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Projected epidemiological trends and burden of liver cancer by 2040 based on GBD, CI5plus, and WHO data

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Incidence of liver cancer as one of the most common cancers worldwide and become the significant contributor for the mortality among cancer patients. The disease burden, risk factors, and trends in incidence and mortality of liver cancer globally was described subsequently estimated the projections of liver cancer incidence or mortality by 2040. Data regarding age-standardized incidence and mortality rates for liver cancer was obtained from multiple databases, including GLOBOCAN 2020, CI5 volumes I–XI, WHO mortality database, and Global Burden of Disease (GBD)-2019. Concentrating on worldwide variations, this thorough analysis offers insights into patterns of incidence and mortality based on gender and age. Our findings encompass significant indicators, including age-standardized rates (ASRs), average annual percentage change (AAPC), and future projections extending up to the year 2040. Liver cancer holds the sixth position in terms of most frequently diagnosed cancers and stands as the sixth leading cause of cancer-related deaths worldwide in 2020, accounting for 905,677 new cases and 782,000 fatalities. Additionally, liver cancer contributed to 12,528,421 age-standardized disability-adjusted life years (DALYs), with an age-standardized DALYs rate of 161.92 in 2019 worldwide. The age-specific incidence rates exhibited significant variations across different regions, showing a fivefold difference in males and females. A significant increase in incidence was observed in North Europe and Asia, while North African countries reported a higher mortality burden (ASR, 10 per 100,000) compared to developed countries. Since last few years, the incidence and mortality rates have increased and attained Annual Average Percentage Change (AAPC) incidence rate of 7.7 (95% CI 3.9–11.6) for men and the highest AAPC mortality rate of 12.2 (95% CI 9.5–15.0) for women. In 2019, Western Europe emerged as the high-risk region for DALYs related to smoking and alcohol consumption, while high-income North America carried a high risk for DALYs associated with a high body-mass index. The projected trend indicates a surge in new liver cancer incident cases, expected to rise from around 905,347 to an estimated 1,392,474 by 2040. This study described the evidence pertinent to higher incidence trends in liver cancer, particularly among both young and older adults, encompassing males and females, as well as those who are HIV-infected and HBsAg positive. A significant rise in the young population poses a significant public health concern that warrants attention from healthcare professionals to prioritize the promotion of health awareness and the development of effective cancer prevention strategies, particularly in many developing countries.
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Projected epidemiological trends
and burden of liver cancer by 2040
based on GBD, CI5plus, and WHO
data
Qianqian Guo1,9, Xiaorong Zhu2,3,9, Narasimha M. Beeraka4,6,7,8, Ruiwen Zhao1,2,
Siting Li1,2, Fengying Li1,2, Padukudru Anand Mahesh5, Vladimir N. Nikolenko7,
Ruitai Fan1,2 & Junqi Liu1,2
Incidence of liver cancer as one of the most common cancers worldwide and become the signicant
contributor for the mortality among cancer patients. The disease burden, risk factors, and trends in
incidence and mortality of liver cancer globally was described subsequently estimated the projections
of liver cancer incidence or mortality by 2040. Data regarding age-standardized incidence and mortality
rates for liver cancer was obtained from multiple databases, including GLOBOCAN 2020, CI5 volumes
I–XI, WHO mortality database, and Global Burden of Disease (GBD)-2019. Concentrating on worldwide
variations, this thorough analysis oers insights into patterns of incidence and mortality based on
gender and age. Our ndings encompass signicant indicators, including age-standardized rates
(ASRs), average annual percentage change (AAPC), and future projections extending up to the year
2040. Liver cancer holds the sixth position in terms of most frequently diagnosed cancers and stands as
the sixth leading cause of cancer-related deaths worldwide in 2020, accounting for 905,677 new cases
and 782,000 fatalities. Additionally, liver cancer contributed to 12,528,421 age-standardized disability-
adjusted life years (DALYs), with an age-standardized DALYs rate of 161.92 in 2019 worldwide. The
age-specic incidence rates exhibited signicant variations across dierent regions, showing a vefold
dierence in males and females. A signicant increase in incidence was observed in North Europe and
Asia, while North African countries reported a higher mortality burden (ASR, 10 per 100,000) compared
to developed countries. Since last few years, the incidence and mortality rates have increased and
attained Annual Average Percentage Change (AAPC) incidence rate of 7.7 (95% CI 3.9–11.6) for men
and the highest AAPC mortality rate of 12.2 (95% CI 9.5–15.0) for women. In 2019, Western Europe
emerged as the high-risk region for DALYs related to smoking and alcohol consumption, while high-
income North America carried a high risk for DALYs associated with a high body-mass index. The
projected trend indicates a surge in new liver cancer incident cases, expected to rise from around
905,347 to an estimated 1,392,474 by 2040. This study described the evidence pertinent to higher
incidence trends in liver cancer, particularly among both young and older adults, encompassing
males and females, as well as those who are HIV-infected and HBsAg positive. A signicant rise in the
young population poses a signicant public health concern that warrants attention from healthcare
professionals to prioritize the promotion of health awareness and the development of eective cancer
prevention strategies, particularly in many developing countries.
Keywords Liver cancer, Gender, Age standardized mortality rate, 2040 Projections rates, HDI, WHO
database, GBD database, CI5 volumes I–XI
1Department of Oncology, The First Aliated Hospital of Zhengzhou University, No. 1, Jianshe East Road,
Zhengzhou 450000, People’s Republic of China. 2Department of Radiation Oncology and Cancer Center, The First
Aliated Hospital of Zhengzhou University, No. 1, Jianshe East Road, Erqi District, Zhengzhou 450000, Henan
Province, People’s Republic of China. 3Cancer Center, The First Aliated Hospital of Zhengzhou University, No.
1, Jianshe East Road, Zhengzhou 450000, People’s Republic of China. 4Raghavendra Institute of Pharmaceutical
Education and Research (RIPER), Anantapuramu, Chiyyedu, Andhra Pradesh 515721, India. 5Department of
Pulmonary Medicine, JSS Medical College, JSS Academy of Higher Education and Research (JSS AHER), Mysuru,
Karnataka, India. 6Department of Pediatrics, Herman B. Wells Center for Pediatric Research, Indiana University
OPEN
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School of Medicine, 1044 W. Walnut Street, R4-168, Indianapolis, IN 46202, USA. 7Department of Human Anatomy
and Histology, I.M. Sechenov First Moscow State Medical University (Sechenov University), 8/2 Trubetskaya
Street, Moscow, Russian Federation119991. 8 Department of Studies in Molecular Biology, University of Mysore,
Mysore, Karnataka 570006, India. 9These authors contributed equally: Qianqian Guo and Xiaorong Zhu. email:
bnmurthy24@gmail.com; biraka_n@sta.sechenov.ru; fccfanrt@zzu.edu.cn; fccliujq@zzu.edu.cn
Based on GLOBOCAN estimates, liver cancer recorded approximately 905,677 new cases and 830,180 deaths in
2020. Incidence and mortality rates were 2–3 times higher in males than in females. Regions such as Sub-Saharan
Africa and parts of Asia (Southeast, East, and Central), along with high-income Asia Pacic, exhibited elevated
age-standardized incidence rates (ASIR) and age-standardized mortality rates (ASMR)1. e highest incidence
of liver cancers is observed in Mongolia and China2. Globally, liver cancer ranks as the second-leading cause
of cancer-related mortality in men3. Meanwhile, rapid changes in lifestyle and aging are generally considered
as the risk factors for the incidence of liver cancer. Identifying modiable risk factors is crucial to prevent the
development of liver cancer and for early intervention. Recent research has identied alcohol consumption,
gender, aging, obesity, gut microbial dysbiosis, and genetic variations as crucial factors inuencing the onset of
alcohol-associated cirrhosis and hepatocellular carcinoma (HCC)46.
Furthermore, viral infections such as HBV, HCV, HDV also are considered as the crucial risk factors for
the incidence of liver cancer. In Europe and the USA, around 8–16% of individuals with HIV attain chronic
infection with HBV711. e estimated number of HIV-infected individuals who are also chronically infected
with HBV is approximately 2.7 million12,13 with a signicant portion of these cases conned to HBV-endemic
regions in Asia and Africa8,14. e likelihood of acquiring chronic HBV infection is 3–6 times greater in HIV-
infected patients15. e progression of liver disease in co-infections with HIV/HCV and HIV/HBV is driven
by multifactorial mechanisms. ese include HIV-induced immune suppression due to CD4+T-cell depletion,
systemic immune activation, enhanced apoptosis of lymphocytes and hepatocytes, oxidative stress, inammation,
impaired immune responses, promotion of retroviral infection of hepatic stellate cells and Kuper cells, and
microbial translocation16. Compared to HBV monoinfection, patients co-infected with HIV and HBV are at a
signicantly higher risk of accelerated progression of liver brosis to end-stage liver disease, which is associated
with substantial morbidity and mortality17,18. e acceleration of HBV-induced liver brogenesis in patients
with HBV/HIV co-infection can be attributed to the combined eects of HIV, the HIV envelope glycoprotein
gp120, and excessive upregulation of transforming growth factor-beta 1 (TGF-β1). Additionally, targeting HIF-
1α may hold promise as an eective approach for treating patients with HBV/HIV co-infection and mitigating
the progression of liver disease19. Our study is specically explored the association of liver cancer and HIV, HBV,
and other risk factors.
e aging population is susceptible to liver cancer, and there is a projected increase in the incidence rate in
the upcoming decades among these individuals due to aging. However, the incidence of liver cancer among the
younger population should be evaluated. erefore, comprehending the distribution of diseases across dierent
age groups and addressing the global burden of liver cancer within specic age populations is a crucial public
health concern with signicant economic implications, encompassing both healthcare expenditures and income
support. While numerous studies at regional and national levels have explored the morbidity and mortality
associated with liver cancer, there is a scarcity of comprehensive global assessments that thoroughly examine
the burden and risk factors of this disease. e objective of this study is to analyze incidence and mortality
estimates by ascertaining ASRs using GLOBOCAN 2020 data related to various geographical regions. Temporal
trends in morbidity and mortality due to liver cancer were examined comparatively by ascertaining the AAPCs
retrieved from the CI5 volumes I–XI and WHO mortality database. Additionally, we investigated the correlated
risk factors and described DALYs. Furthermore, we presented global demographic projections for the year 2040.
were examined in this study.
Methods
Data collection
We assessed the current and future burdens of liver cancer using data from the GLOBOCAN-2020 database,
sourced from the Global Cancer Observatory (GCO) website. e GCO website20 described details on the
incidence, mortality, and prevalence of various cancers in 185 countries or regions, with a primary emphasis on
the human development index (HDI)21. GLOBOCAN database was used for examining the current liver cancer
burden and forecasting the future burden analysis.
Our assessment involved a comprehensive estimation of the relationship between age-adjusted prevalence
of various health-related risk factors and the global incidence and mortality patterns of liver cancer, with a
specic focus on the year 2016. e risk factors analyzed included obesity, alcohol consumption, lipoprotein
levels, elevated fasting blood glucose, insucient physical activity, and smoking. Country-specic data for these
risk factors were meticulously collected from the WHO, GHO database. e age-adjusted prevalence rates were
calculated to account for demographic dierences across countries, ensuring a standardized comparison. is
approach allowed us to isolate the impact of each risk factor on liver cancer incidence and mortality.
Additionally, advanced statistical methods, such as multivariate regression analyses, were employed to
quantify the strength and signicance of these associations. Confounding variables, including socioeconomic
status, healthcare access, and genetic predispositions, were controlled to ensure the robustness of our ndings. By
integrating these diverse data sources and analytical techniques, our study provides a detailed and scientically
rigorous examination of how health-related risk factors contribute to liver cancer patterns globally22. For
instance, to evaluate the inuence of risk factors on liver cancer, we gathered prevalence data for individuals
aged 18years and older, along with ASRs for both incidence and mortality. For a comprehensive denition
of risk factors, please refer to the GHO database or Supplementary Table 1. Our analysis typically focused on
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exploring the correlation among HIV incidence, HBsAg prevalence, and ASIRs of liver cancer across individuals
of all ages in 125 countries, predominantly in Africa. Data pertinent to this information were retrieved from the
AIDSinfo website and WHO23.
Data on cancer incidence and the corresponding populations at risk in 42 countries were collected from
volumes VII–XI of the Five Continents Time Trends (CI5plus) database, oered by the International Agency for
Research on Cancer (IARC), covering the period from 1998 to 201220. is approach facilitates the examination
of long-term trends associated with liver cancer incidence or mortality. Mortality data for each year within
the study period, ranging from 1998 to recent years, were obtained from the WHO database24. Mainly, the
number of liver cancer cases and deaths from Volumes VII–XI of the Five Continents Time Trends (CI5plus)
database and the WHO database were used to calculate the ASIR and ASMR by sex and age groups (0–60years,
0–75years, 60years and over, 75years and over). ese data were also utilized to determine the average AAPC
in cancer incidence and mortality in Five Continents for historical trend analysis. Additionally, data from the
GBD-2019 study were utilized to estimate DALYs from 1990 to 202025. We obtained liver cancer data from
cancer databases using the ICD-10 codes (C22). Supplementary Table 1 provides information on the periods and
countries examined in this study. To enable comparisons among populations with dierent age structures, ASRs
per 100,000 population were calculated by country, gender, and age, employing the world standard population26.
Statistical analysis
We analyzed the data using R soware (version 4.3.1) and the Joinpoint Regression Program (version 5.0.2).
Pearsons correlation analysis was employed to examine the relationship between ASRs and HDI within specic
age groups for liver cancers27. e establishment of statistical models, such as the “Generalized Additive Model
(GAM),” provided a conceptual framework for the study. GAM analysis was implicated in investigating the
correlation between HIV and HBsAg and their impact on incidence. It also explored the correlation between
lifestyle risk factors and either incidence or mortality. GAM demonstrated its advantage in managing complex
nonlinear response relationships and enabling the tting of a single response variable by multiple predictors in
an additive manner2830.
GAM is
g(Y)=ε+n
i=1 si(Xi)
[Y: response variable, X: predictor, n: number of predictors, ε: random error term, si (): nonparametric
smooth function].
Furthermore, cases with undisclosed ages at diagnosis were omitted from the analysis. e mortality-to-
incidence ratio (MIR) was determined by dividing the ASMR by the ASIR serving as a high-level comparative
indicator of inequities in cancer outcomes. is change enhances the precision of our analysis, as the MIR oers a
more robust measure of disease burden and outcome disparities by accounting for both mortality and incidence
rates31. e ASR expressed per 100,000 individuals, was calculated by multiplying the age-specic rate by the
population of the corresponding age subgroup in the selected reference standard population and then dividing
it by the sum of the standard population weights32.
A general formula for the ASR measure can be expressed as:
ASR
=
A
i=1aiwi
A
i=1wi
×100,000
(ai, where ‘i’': the age
class and the number of persons (or weight), wi: in the same age subgroup i of the selected reference standard
population.)
Liver cancer trends were illustrated using AAPCs accompanied by corresponding 95% condence intervals
(CIs)33. AAPC analysis and the Joinpoint linear regression were calculated according to the procedures given by
Clegg LX et al.34 and Murray CJ ET AL (2010)35. In case of missing data or zero values during trend analysis, the
Joinpoint analysis was not executed. p < 0.05 was considered as statistically signicant.
Later, we also provided projections for the expected number of liver cancer cases and deaths worldwide in
2040. is was accomplished by utilizing demographic projections and the global-level incidence and mortality
rates for liver cancer in 2020. e forecasted gures for new cases or deaths were calculated by applying the age-
specic incidence or mortality rates from 2020 to the estimated world population. ese projections assume the
continuity of national rates without signicant changes over the next two decades. Consequently, any variations
in case or death numbers are solely linked to population growth and aging. For showing the impact of changes
in rates on the future primary liver cancer burden, we also predicted number of cases and deaths from seven
scenarios of uniformly increasing or decreasing rates by 3%, 2%, and 1% annually from the baseline year of
2020–2040 by HDI classication.
Results
Liver cancer incidence and mortality rates estimates in 2020 and comparison by HDI
According to the GLOBOCAN estimates, there were 905,000 new liver cancer incidence cases whereas 830,000
deaths worldwide in 2020. Globally, the crude rate and ASIR for liver cancer stood at 11.6 and 5.2 per 100,000
population, respectively. ASIRs of liver cancer pertinent to the males varied to 60-fold, with a range of ASIRs
from 106.0 (Mongolia) to 1.6 (Botswana) for the dierent nations. High-income countries acknowledged a
substantial burden of liver cancer, with the highest incidence rates observed in Eastern Asia (ASIR: 54.3 per
100,000 individuals), with Mongolia having the highest ASIR 85.6 per 100,000 individuals (Table 1).
On a global scale in 2020, crude rate and ASMR were 10.7 and 4.8 per 100,000 individuals, respectively.
e highest mortality rate (ASR, 80.6 per 100,000 individuals) was observed in Mongolia, whereas the lowest
mortality rate (ASR, 1.1 per 100,000 individuals) was observed in Sri Lanka (Fig.1). In various continents or
regions, higher mortality rates were observed in Northern Africa (ASR, 10 per 100,000 individuals), Melanesia
(ASR, 8.9 per 100,000 individuals), and Eastern Asia (ASR, 8 per 100,000 individuals) (Table 1).
Table 1 described estimated liver cancer burden by HDI status. Countries with a high HDI contributed to
60.6% of liver cancer cases and 63.2% of liver cancer related deaths. In contrast, medium and low HDI countries
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were responsible for only 14.7% of liver cancer cases but accounted for 15.4% of liver cancer deaths (Table 1). In
our study, we observed a more than two-fold increase in ASIRs in high HDI countries compared to populations
in countries with a very high HDI. Additionally, ASMRs were nearly three times higher. e correlation analysis
using Pearsons method illustrates the association between case fatality rates of liver cancer and HDI levels,
as shown in Fig. S1. Across all 185 countries, there was an observed decrease in the case fatality rates of liver
cancer with higher HDI levels (R = 0.59, P < 2.2e16). e case fatality rates for high HDI, moderate HDI,
and low HDI are comparable, each around 95%, while the case fatality rate for very high HDI is comparatively
lower (Table 1). Notably, the ASIRs for liver cancer were consistently high, exceeding 70%, across all HDI levels,
ranging from 72.86 to 96.77%.
In terms of global regions, only Australia and New Zealand, as well as North America, exhibited liver cancer
case fatality rates below 70%. In contrast, Africa, Asia, Latin America, and the Caribbean all recorded rates
exceeding 90%. Especially, Melanesia was reported with the highest reported case fatality rate for liver cancer
reaching an extraordinary 100%. e ASRs for liver cancer incidence and mortality were consistently higher
among males when compared to females across all continents and regions, indicating substantial gender
disparities.
e Male: Female ratios for incidence ranged from 1.8 in low HDI countries to 2.8 in high HDI and very
high HDI countries. Similarly, the mortality Male: Female ratios followed the same range. e incidence and
mortality of Micronesia has the largest dierence between men and women, the ASIR of Male: Female ratio is
Continents/regions
Incidence Mortality e
mortality-
to-
incidence
ratio
(MIR)
(%)Cases Proportion (%) Crude
rate ASIR M:F Deaths Proportion (%) Crude
rate ASMR M:F
Wor ld 905,677 100 11.6 5.2 2.7 830,180 100 10.7 4.8 2.7 91.58
Very high HDI 223,321 24.7 14.3 3.8 2.8 178,107 21.5 11.4 2.8 2.8 72.86
High HDI 548,935 60.6 18.9 7.5 2.8 524,307 63.2 18 7.1 2.8 95
Medium HDI 99,994 11 4.3 2.9 2.3 95,859 11.6 4.1 2.7 2.4 95.74
Low HDI 33,097 3.7 3.3 4.4 1.8 31,602 3.8 3.2 4.3 1.8 96.77
Africa 70,542 7.8 5.3 6.1 1.9 66,944 8.1 5 5.9 1.9 96.59
Eastern Africa 12,326 1.4 2.8 3.9 1.6 11,542 1.4 2.6 3.8 1.6 96
Middle Africa 6072 0.7 3.4 3.7 2.4 5716 0.7 3.2 3.6 2.3 96.72
Northern Africa 31,913 3.5 13 10.5 1.9 30,352 3.7 12.3 10 1.9 95.39
Southern Africa 2601 0.3 3.9 3 2.2 2447 0.3 3.6 2.7 2.3 93.48
Western Africa 17,630 1.9 4.4 5.6 2 16,887 2 4.2 5.5 2 96.43
Asia 656,992 72.5 14.2 6.2 2.8 608,898 73.3 13.1 5.7 2.8 92.24
Eastern Asia 491,687 54.3 29.3 8.9 3 449,534 54.1 26.8 8 3.1 90.45
South-Central Asia 54,698 6 2.7 2 2.2 52,769 6.4 2.6 1.9 2 93.33
South-Eastern Asia 99,265 11 14.8 7.1 3 95,668 11.5 14.3 6.7 3.1 96.35
Western Asia 11,342 1.3 4.1 3.3 1.9 10,927 1.3 3.9 3.2 1.9 95.74
Europe 87,630 9.7 11.7 2.8 2.9 78,415 9.4 10.5 2.4 2.8 84.62
Central and Eastern
Europe 24,782 2.7 8.5 2.6 2.6 23,002 2.8 7.9 2.4 2.5 90.70
Northern Europe 11,924 1.3 11.2 3.2 2.1 10,513 1.3 9.9 2.6 2.1 79.59
Southern Europe 24,796 2.7 16.2 3.2 3.3 21,243 2.6 13.8 2.5 3.2 76.12
Western Europe 26,128 2.9 13.3 2.6 3.3 23,657 2.8 12.1 2.3 3 83.33
Northern America 46,599 5.1 12.6 3.7 2.7 34,818 4.2 9.4 2.8 2.4 69.12
Latin America and
the Caribbean 39,495 4.4 6 4 1.5 37,566 4.5 5.7 3.7 1.5 95.83
Central America 11,819 1.3 6.6 5.7 1.2 11,231 1.4 6.3 5.4 1.2 93.65
South America 24,293 2.7 5.6 3.3 1.7 23,153 2.8 5.4 3.2 1.6 95.35
Caribbean 3383 0.4 7.8 4.3 1.6 3182 0.4 7.3 3.9 1.6 90.91
Oceania 4419 0.5 10.4 3.9 2.7 3539 0.4 8.3 3.3 2.3 76.39
Australia and New
Zealand 3344 0.4 11 2.9 3.3 2503 0.3 8.3 2.3 2.7 67.21
Melanesia 933 0.1 8.4 9 1.5 911 0.1 8.2 8.9 1.6 100.88
Polynesia 58 0 8.5 4.2 2.8 55 0 8 4.2 2.5 93.67
Micronesia 84 0 15.3 5.3 4.6 70 0 12.8 5.3 3.6 82.19
Tab le 1. Estimates of liver cancer incidence, mortality rates, and case fatality rates in 2020, with a comparison
based on Human Development Index (HDI) for the nations across dierent continents.
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4.6, and the ASMR of Male: Female ratio is 3.6 (Table 1). No correlation was observed between a country’s HDI
and ASRs for liver cancer incidence or mortality when considering gender dierences (Fig. S2).
HIV prevalence and liver cancer
HIV could potentially contribute to the development of specic types of liver cancer.
However, the connection with this broader category of liver cancer remained uncertain. e correlation
between HIV prevalence in 2020 and the estimated ASIR of liver cancer for both sexes combined was given
(Fig.2). ese estimates of HIV prevalence varied depending on country and region, but a correlation between
a HIV incidence in a country and ASRs for liver cancer incidence was not observed.
Our study employed a generalized additive model to investigate the correlation between ASIRs of liver cancer
and various factors such as HIV and HBsAg. Notably, a nonlinear relationship was observed between HBsAg
and ASIRs. Before the prevalence of HBsAg reached 13, the ASIR of liver cancer demonstrated a signicant
increase with the rise of HBsAg (p < 0.001) (Fig.2). While the direct relationship between HIV and ASIR was
not directly observed, the establishment of a generalized additive model involving HBsAg and HIV revealed an
upward trend in HBsAg as HIV increased before the HIV prevalence reached 1 (p < 0.001) (Fig. 3). Applying
the same model to explore the connection between the incidence and mortality of liver cancer and lifestyle risk
factors by genders, we found that obesity and insucient physical activity had a reverse impact on the ASIR
and ASMR of liver cancer. Additionally, there was a positive linear relationship between obesity and insucient
Fig. 1. Liver cancer-related incidence and mortality rates estimates in 2020 for dierent age groups among
males or females. (A) Age-standardized incidence rates (ASIR) and (B) Age-standardized mortality rates
(ASMR).
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physical activity. Smoking exhibited dierential eects on liver cancer incidence and mortality in men and
women (Figs. S3S6).
Global incidence trends of liver cancer and HDI
Liver cancer in the elderly imposes a considerable disease burden, with the highest incidence occurring at the
age of 60 or older, making a signicant contribution to the overall incidence. e study observed relatively stable
truncated ASIRs36 of liver cancer in 25 out of 45 countries, while they exhibited signicant uctuations in 10
countries, notably Uganda. In the United States, truncated ASIRs among individuals younger than 60years old
were increasing, while those among individuals older than 60years old were decreasing (Fig. S7). In the male
population, incidence increased in 32 countries, with AAPCs ranging from 0.3 to 7.7, as illustrated in Fig.4A.
Out of the 32 countries with increasing trends, especially in Northern Europe, Iceland (AAPC, 7.7 [95% CI 3.9–
11.6]) and Ireland (AAPC, 6.1 [95% CI 4.3–8.0]) reported with a higher rate of incidence. In contrast, among
countries with decreasing trends, the AAPCs for liver cancer incidence were decreased in Southern Europe,
South America, and Asia. Particularly, Japan (AAPC, 3.5 [95% CI 3.9 to 3.0]), Chile (AAPC, 2.1 [95%CI
7.2 to 3.6]), and China (AAPC, 2.4 [95% CI 2.9 to 1.9]) exhibited a downward trend of higher than 2%.
In case of women (Fig.4B), in Iceland, Ireland and Australia, the ASIRs have enhanced by 5.3%, 5.0%, and
4.1%, respectively on annual basis. Among the 41 countries, these three nations observed the most substantial
growth rates. In gender-specic subgroups, there were more countries exhibiting a declining trend for women
than for men.
Liver cancer incidence rates have increased among the nations with high ASIRs; a notable increase was
observed in the nations with the lowest ASIRs, mainly among the individuals aged older than 60years (Fig.5).
e association between ASIR and the HDI was not clearly delineated, as similar ASIRs were observed in both
low and high HDI countries. However, as the ASIR increased in 1998, highly developed nations exhibited a
convergence around an AAPC of 2.5% for individuals under the age of 60. is indicates that despite variations
in HDI, the trend in ASIR among developed countries showed a consistent increase in younger populations.
e incidence of liver cancer showed an increase in 38 populations (AAPCs, 0.1–6.2) among individuals
under the age of 60. Substantial rise in the morbidity rates were observed in ailand (AAPC, 6.2 [95% CI
Fig. 3. While a direct relationship between HIV and ASIR was not directly observed, the creation of a
generalized additive model (GAM) incorporating HBsAg and HIV described an increasing trend in HBsAg as
HIV prevalence increased, up to the point where HIV prevalence reached 1.
Fig. 2. Signicantly, a nonlinear correlation was observed between HBsAg and ASIRs. e ASIR of liver
cancer exhibited a notable increasing trend with the increase in HBsAg prevalence until it reached 13.
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4.5–7.8]), Slovenia (AAPC, 4.5 [95% CI 2.8–6.2]), and South Korea (AAPC, 4.4 [95% CI 4.0–6.9]). A similar
trend was observed for the individuals older than 60, as ASIRs increased in 24 countries (AAPCs, 0.2–6.6).
Furthermore, a notable increase was observed in Bahrain (AAPC, 6.6 [95% CI 2.6–10.8]), Ecuador (AAPC, 5.4
[95% CI 2.3–8.5]), and ailand (AAPC, 4.2 [95% CI 2.3–6.1]) (Fig.5).
In individuals under 75years of age, signicant increases in liver cancer incidence were observed in 30
populations. e most pronounced rises were recorded in ailand (AAPC: 5.6 [95% CI 4.4–6.9]), Turkey
(AAPC: 5.3 [95% CI 2.9–7.8]), and South Korea (AAPC: 4.3 [95% CI 3.2–5.5]) (Fig. S9). Additionally,
approximately one-third of the countries showed increasing ASIRs over a 15-year period in the subgroup of
patients aged 75years or older (Fig. S9).
Global mortality trends of liver cancer
In various age groups, mortality rates have generally been decreasing across most continents and regions, with
the exception of northern Europe and western Europe, where rates have increased in the recent years. e
United Kingdom and Canada were reported to be with the higher mortality rates in Europe and America,
respectively. e ASMRs for liver cancer exhibited a signicant downward trend (AAPC, 10.9 [95% CI 17.0
to 4.3]) among the individuals aged 60 and older in Bahrain. While there was an overall increase in rates for
female patients in several regions, over half of the countries reported a decreasing AAPC of ASMRs, with decline
ranging from 0.2 to 4.5% (Fig.6).
e AAPC of ASMRs increased for individuals under 75years of age and decreased for those aged 75years
and older for certain countries such as Chile, Turkey, and Sweden (Fig. S8). In conclusion, the percentage change
in the ASMR diered signicantly among the nations, but the disparities between age groups are not as obvious
as those between gender groups (Fig. S10).
Global trends of age-standardized DALY rates, the percent of DALYs of liver cancer and
burden attributable to smoking, alcohol use and high BMI
In 2019, liver cancer contributed to a global age-standardized DALYs rate of 161.92, accompanied by the 23%
reduction when compared to the rate recorded in 1990. During this period, age-standardized DALYs have
increased in many regions, include North America, Western Europe, North Africa and Middle East nations. Age-
standardized DALYs have stabilized in specic regions, including South Asia, Latin America, and the Caribbean.
Fig. 4. (A) Among the male population, liver cancer incidence surged in 32 countries, with Average Annual
Percent Changes (AAPCs) spanning from 0.3 to 7.7. (B)In the case of women in Iceland, Ireland, and
Australia, the age-standardized incidence rates (ASIRs) demonstrated annual increases of 5.3%, 5.0%, and
4.1%, respectively. In gender-specic subgroups, more countries exhibited a downward trend for women than
for men.
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e incidence of liver cancer increased annually until 1996 subsequently decreased annually; thereaer, a
signicant decline in age-standardized DALY rates were remarkably decreased by 46% between 1996 and 2019.
In 2019, approximately 46.3% of liver cancer-related DALYs in both sexes were linked to hepatitis B globally,
whereas 23% to hepatitis C, 17.4% to alcohol use, 6.4% to non-alcoholic steatohepatitis (NASH), and 7% to other
causes. Among men, liver cancer DALYs in most regions were primarily attributable to hepatitis B and alcohol
use, while almost were attributed to C for women except for Sub-Saharan Africa, Southeast Asia, East Asia, and
Oceania, which were attributed to hepatitis B. High-income Asia Pacic was associated with a higher liver cancer
DALYs which reached to 491.4% (Figs.7A–B and 8A).
On a global scale, smoking, alcohol use, and high body-mass index were signicant contributors to age-
standardized DALYs, accounting for proportions of 16.96%, 19%, and 12.88%, respectively. ese contributions
were typically higher in males when compared to females, particularly for smoking and alcohol use (Fig.8B).
e highest proportion of age-standardized DALYs (24.02%) was evident in the high-income North America
because of increased body-mass index. ese ndings align with previously identied risk factors linked to
morbidity and mortality.
Future global liver cancer burden in 2040
Assuming that ASIR in 2020 remains unchanged, the anticipated global number of new liver cancer cases is
expected to increase from around 905,347 to an estimated 1,392,474 by 2040, reecting a corresponding growth
of 53.8% over a span of 20years. Nations or regions in transitional economies with low HDI exhibit heightened
vulnerability, with a signicant surge of 101% in both incidence and mortality from 2020 to 2040 (Fig.9A–B).
High HDI countries are expected to undergo a substantial rise of 150.2% in both incidence and mortality by
2040 among the individuals aged 75years and older, based on global rates estimated in 2020 (Fig.9C–D). In
addition to the demographic shis inuencing the population base, we also considered the impact of risk factors
on the changes in ASRs. Our predictions encompassed seven scenarios, each representing annual changes in
ASRs ranging from 3% to + 3%. In low HDI countries, all scenarios indicated a potential increase in the annual
number of liver cancer cases and deaths by 2040. Notably, the dierence between the predicted new cases and
deaths of liver cancer by 2040 was minimal, particularly in low and medium HDI countries. is suggests a
consistent rise in both incidence and mortality regardless of the specic scenario. ese ndings elucidate the
signicant burden of liver cancer expected in low and medium HDI countries, driven by both population growth
and increased exposure to risk factors. e projected trends highlight the urgent need for targeted public health
Fig. 5. (A, B)Liver cancer incidence rates have risen in nations with high age-standardized incidence rates
(ASIRs), and a signicant increase has been observed in nations with the lowest ASIRs, particularly among
individuals aged over 60years.
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interventions and policies aimed at mitigating risk factors and improving cancer outcomes in these vulnerable
regions (Fig.10).
Discussion
Epidemiology of liver cancer pertinent to incidence and mortality are the signicant factors for prediction,
diagnosis, and treatment. Liver cancer and related diseases pose signicant global health challenges. While organ
transplantation, surgical resection, and anticancer drugs are considered as the primary treatment strategies, the
absence of donor livers and tumor heterogeneity hinders the signicant therapeutic modalities to ameliorate
liver cancer. Recently, there has been signicant advancements of tumor organoid technology, which can
replicate the spatial constructs and pathophysiological characteristics of tumorigenesis3739. Signicant ndings
of this report. (1) the geographical distribution of liver cancer burden dierent signicantly, with increased
case fatality rate in the nations with lower HDI. Regions characterized by a high HDI, especially Eastern Asia,
contribute signicantly to the global morbidity and mortality associated with liver cancer (Table 1). (2) AAPC
of Incidence rates are higher among the younger populations and adults of Northern Europe and Asia (Fig.5).
(3) Liver cancer DALYs in most regions were mainly attributed to hepatitis B and alcohol use for men, while
hepatitis C was the primary contributor for women. Notably, alcohol intake had a greater impact on DALYs
compared to smoking and a high body-mass index (Fig.7). (4) e projected estimate indicates a nearly 50%
rise in the number of new liver cancer cases over a span of 2 decades assuming the incidence rate was unchanged
and there was not much dierence between the predicted new cases and deaths of liver cancer by 2040 especially
in low and medium HDI countries (Fig.8). Our study results were still somewhat dierent from the incidence
and mortality trends in GBD studies in some countries and regions, mainly because of variations in data sources
and estimation methods. Although there is reduction in age-standardized DALY rates compared to 1990, age-
standardized DALYs have been gradually increasing in recent years across almost all regions, except for South
Africa. is is attributed to alterations in the age structures and population growth, resulting in a continued rise
in liver cancer cases and deaths in many areas40,41.
In certain geographical regions, there was a notable increase in age-standardized death rates, even as ASIRs
decreased. Specically, during the study period, ASIRs decreased in Western Europe and North America for
individuals aged 75years or older. However, there was a concurrent increase in age-standardized mortality
and attributable DALY rates. is kind of patterns are due to the slow decline in incidence rates and recurrent
renement of disease prediction measures such as vaccination of hepatitis virus.
Fig. 6. (A, B)e age-standardized mortality rates (ASMRs) for liver cancer showed a signicant decline
(AAPC, 10.9 [95% CI 17.0 to 4.3]) among the individuals aged 60 and older in Bahrain. Although there
was a general increase in rates for female patients in various regions, more than half of the countries reported a
decreasing AAPC of ASMRs, with decline ranging from 0.2 to 4.5%.
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Fig. 7. (A, B) Among men, liver cancer Disability-Adjusted Life Years (DALYs) in most regions were primarily
linked to hepatitis B and alcohol use, while almost all were attributed to hepatitis C for women, except for
Sub-Saharan Africa, Southeast Asia, East Asia, and Oceania, where hepatitis B played a signicant role. High-
income Asia Pacic showed a higher prevalence of liver cancer DALYs, reaching 491.4%. Globally, smoking,
alcohol use, and high body-mass index were major contributors to age-standardized DALYs, constituting
proportions of 16.96%, 19%, and 12.88%, respectively. ese contributions were generally higher in males
compared to females, particularly for smoking and alcohol use.
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Fig. 8. (A, B) Estimated number of new liver cancer cases and deaths from 2020 to 2040. Predicted number of
new liver cancer cases and deaths by HDI classication, assuming seven scenarios of annual change in global
rates between 2020 and 2040, for both sexes and all age groups (0–85+). Countries or regions with low HDI are
projected to experience a signicant increase of 101% in both incidence and mortality pertinent to liver cancer
from 2020 to 2040, highlighting their increased vulnerability. Conversely, high HDI countries are expected to
see a substantial increase of 150.2% in both incidence and mortality among individuals aged 75years and older
by 2040, based on GLOBOCAN global rates estimated in 2020.
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Liver cancer treatment strategies are primarily determined by the stage of the disease and the liver’s functional
status. Early-stage HCC can oen be treated with curative intent through surgical resection, liver transplantation,
and/or ablation. In contrast, intermediate-stage disease may necessitate additional treatment modalities such
as embolization and/or radiation therapy. Systemic therapy, encompassing chemotherapy, molecular targeted
therapy, immunotherapy, and gene therapy, remains the cornerstone of treatment for patients with intermediate
or advanced-stage HCC42,43. Since 2012, there has been rapid progress in the eld of articial intelligence (AI).
e most appropriate technical approaches within the various sub-elds of AI research have been the subject of
intense debate for decades44. e application of AI in the management of primary liver cancer is a burgeoning
area of research, driven by numerous unmet clinical needs and the complexity of clinical decision-making.
Potential AI applications include diagnostic automation, patient stratication, biomarker development, and
drug development. e landscape of systemic therapy for both HCC and intrahepatic cholangiocarcinoma has
undergone signicant changes in recent years, with high expectations for improved prediction of responses
to systemic treatment45. Certain geographical areas have demonstrated advancements in the treatment and
management of liver cancer. In these regions, individuals diagnosed with liver cancer may undergo more eective
treatment and monitoring measures, particularly in developed countries. ese interventions could promote the
overall survival rates of patients diagnosed with liver cancer. Despite a decrease in the incidence rate, mortality
and the increase in the DALYs is due to the prolonged overall survival of liver cancer patients. Additionally,
hepatitis B virus could be a major risk factor for liver cancer. Albeit HBV vaccination during early neonatal
period is recommended in several nations, vaccine coverage yet remains less than 70% in several nations across
the African continent, where the incidence rates of HCC continue to be high46. Certain individuals infected
with the hepatitis B virus may die due to other causes before liver cancer progresses to advanced stages, leading
to increased mortality and DALYs. Furthermore, despite advancements in liver cancer diagnosis and treatment
increasing the likelihood of curing the disease at early stages, a majority of patients experience relapses and
Fig. 9. (AD) In case of ASIR during 2020 remains unchanged, the future projections of liver cancer cancers
is anticipated to enhanced in both sexes; mainly, the regions in transitional economies with minimal HDI
resulted in a higher vulnerability, accompanied by the typical raise of 101% in both incidence as well as
mortality from the period of 2020 to 2040. In case of nations with high HDI are expected to be associated with
a greater enhancement in both incidence and morality by 2040 typically among the individuals of age greater
than 75 years depending on global rates estimated in 2020.
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eventually succumb to other illnesses47. erefore, even if the incidence rate is reduced, a higher mortality and
DALYs due to the poor treatment ecacy.
Another signicant risk factor for the incidence of liver cancer was HBV infection and the positive correlation
between HIV infection and the incidence of liver cancer was not observed; but HIV infection rate increased
in the specic concentrated area, which accompanied by an increase in HBV infection. However, the direct
Fig. 10. Projected trends of liver cancer incidence and mortality by 2040 depending on the low HDI, medium
HDI, high HDI and very high HDI and the projection predictions are encompassed in the range of each
representing annual changes in ASRs ranging from 3% to + 3%.
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correlation between HIV infection prevalence and the incidence of liver cancer remained unclear. HIV-induced
immune impairment could enhance the risk of getting chronic viral hepatitis, which could enhance HBV or
HCV load, consequently cause progression to cirrhosis and liver cancer37.
e present report investigated association of preventable risk factors with the incidence and mortality of
liver cancer by genders, including obesity, alcohol, insucient physical activity, non-HDL cholesterol, raised
fasting blood glucose, smoking. Among these risk factors, nations with individuals characterized by higher levels
of alcohol consumption, non-HDL cholesterol, and elevated fasting blood glucose are anticipated to exhibit
higher incidence and mortality rates of liver cancer. Additionally, there is a gender disparity in the impact of
smoking on liver cancer, with variations between men and women. However, ASIRs and ASMRs of liver cancer
are observed in the regions where individuals associated with low obesity rates and insucient physical activity.
Furthermore, there is a positive correlation between these two risk factors.
Previous research has described a positive relationship between obesity and the incidence rate of liver cancer.
Obesity and diabetes are signicant risk factors for metabolic dysfunction-associated steatotic liver disease
(MASLD), formerly known as non-alcoholic fatty liver disease, and these conditions have been independently
associated with an increased risk of cholangiocarcinoma48,49. However, our study elucidated a more nuanced
perspective by highlighting the role of confounding factors, such as healthcare levels and socio-economic status,
which may lead to varying relationships between obesity and liver cancer incidence. Furthermore, our study
reveals that in countries and regions with lower HDI scores, obesity rates are generally lower compared to those
in higher HDI regions. is discrepancy highlights the complex interplay between socio-economic factors
and health outcomes. Notably, in low-HDI countries, the incidence of liver cancer is more strongly associated
with viral hepatitis infections, such as hepatitis B and C, long-term alcohol consumption, cirrhosis, genetic
predispositions, and environmental carcinogens4850.
Our study lies in its comprehensive analysis of these multifactorial inuences. We described how dierent
risk factors contribute to liver cancer incidence in diverse socio-economic contexts. By incorporating data
from various countries and regions with diering HDI levels, we provide a more detailed understanding of
how socio-economic status inuences the prevalence of liver cancer risk factors. is approach allows us to
identify the highest contributing factors in each context, such as the prominent role of viral hepatitis in low-HDI
regions. In lower HDI countries, healthcare interventions focusing on viral hepatitis prevention and treatment
could be more eective, while higher HDI regions might benet from addressing obesity and metabolic health.
is targeted approach enhances the potential for reducing liver cancer incidence globally by addressing the
most relevant risk factors in each specic context. Overall, our study oers a novel perspective by integrating
socio-economic dimensions into the analysis of liver cancer risk factors. is comprehensive approach not only
advances our understanding of the disease but also provides actionable insights for developing targeted public
health interventions.
So these factors eected the results in the study.
erefore, obesity is a signicant health problem that aects several individuals in several nations around
the world especially those with high HDI51. Improved liver cancer screening ad early diagnosis measures, good
vaccination eorts, and good public health awareness, restrictions on alcohol consumption, and preventive
measures to limit occupational exposure to carcinogens in the high HDI nations could enhance the overall
survival of patients diagnosed with obesity-mediated liver cancer.
In a previous study by Harriet et al.52 it was found that the ASRs of both incidence and mortality for liver
cancer were higher in males than females across all world regions, with male-to-female ASR ratios ranging from
1.2 to 3.6. e study projected a signicant increase in liver cancer cases, predicting a 55.0% rise from 2020
to 2040, potentially reaching 1.4 million new cases annually by 2040. Our study builds on this foundation by
providing a more nuanced and comprehensive analysis of liver cancer rates. We compared the ASIR and ASMR
of liver cancer using data from multiple sources, including GLOBOCAN 2020, CI5plus, the WHO mortality
database, and the GBD-2019 database. is multi-dimensional approach allowed us to explore the trends in
liver cancer incidence and mortality across dierent regions and demographic groups worldwide. Our ndings
reveal signicant trends in liver cancer rates. For instance, we observed an AAPC in incidence rates of 7.7
(95% CI 3.9–11.6) among men and a typically high AAPC in mortality rates of 12.2 (95% CI 9.5–15.0) among
women. ese gures indicate a sharper rise in liver cancer mortality among women compared to previous
studies. Additionally, we identied Western Europe as a high-risk region for DALYs related to smoking and
alcohol consumption in 2019. In contrast, high-income North America showed a high risk for DALYs associated
with a high body-mass index. Our projections also suggest a substantial increase in new liver cancer cases,
rising from approximately 905,347 in 2020 to an estimated 1,392,474 by 2040. e signicance of our study lies
in its comprehensive analysis and identication of specic regional risks and trends, which provide a deeper
understanding of the factors contributing to liver cancer. is detailed insight is crucial for developing targeted
interventions and policies to address the rising burden of liver cancer globally.
Our study includes limitations. For instance, the comparative studies of data sources from GLOBOCAN
related to dierent geographical regions excludes the nations with limited population-based high-quality cancer
registries and low HDI. Even though the usage of these databases, could introduce a few statistical variations, the
overreaching trend remains consistent. Furthermore, the extensive data collection and precise morphological
subtypes analysis, age, ethnicity, and stage at the diagnosis of liver cancer are imperative to identify potential
survival dierences in large cohorts. Moreover, it is crucial to acknowledge that data quality dierent among
dierent nations, particularly in several low- and middle-income nations conned to the sub-Saharan Africa,
where low-quality data may result in signicant uncertainties into the estimates.
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Data availability
e datasets generated and/or analysed during the current study are available in the GLOBOCAN 2020 [ h t t p s :
/ / g c o . i a r c . f r / t o d a y / d a t a / f a c t s h e e t s / p o p u l a t i o n s / 9 0 0 - w o r l d - f a c t - s h e e t s . p d f ] , CI5 volumes I–XI, WHO mortality
database, and Global Burden of Disease (GBD)-2019 repository [https://gco.iarc.fr/].
Received: 6 January 2024; Accepted: 24 October 2024
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Acknowledgements
Authors thank the supporting sta of the cancer center, e First aliated hospital of Zhengzhou University
Author contributions
Qianqian Guo (QG), Xiaorong Zhu (XZ), Narasimha M. Beeraka (NMB), Ruiwen Zhao (RZ), Siting Li (SL),
Fengying Li (FL), Padukudru Anand Mahesh (PAM), Vladimir N Nikolenko (VNN), Ruitai Fan (RF), Junqi Liu
(JL) designed the concept and RF, JL, NMB analyzed gures, study design, data collection, data analysis, data in-
terpretation, writing the manuscript; JL, PAM, NMB, RF, performed study design, data collection, data analysis,
data interpretation, writing, proofread, edited and analyzed the content of the article. All authors reviewed the
manuscript and approved it before submission.
Funding
is study was supported by the Henan Natural Science Foundation of China (222300420534). e funder has
no role, if any, in the writing of the manuscript or the decision to submit it for publication.
Declarations
Competing interests
e authors declare no competing interests.
Ethics approval
is study does not involve any animal or human experimental models. Hence, ethical approval is not
required.
Consent for publication
Not applicable.
Additional information
Supplementary Information e online version contains supplementary material available at h t t p s : / / d o i . o r g / 1
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