusted incidence rate among men was
10.4 per 100,000, while the rate among women was 2.9 per 100,000. The greatest sex differences
are seen in Europe, where rates among men can be greater than four-fold higher than rates among

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 women (e.g., France M:F ratio = 5.0 and Malta M:F ratio = 4.8) (2). In some countries, however, the
Accepted Article
rates among men and women are much more similar. For example, Uganda (M:F ratio = 1.1), Costa
Rica (M:F ratio = 1.6), Ecuador (M:F ratio = 1.0) and Colombia (M:F ratio = 1.6) report nearly equal
rates (2).
Race/ethnicity. In multi-ethnic societies such as the US, racial/ethnic disparities can be
striking. In 2001, Asians/Pacific Islanders had the highest HCC rates in the US (11.3 per 100,000), but
rates among Asians/Pacific Islanders began declining thereafter. As a result, in 2016, American
Indians/Alaskan Natives had the highest incidence (11.4), followed by Hispanics (9.8), Asians/Pacific
Islanders (9.1), non-Hispanic blacks (8.1), and non-Hispanic whites (4.6) (7).
The wide variability in incidence of HCC by geographic region, age, sex and race/ethnicity is
largely, but not entirely, related to the prevalence, and age at acquisition, of major risk factors.

Risk factors
Hepatitis B Virus (HBV). HBV is a DNA virus that induces chronic necroinflammatory disease
that promotes mutations in liver cells and leads to HCC (9). When evaluating tumor tissue from HBV
carriers, HBV DNA is commonly integrated into the genome (10).
The lifetime risk of developing HCC among HBV carriers ranges from 10-25% (10). In a US
study, the annual HCC incidence was estimated to be 0.42% overall (11), but incidence can vary
depending on whether the person has an active HBV infection and/or cirrhosis (12). Cofactors that
also increase risk among HBV carriers include demographic characteristics (e.g., male sex, older age,
Asian or African ancestry, family history of HCC), viral factors (e.g., high HBV replication levels, HBV
genotype, infection duration, coinfection with HCV or HIV), and environmental exposures (e.g.,
aflatoxin, alcohol, tobacco, obesity, diabetes) (12). Some risk factors have been incorporated into
scoring systems or surveillance recommendations, such as the one devised by the American
Association for the Study of Liver Diseases based on cirrhosis, family history of HCC, age, and Asian
or African American race/ethnicity. However, these recommendations may not be accurate for
predicting HCC risk among HBV carriers who undergo antiviral therapy (13). Further, US data show

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 that HCC risk is extremely low among individuals, including African Americans, who are less than 40
Accepted Article
years of age.
Randomized controlled trials have shown that antiviral treatment of HBV infection can
achieve sustained reductions in HBV-DNA levels and improve liver function and histology (14). The
primary drugs used are nucleos(t)ide analogs (NAs) (15). Increasing evidence suggests that NA
treatment can reduce, but not eliminate, the short and medium-term risk of HCC (16, 17). A meta-
analysis found that HCC incidence was significantly lower among persons treated with the first NAs
introduced, primarily lamivudine (17). Fewer studies have evaluated risk reduction with the newer
NAs. Studies from Taiwan and Japan, however, have reported significantly lower risks of HCC in
conjunction with entecavir therapy (18, 19). A US study investigating the effect of entecavir or
tenofovir reported that the 5-year HCC risk was lower among persons with cirrhosis, but the overall
risk was still higher than among persons without cirrhosis (20). Among patients on long-term NA
therapy, older age, male sex, cirrhosis, low platelet count, and diabetes are likely HCC co-factors and
have been incorporated in validated risk scores for HCC prediction (21).
HBV vaccination programs are a key HCC prevention strategy. The 30-year report on the
neonatal HBV vaccination effort in Taiwan noted that HCC incidence declined 80% and mortality
declined 92% in cohorts born after the vaccination program began (22). Many other countries that
implemented programs in the 1980s, such as China, Singapore, and Spain are seeing reductions
similar to those of Taiwan in the prevalence of HBV in vaccinated cohorts (10).
Hepatitis C Virus (HCV). Chronic HCV infection is a firmly established risk factor for HCC,
increasing risk by 10-20 fold (9). HCV is a RNA virus that does not integrate into the host’s genome
and is, thus, unlikely to be the primary initiator of tumorigenesis. Rather, as approximately 90% of
HCV-associated HCC cases are preceded by cirrhosis, HCV likely promotes tumorigenesis through
repetitive damage, regeneration and fibrosis (23). The annual incidence of HCC in persons with HCV-
related cirrhosis ranges from 0.5-10% (24).
A US model based on a population of HCV carriers estimated that the number of HCV-
associated HCC cases increased by 130% between 1990-1999 and 2000-2009 (25). As the 1945-1965

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 birth cohort has a higher HCV prevalence than other birth cohorts, it has been estimated that the
Accepted Article
numbers of HCV-associated HCCs in the US will peak around 2020 (24, 26).
Among persons with active HCV infections, co-factors for HCC include male sex, Hispanic
ethnicity, HCV genotype 3, longer duration of infection, coinfections with HBV or HIV, insulin
resistance, obesity, diabetes, tobacco and alcohol (24, 27). The main factor that decreases HCC
incidence is sustained virologic response (SVR) achieved via antiviral therapy (28). Several large
studies of direct-acting antiviral (DAA) therapy, and meta-analyses of these studies (29), have
demonstrated that HCC risk, while not eliminated, is reduced by 50-80% among persons who
achieve SVR (30, 31). While HCC risk is reduced with SVR, the rates do not revert to baseline,
especially among persons with cirrhosis. For example, it has been reported that the risk of HCC was
reduced 76% in a cohort of patients who achieved SVR and the annual incidence of HCC was 0.9%,
with the highest rate (1.0-2.2%) seen in conjunction with cirrhosis (32). Longer follow up of this
cohort showed that cumulative 1, 2, and 3-year risks of HCC were 1.1%, 1.9% and 2.8%, respectively.
These incidence rates are at, or below, the threshold for cost-effective HCC surveillance (32). Among
patients who achieve SVR, HCC risk if higher in association with alcohol use, older age, infection with
HCV genotype 3, and elevated markers of hepatic fibrosis (33).
Alcohol. While excessive alcohol consumption is a well-established risk factor for liver cancer
(34), the effect of lower levels of consumption has not been as thoroughly investigated. In a meta-
analysis of prospective studies, heavy alcohol consumption (≥3 drinks/day) was associated with a
16% increased risk of HCC, but there was no association with lower levels of consumption (<3
drinks/day) (35). A US pooling project found, however, that lower levels of consumption (<3
drinks/day) were associated with a significantly decreased risk of HCC, even after excluding non-
drinkers (36). The relationship varied by diabetes status however; there was no association with
lower level consumption among persons with diabetes, while there was a 35% decreased risk among
persons without diabetes (36). In addition, alcohol may have a stronger association with HCC risk
among women than men. This could be due to differences in alcohol dehydrogenase activity (37), or
due to a stronger association between alcohol and cirrhosis among women (38). In a meta-analysis
examining heavy drinking (>4 drinks/day), alcohol was associated with an almost four-fold increased

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 risk among women, but only a 59% increased risk among men (34). The trends of alcohol use and
Accepted Article
alcoholic liver disease vary among countries. In the US, several recent reports have reported a
notable increase (39).
Metabolic Syndrome, Diabetes, and Obesity. Increasing evidence suggests that metabolic
syndrome, a collection of conditions including insulin resistance, abdominal obesity, atherogenic
dyslipidemia and hypertension, increases risk of HCC. A 2014 meta-analysis estimated that
metabolic syndrome was associated with an 81% increased risk (40). Treating one of the metabolic
syndrome conditions, dyslipidemia, with statins, however, may ameliorate risk by 37-42% (41, 42).
Studies in diverse populations have reported that diabetes is associated with a 2 to 3-fold
increased risk of HCC, with a significantly greater relative risk among men than women (43). Longer
duration of diabetes may be also associated with an incremental increase in risk of HCC, but the
relationship between diabetes severity or blood sugar control and HCC risk is unclear (44). The
treatment of type 2 diabetes with metformin has been reported to decrease the risk of HCC,
whereas treatment with insulin or sulfonylureas has been reported to increase risk (45-47).
Metformin is a first-line therapy, however, while insulin and sulfonylureas are not, thus the
correlation of medication with disease severity might lead to an overestimation of risk reduction by
metformin (10).
It is well-established that excess adult adiposity increases the risk of liver cancer (48), but
several studies also suggest that there is an effect of adiposity at earlier ages. A Danish study
reported that a one-unit increase in body mass index (BMI) z-score at ages 7 or 13 years was
associated with a 20-30% increased risk of liver cancer (49), while studies from the US and Sweden
found that obesity in early adulthood was associated with 2 to 3-fold increased risk (50-52). BMI
may not accurately capture important elements of obesity, thus recent studies have examined waist
and hip circumference as measures of excess abdominal and gluteofemoral adiposity, respectively.
Cohort studies in Europe and the US have reported that persons with the high waist circumference
have a 2-fold increased HCC risk, which remains unchanged after adjustment for BMI or hip
circumference (53-55). Further, excess abdominal size in one of the studies was associated with an

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 increased HCC risk, even among individuals who had a BMI of 18.5–≤25 kg/m2, but excess
Accepted Article
gluteofemoral size alone conferred no increased risk (54).
Nonalcoholic Fatty Liver Disease (NAFLD). The overall prevalence of NAFLD among US adults
is 32.8%, but the prevalence varies by sex (men 34.7%; women 31.0%), and race/ethnicity (Mexican-
Americans 41.2%; whites 32.5%; blacks 29.1%) (56). Among persons with NAFLD, 20-30% are
estimated to progress to non-alcoholic steatohepatitis (NASH), which then progresses to cirrhosis in
10-20% of cases (57, 58). NAFLD is now a leading cause of cirrhosis and NASH is the second-leading
cause of liver transplantation related to HCC in the US (59). The increasing number of HCCs due to
NASH could offset the reductions in HCV-related HCC expected after 2020 (24). Factors related to
HCC risk associated with NAFLD include clinical factors (cirrhosis, diabetes, obesity, hypertension),
demographic characteristics (age, race/ethnicity), and genetic susceptibility (e.g., genetic variability
in PNPLA3).
Between 70 and 80% of NAFLD-related HCCs develop in cirrhotic livers, but the HCC risk is
lower than that associated with HCV-related cirrhosis. While 20-30% of NAFLD-related HCCs
develop in the absence of cirrhosis (60), the determinants of this proportion are unclear.
An analysis of studies investigating the link between NAFLD and HCC risk found that HCC risk varied
from 0 to 38% after follow-up of 5-10 years. In comparison, persons with NAFLD-related cirrhosis
had an HCC incidence ranging from 2.4 to 12.8%. A recent large cohort study reported an HCC
incidence of 0.21 per 1000 person-years among persons with NAFLD, which was significantly higher
than the risk among persons without NAFLD (60). There was also an increase in risk with each
additional metabolic trait; for example, HCC risk was 2.6-fold higher in NAFLD patients with diabetes,
obesity, dyslipidemia and hypertension compared to NAFLD patients without any of these traits (61).
While weight loss can reduce NAFLD severity, no studies have shown weight loss to affect HCC risk.
There is no high-level evidence to support or refute the value, method, or frequency of HCC
surveillance among the NAFLD population. However, based on cost-effectiveness modelling, clinical
practice guidelines recommend considering HCC surveillance among persons with cirrhosis when the
expected annual HCC incidence is 1.5% or higher (62).

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 Aflatoxin B1. Aflatoxins, mycotoxins produced by fungi of the Aspergillus species,
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contaminate a variety of foodstuffs, most notably, maize, ground nuts, and tree nuts. Of the four
principal aflatoxins, B1, B2, G1, and G2, the most potent is aflatoxin B1 (AFB1) (63). AFB1 occurs in
many locations around the world, especially in countries with warm, humid environments. The
development of AFB1 biomarkers enabled the link between HCC and AFB1 to be definitely
established and prompted IARC to classify AFB1 as a group 1 human carcinogen (63). AFB1 is
particularly carcinogenic when it co-occurs with chronic HBV infection as the combination of factors
has a synergistic effect on HCC risk. A 2012 meta-analysis estimated that AFB1 alone increased HCC
risk by 6-fold, HBV alone by 11-fold, and the two factors together by 54-fold (64).
AFB1 contamination of crops is difficult to combat because contamination can occur both
pre- and post-harvest (65). A very successful effort, however, was the replacement of maize with
rice as the dietary staple in parts of China; an effort has been largely credited for the current decline
in HCC rates (66, 67). However, the single most effective way to reduce HCC risk in regions where
AFB1 and HBV co-occur is to vaccinate against HBV in order to eliminate the synergistic effect on risk.
Tobacco. In a review of 113 studies, the 2014 US Surgeon General’s report found that
current cigarette smoking was associated with a 70% increased risk of liver cancer, while former
smoking was associated with a 40% increased risk (68). A recent study, however, reported that
years since smoking cessation was inversely associated with HCC risk, with individuals who stopped
smoking >30 years ago having an HCC risk similar to that of never-smokers (36).
Dietary factors. Coffee has been consistently associated with decreased risk of liver cancer
(69). A 2017 meta-analysis of both cohort and case-control studies reported that an extra two cups
of coffee per day was associated with a 35% reduced risk (70). Coffee has also been associated with
lower liver enzyme levels, slower progression of fibrosis, and lower risk of diabetes. The
mechanisms underlying a possible protective effect of coffee, however, are not clear. Experimental
evidence suggests there may be beneficial effects of caffeine as well as many other coffee
components (e.g., diterpenes) in reducing inflammation, fibrosis, insulin resistance and oncogenesis
(71).

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 High iron intake has been long associated with increased risk (72, 73). The consumption of
Accepted Article
traditional iron-rich beer is associated with HCC in southern and central Africa (74). Further, a
recent meta-analysis of prospective studies in Asia, Europe, and the US found that higher serum
ferritin levels were associated with a 49% increased HCC risk, while higher serum iron levels were
associated with a 2.5-fold greater risk (72).

Genetic susceptibility
Mutations in the genes for hemochromatosis (HFE), alpha 1-antitrypsin deficiency
(SERPINA1), glycogen storage diseases (G6PC, SLC37A4), porphyrias (HMBS, UROD), tyrosinemia
(FAH) and Wilson’s Disease (ATP7B) increase susceptibility to HCC. Polymorphisms, originally
examined in candidate-locus studies, have also been related to risk. A 2011 meta-analysis found
that polymorphisms in UGT1A7, MnSOD and IL-1B were all significantly associated with risk (75).
More recently, genome-wide association studies (GWAS) conducted in Asian populations where HBV
or HCV were factors reported increased risks in association with a number of loci, most commonly
ones located in the HLA region (HLA-DP, HLA-DQ, HLA-DR, MICA) (76-85). Another reported
association maps to chromosome 1p36.22, a region that may harbor a tumor suppressor gene for
HCC (85). The KIF1B gene in this region has been reported to be associated with apoptosis, and its
association with HCC was replicated in subsequent studies from other Asian populations.
Associations with STAT4, GRIK1, EFCAB11, and EFCAB11 have also been found (77, 78, 80). In non-
Asian populations, a polymorphism in the PNPLA3 gene has been demonstrated to be associated
with HCC. The rs738409 SNP was first reported to be related to NAFLD (86), conferring a 4-fold
increased risk among persons homozygous for the risk allele and an almost 2-fold increased risk
among heterozygotes (87). Subsequent examinations of the polymorphism and risk of HCC also
found associations. As reported by a recent meta-analysis, there is evidence of a significant
association among white populations (OR=1.75), but no evidence of an association among Asian
populations (88).

Population Attributable Risks

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 The extent to which individual risk factors contribute to the HCC burden can be estimated by
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calculation of population attributable fractions (PAFs), which are important measures for developing
cancer control policies. PAFs are dependent on the strength of the risk factor-HCC association and
the prevalence of the risk factor in the population, thus, PAFs vary widely by geographic location.
For example, although it has been estimated that the global HBV PAF is 56%, the PAF for North
America is estimated at just 7%, while the PAF for Eastern Asia is estimated at 69% (89). Similarly,
the global HCV PAF is estimated at 20%, but the PAF for Eastern Asia is estimated at 11% while the
PAF for Northern Africa is estimated at 79% (89). The global AFB1 PAF is estimated to be 17%, but
the PAF ranges from 8% to 21% in populations where HBV is absent versus present, respectively
(64). For alcohol, the global PAF is estimated at 26%, although the PAF in Eastern Europe is notably
higher (39%) than the PAF in South Asia (13%). For obesity, the global PAF is estimated at 9%, with
notably higher PAFs in North America (24%) than in Southeast Asia (4%) and sub-Saharan Africa
(4%). For diabetes, the global PAF is estimated to be 7%, with higher PAFs in Oceania (12%) and the
Middle East (12%) and lower PAFs in sub-Saharan Africa (4-5%).

Conclusions
HBV and HCV remain the most important global risk factors for HCC. However, the prevalence of
both factors should decline in the coming years due to HBV vaccination of newborns, and more
effective treatment of both HBV and HCV carriers. The prevalence of NAFLD/NASH is increasing and
may soon overtake viral factors as the major cause of HCC globally. Excessive alcoholic consumption
also remains an important risk factor. Due to climate change, so AFB1 could become a more
dominant risk factor in the coming decades. These changing trends suggest that more effort needs
to be focused on combating obesity and diabetes to decrease the incidence of NAFLD, and more
effective strategies to control alcohol use and mycotoxin growth need to be implemented.

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Accepted Article
Figure 1. Global age-adjusted incidence rates of liver cancer, estimated for 2018. Data source: GLOBOCAN 2018. Graph production: IARC
(http://gco.iarc.fr/today), World Health Organization.

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 Figure 2. Trends in hepatocellular carcinoma incidence rates by country, 1978-1982 through 2008-2012. Rates
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are per 100,000 person-years and age-adjusted to the world standard population.

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Accepted Article

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