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RESEARCH 

Liver cancer incidence and mortality: 
Disparities based on age, ethnicity, health 
and nutrition, molecular factors, and 
geography 
 

Santosh Kumar Singh and Rajesh Singha* 

aDepartment of Microbiology, Biochemistry and Immunology, Cancer Health Equity Institute, Morehouse 
School of Medicine, Atlanta, GA, USA, 30310 

*Corresponding author: Rajesh Singh, E-mail: rsingh@msm.edu 

ABSTRACT 
Liver cancer (LCa) is the fifth and eighth leading cause of cancer death for men and women, 
respectively. However, despite improvements in treatment strategies and options, it has limited 
therapeutic options. Worldwide, the prevalence of LCa varies widely. Various factors are associated with 
the development of LCa, and its incidence, morbidity, and mortality rates differ due to disparities that 
are multifactorial and complex, including genetic and geographic factors. The frequency of LCa varies 
by race/ethnicity, age and sex and relates to viral infections, lifestyle, nutrition, obesity, and health. In 
addition, various molecular factors, including cytokines, hormones, apoptosis, and mutations, are 
involved in disparities in the progression and mortality of LCa. Here, we provide an overall perspective 
on LCa by presenting available information on these associated factors and discussing their importance 
in its disproportionate incidences and clinical outcomes. 

KEYWORDS: Liver cancer, health disparity, nutrition and health, morbidity 

Citation: SK Singh and R Singh (2019) Liver cancer incidence and mortality: Disparities based on age, 
ethnicity, health and nutrition, molecular factors, and geography. Cancer Health Disparities 4: e1-e10. 
doi:10.9777/chd.2019.1014 
 
 
  

mailto:rsingh@msm.edu


 
 
 
 
 

 
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Introduction 

In the United States, liver cancer (LCa), including 
intrahepatic bile duct cancer, is the fifth and eighth 
leading cause of cancer for men and women, 
respectively (Chen, 2018). For the United States, 
42,030 cases are expected to be diagnosed in 
2019, and 31,780 deaths are predicted (Siegel et 
al., 2019). The death rates for LCa are increasing at 
a faster pace than those for other cancers (Islami 
et al., 2017; Jemal et al., 2017). In the United States, 
the incidence of liver cancer is projected to rise 
continuously from the mid-1970s through 2030. A 
factor contributing to this increase is the hepatitis 
C virus (HCV) infections in those called “baby 
boomers,” who were born during 1945 to 1965 
(Geboy et al., 2016). 

A decline in overall cancer mortality rates in the 
United States was evident in the 1990’s, due to 
widespread cancer screening, improvements in 
treatments, and reductions in cancer risk factors 
such as tobacco smoking (Jemal et al., 2017; 
O'Keefe et al., 2015). However, the mortality rate 
for LCa increased, with an unequal distribution 
throughout the population. Additionally, 
hepatocellular carcinoma (HCC), reported more 
often in Asia than in the United States, is the third 
leading cause of cancer mortality worldwide 
(Altekruse et al., 2009). Thus, HCC is one of the 
most fatal cancers, with only a 7% 5-year survival 
(Ruggieri et al., 2010). Moreover, in the United 
States, geographical and biological factors are 
associated with racial disparities. In the 
development of HCC, exposure to hepatitis B virus 
(HBV) and HCV infections, alcoholic liver disease, 
hemochromatosis, and non-alcoholic 
steatohepatitis are involved; there are also genetic 
and environmental contributions (Ruggieri et al., 
2010). Furthermore, some racial groups are more 

affected, as shown by data on cancer incidence 
and mortality (Deshmukh et al., 2017). In the 
United States, the mortality for African Americans 
(AA) with HCC is worse than for any other racial 
group. In addition, in Eastern and Southern Asia, 
Middle and Western Africa, Melanesia, and 
Micronesia/Polynesia, the incidence of HCC is 
higher for males than females (Ferlay et al., 2010). 
According to the NIH Surveillance, Epidemiology, 
and End Results (SEER) database, the annual 
incidence of HCC has tripled between 1975 and 
2005 (Altekruse et al., 2009). The statistical data of 
the National Institutes of Health (NIH) and the 
Centers for Disease Control and Prevention (CDC) 
show a difference in the LCa-based mortality rates 
by race/ethnicity. A schematic presentation of liver 
cancer disparity associated factors are shown in 
Figure 1. In the present review, our focus was to 
estimate the worldwide burden of LCa disparities 
based on race/ethnicity, health and nutrition, and 
molecular and geographical factors. 

 

Figure 1. Schematic presentation of liver cancer 
disparity associated factors  

Factors associated with LCa 

Disparities of LCa occurrence by sex and 
race/ethnicity 
The incidence of LCa varies by race/ethnicity due 
to differences in the prevalence of risk factors and, 
to some extent, disparities in access to high-quality 
care. Recently, an annual report on cancer 



 
 
 
 
 

 
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incidences from 1975-2012 and/or 2014 (Islami et 
al., 2017; Ryerson et al., 2016), showed lower rates 
of overall cancer incidences among both men and 
women but increased rates of LCa-related deaths 
for both sexes. From 2003 through 2012, the 
mortality rates were higher among men (Ryerson 
et al., 2016). Early 2000 estimates indicated that 
LCa incidence was the fifth most common cancer 
in men and eighth for women worldwide, with 
male/female ratios regularly averaging between 
2:1 and 4:1. (Montalto et al., 2002). However, for 
countries with low incidences of LCa, the age 
distribution for males and females was rare before 
the age of 50. Among high-risk countries such as 
those in Southeast Asia and West and Coastal 
Africa, the occurrence of LCa was evident before 
the age of 20; gender ratios were higher, and the 
male excess was greater for those less than 50 
years of age. In addition, clinical observations and 
death statistics showed that LCa due to hepatitis 
infections appeared to progress more in males 
than females and that cirrhosis was largely a 
disease of men and postmenopausal women 
(Giannitrapani et al., 2006; Ruggieri et al., 2010). 

In the United States, there were disparities in the 
rates and survival for various races/ethnicities and 
between states; the relative risk of death for all 
cancers combined was 33% higher for non-
Hispanic (NH) blacks and 51% higher for NH 
Indian/Alaska Natives compared to NH whites 
(Islami et al., 2017). However, there was a disparity 
in LCa incidence in that it was higher among NH 
whites, NH blacks, and Hispanic men and women 
born after 1938-1947; it was minimal for NH Asian 
and Pacific Islanders (Ryerson et al., 2016). Among 
Hispanics, the disparities in LCa incidence and 
mortality were related to their nativity. The HCC 
incidence was twice as high for US-born Hispanic 
men compared to the foreign-born Hispanic men 
(Setiawan et al., 2016). The risk factors of smoking 
status, hepatitis B/C infection, and diabetes 
accounted for HCC among US-born Hispanics. An 
overview of the disparities of LCa incidence 
according to race and ethnicity is presented in 
table 1. 

 

Table 1. Disparities of LCa incidences according to race and ethnicity. 
Region 
born 

Ethnicity/ 
Gender 

Incidence 
(per 

100,000) 

Severity Causes Mortality 
(per 

100,000) 

Reference 

US born 

Men (overall) 21-35  ----  (Altekruse et 
al., 2009) 

Women 
(overall) 

3.8-13.6  ----  (Altekruse et 
al., 2009) 

Hispanic 
(men/women) 

1.8-60.2/1.2-
48 

Localized to 
advanced and 

unknown 

Chronic 
hepatitis/fibrosis/ 

alcohol-related/other 

63/42 (Setiawan et 
al., 2016) 

Asian 
(men/women) 

35-83/5.9-
37.9 

Localized to 
advanced 

HCV/HBV infection  (Altekruse et 
al., 2009) 

African 
(men/women) 

37-40/6.9-
13.6 

Localized to 
advanced 

HCV/HBV 
infection/other 

 (Altekruse et 
al., 2009) 

White 16.5-28/3-
10.2 

Localized to 
advanced 

HCV/HBV 
infection/obesity/0ther 

 (Altekruse et 
al., 2009) 



 
 
 
 
 

 
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Non-US 
born 

Men 75.9  -----   (Njei et al., 
2015) 

Women 24.5  -----  (Njei et al., 
2015) 

Hispanic 
(men/women) 

0-44/0-50 Localized to 
advance and 

Unknown 

Chronic 
hepatitis/Fibrosis/Alco

hol related/Other 

35/19 (Setiawan et 
al., 2016) 

Asian 18.9-24 Localized to 
advanced 

HCV/HBV infection  (Njei et al., 
2015) 

African 10.9-12.5 Localized to 
advanced 

HCV/HBV 
infection/other 

 (Njei et al., 
2015) 

White 67 Localized to 
advanced 

HCV/HBV 
infection/obesity/other 

 (Njei et al., 
2015) 

 

Geographical factors associated with disparities in 
LCa 
HCC is the dominant histologic type of LCa, 
accounting for approximately 80% of total cases 
globally (Petrick et al., 2016). HCC poses a 
prominent disease burden throughout the world 
and particularly in Africa and Asia where HBV is 
the principal cause (Bosch et al., 2005). In Western 
countries, chronic alcohol abuse is the primary 
factor associated with HCC. High disease levels in 
Northern Thailand are due to chronic infections 
with the liver fluke, Opisthorchis viverrini, which is 
ingested through infected raw fish (Petrick et al., 
2016; Sripa et al., 2012). 

In countries undergoing socio-economic 
development, such as some in Asia, HCC cases 
account for nearly 75% of all LCas, and China 
accounts for 56% of the world’s burden. The 
highest incidence of HCC occurs in Mongolia; the 
lowest incidence is in Nepal (Baatarkhuu et al., 
2017; Shrestha, 2018). However, HCC incidence has 
been increasing in several other countries, but 
there have been declines in some Asian countries 
(McGlynn and London, 2011; McGlynn et al., 2015; 
McGlynn et al., 2001; Zhang et al., 2015). However, 
the rates of HCC remain highest in Asian counties 
(Petrick et al., 2016). Although there was a 

decrease in HCC burden in these high-risk 
countries, there was a rise in India as well as in 
low-risk countries of Africa, Europe, the Americans, 
and Oceania; in Thailand, France, and Italy, there 
was a decline. The decreased incidence in high-
risk countries was likely due to a lower prevalence 
of HBV infections. Particularly in low-risk countries, 
a reduction in HCC burden will be seen when 
incidences of HCV, diabetes, and obesity are 
lowered. 

Disparities of LCa from the nutritional and health 
perspective 
“Food insecurity” refers to a lack of access to 
sufficient, safe, and nutritious food that fulfils the 
dietary needs and food preferences for living a 
healthy life. There is evidence suggesting a 
relationship between specific dietary components 
and risk of cancers at various anatomic sites 
(Schutte et al., 2016). The nutritional status of 
patients is related to their performance status and 
to their tolerance for cancer therapy (Schutte et al., 
2016). 

Few studies are investigating the role of diet in 
hepatocarcinogenesis. Risk factors for the 
occurrence of LCa include chronic viral infections 
(hepatitis B and C), excess alcohol consumption, 



 
 
 
 
 

 
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non-alcoholic fatty liver disease, dietary exposure 
to aflatoxin, obesity, smoking, and diabetes 
mellitus (El-Serag and Rudolph, 2007). However, a 
substantial portion of LCa occurs in patients 
without exposure to these risk factors, suggesting 
a role of additional factors. Observational studies 
indicate a protective role of a diet containing 
vegetables, fruits, and cereals (Koumbi, 2017) in 
preventing cancer. Although various studies have 
presented conflicting results, high intakes of red 
meat, fish, and dietary sugars are associated with a 
high risk for Western Europeans (Fedirko et al., 
2013). Among Japanese, Italians, and Europeans, 
high intakes of vegetables, fruits, cereals, eggs, 
milk, and yogurt are associated with a lower 
occurrence of LCa (Kurozawa et al., 2004; Negri et 
al., 1991; Talamini et al., 2006). These results are 
supported by findings of a study of Chinese men 
and women, which showed that a vegetable-
based diet is associated with reduced risk of LCa 
(Zhang et al., 2013). 

For Japanese individuals, overweight or obesity 
moderately increases the risk of LCa (Tanaka et al., 
2014). Obesity among Americans has reached an 
epidemic proportion (Vastag, 2004), and 64% of 
the adult population is overweight or obese. There 
is a positive association between obesity and high 
death rates for liver and other cancers (Calle et al., 
2003). It was estimated that more than 90,000 
cancer deaths per year could be avoided with the 
maintenance of normal weight, and obesity was a 
major risk factor for cancer (Donaldson, 2004). 
Among Americans, obesity, nutrient-sparse foods 
such as concentrated sugars and refined flour 
products that contribute to reduced glucose 
metabolism, low fiber intake, consumption of red 
meat, and an imbalance of omega 3 and omega 6 
fats contribute to excess risk of LCa (Donaldson, 
2004). 

A study focused on the type of therapy and 
patients with diagnosed stages shows that for LCa 
stage A patients, liver transplants, radiofrequency 
ablation (RFA), and embolization were utilized less 
often for Hispanics, NH blacks, patients with 
Medicaid, and patients in the highest income 
quartile. Stage D patients were less likely to receive 
cancer therapy if they had Medicaid insurance 
(Harlan et al., 2015). Additionally, 26.8% of patients 
diagnosed with stage B received surgery, followed 
by 12.4% of those with stage 0. For younger 
patients, those diagnosed and treated at earlier 
stages were more likely to receive surgery than NH 
black Medicaid patients. Furthermore, transplants 
were more frequent for stage 0 (36.5%) and stage 
A disease (48.1%) than for patients aged 50 or 
older, NH blacks, Hispanic patients, and stage B-D 
Medicaid patients (Harlan et al., 2015). In addition 
to surgery and transplantation, RFA was more 
often used for stage 0 (3.7%) and stage A (3.9%); 
for stage B disease, tumor embolization was most 
often performed in combination with systemic 
chemotherapy (15.3%) (Harlan et al., 2015). 

Molecular perspectives related to disparities in LCa 
Morphologically, liver tumors are heterogeneous 
within the same tumor and for different tumors. 
Some subtypes of LCa have stem cell features; 
others have a phenotype intermediate between 
hepatocytes and cholangiocytes (Sia et al., 2017). 
These observations have raised the possibility of 
disparities in the origin of LCa. Hepatic precursor 
cells might generate primary liver tumors as, 
during development, hepatocytes and 
cholangiocytes can arise from a common 
precursor cell. However, tumors developing from 
mature hepatocytes and cholangiocytes could be 
different. Moreover, hepatocytes could be a 
source of LCa as these cells can undergo 
mutations in their genes, dedifferentiate into 



 
 
 
 
 

 
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precursor cells, and ultimately transform into LCa 
cells with precursor cell markers (Chen et al., 2012; 
Sia et al., 2017; Tanimizu et al., 2013). 

The liver is a sexually dimorphic organ. For males 
and females, there are differences in gene 
expression, mitochondrial function and enzyme 
activity, lipids composition of cell membranes, and 
immune responses (Dhir et al., 2006). The 
differentiation of liver gender is maximum at 
puberty, with the elevation of testosterone in 
males associated with the tyrosine phosphorylation 
cascade of Jak2/Stat5, which is involved in the 
transcription of masculine genes that repress 
feminine genes. However, for females, secretion of 
growth hormone continues, but at a lower rate, 
with unphosphorylated Stat5 associated with gene 

transcription. Such differences could account for 
the disparity in the development of LCa between 
the two sexes (Dhir et al., 2006; Waxman and 
Holloway, 2009). Molecular factors involved in the 
disparities of incidence and mortality of LCa are 
shown in table 2. A separate study of HCC showed 
that inhabitants of Asian and African countries 
were more likely to have chronic HBV infections, 
whereas those in Japan and the United States were 
more likely to have HCV infections (El-Serag and 
Rudolph, 2007). In addition, about half of the 
cancers are activated due to TP53 mutations; in a 
clinical study of Chinese patients, nearly half had a 
point mutation at codon 249 (Aravalli et al., 2008). 
Thus, understanding the molecular mechanism of 
HCC is a promising strategy for dealing with 
cancer disparities. 

 

Table 2. Molecular factors involved in disparities in incidence and mortality of LCa. 
Cellular and Molecular 
factors/mechanisms Dysregulation  Associated with  Reference 

Cytokines 

IL-6 Overexpression HCV 
(Rogers et al., 2007); 
(Nakagawa et al., 2009); 
(Wong et al., 2009) 

IL-10 Polymorphism in 
promoter HCV (Paladino et al., 2006); 

(Persico et al., 2006) 
Interferon Overexpression HCV (Rogers et al., 2007) 
Sex hormones 

Androgen, estrogen, and 
progesterone 

Differential 
expression 

Regulation of transcriptional factors NFkB and 
C/EBPβ, immune response, and cell 
proliferation 

(Naugler et al., 2007); 
(Ohnishi et al., 1986) 
 

Reactive oxygen species Production Depletion of antioxidant defences; changes in 
key organelles, including mitochondria  

(Tien Kuo and Savaraj, 
2006) 

Mutations Hypermethylation of 
genes  

LZTR1, EEF1A1, SF3B1, and 
SMARCA4, CCR5 32 delta (et.al., 2017) 

 

Chemokines are the low molecular weight proteins 
that function in leukocyte trafficking and other 
biological activities. They belong to the G-protein 
coupled receptor family, bind to their cognate 
receptors, and determine the metastatic 

destination of tumor cells (Singh et al., 2018). 
Chemokines are involved in liver inflammation, 
which regulates activities of circulating immune 
cells, endothelial cells, and hepatocytes. Moreover, 
they contribute to cell proliferation, pathogenesis, 



 
 
 
 
 

 
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angiogenesis, and the inflammatory 
microenvironment of HCCs (Abdolmohammadi et 
al., 2016). Therefore, we reviewed the role of 
chemokines and their receptors in the regulation 
of LCa disparities. Chemokine receptor 5 (CCR5) 
delta 32 alleles may predispose patients to chronic 
HBV infections. A total of 812 Iranian individuals, 
grouped into HBV-infected and healthy controls, 
demonstrated that CCR5 delta 32 was more 
frequent in healthy controls than in HBV-infected 
individuals (Abdolmohammadi et al., 2016). In 
addition, the CCR5 receptor is a coreceptor for the 
HIV gp120 protein (Wilkin et al., 2010). A CCR5 
delta 32 mutation is present in 10-15% of 
Caucasians. Those who have a copy of the gene 
encoding CCR5 delta 32 have a greater probability 
of recovery from HBV infection (Thio et al., 2007). 
Indians having CCR5 delta 32 heterozygosity are 
more susceptible to HBV-related liver disease 
(Suneetha et al., 2006). This shows that, due to 
differences in genetic background, those with 
CCR5 delta 32 are resistant to HBV infection. The 
CCR5 delta 32 allele is not present in residents of 
Southeast Asian countries, and, in a study of CCR5 
delta 32 polymorphism in China, no mutated allele 
was detected. 

Conclusions 

In the future, the burden of LCa in the United 
States and worldwide is expected to increase. 
Despite improvements in LCa treatments and 
survival rates, the overall prognosis for LCa 
remains poor. Wide disparities in LCa rates by sex, 
age, gender, and ethnicity reflect differences in the 
major risk factors and inequalities in access to 
high-quality care. The increase in obesity in the 
general population, lack of healthy nutrition, 
inappropriate lifestyles, and limited understanding 
of the molecular aspects and origin of LCa are 

impediments in preventing and treating these 
cancers. To curb the rising problem of LCa and its 
disparities, interventions should include the 
application of existing knowledge in prevention, 
early detection, and treatment, maintaining 
healthy body weight, providing access to high-
quality diabetes care, preventing excessive alcohol 
drinking, and controlling tobacco consumption. 

Acknowledgements 
This study was supported in part by the National 
Institutes of Health under Award Number 
SC1CA193758 and U54CA118638, and by the 
Department of Defence, Award Number 
W81XWH1810429. 

Conflict of interest 
All authors declare no potential conflicts of interest. 

Authors’ contributions 
SKS was involved in data collection and drafting of 
the article. RS designed the concept, critically 
reviewed and editing of the final version of the 
manuscript. All authors read and approved the final 
manuscript. 

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