Worldwide burden of liver cancer across middle-aged and elderly people, 1990-2021: a decomposition, cross-country inequality and frontier analysis

Worldwide burden of liver cancer across middle-aged and elderly people, 1990-2021: a decomposition, cross-country inequality and frontier analysis | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Worldwide burden of liver cancer across middle-aged and elderly people, 1990-2021: a decomposition, cross-country inequality and frontier analysis Weifan Sui, Yuxin Duan, Zefeng Cai, Yimao Xia, Jianyun Li, Jianhua Fu This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-5913454/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective Liver cancer is a significant contributor to the global disease burden. we first provide estimates of the worldwide burden of liver cancer from 2000 to 2021 in middle-aged and elderly people with decomposition, cross-country inequality and frontier analysis. Methods The age-standardized rate (ASR) and estimated annual percentage change (EAPC) were utilized for measuring prevalence, incidence, deaths and disability-adjusted life years (DALYs) rate trends. Decomposition, cross country inequalities and frontier analysis to estimate the burden. Results In 2021, the number of liver cancer prevalence and the incidence was increased compared to 1990, while the number of deaths and DALYs slightly decreased. The burden of liver cancer was higher in males than in females. Population growth led to an increase in the burden. Aging and epidemiological changes made significant contributions to the reduction of the liver cancer burden. There was a V-shaped relationship between the DALYs rate and SDI regions. There was a significant absolute inequality across countries. 15 countries and regions had considerable potential for improvement in reducing the burden . Conclusion This study reveals the complex dynamic changes in the global burden of liver cancer across middle-aged and elderly people. In the future, it is necessary to strengthen international cooperation, promote the fair distribution of medical resources, and formulate and implement differentiated strategies. liver cancer global burden disease disability-adjusted life years incidence prevalence Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Figure 6 Figure 7 Figure 8 Introduction Primary liver cancer (PLA), the third most common cause of cancer-related mortality globally in 2020[ 1 ], encompasses three distinct pathological entities: Hepatocellular carcinoma (HCC), Intrahepatic cholangiocarcinoma (ICC), and Combined hepatocellular-cholangio carcinoma. These subtypes exhibit significant differences in their etiology, biological characteristics, histological features, therapeutic approaches, and prognoses. HCC predominates, constituting 75–85% of cases, followed by ICC, which accounts for 10–15%[ 2 ]. Risk factors for PLA encompass chronic infections with HBV, HCV, and HIV, as well as lifestyle factors such as excessive alcohol intake, smoking, liver flukes, aflatoxin exposure through contaminated food, and conditions like diabetes, obesity, and non-alcoholic fatty liver disease[ 3 – 5 ]. The geographical variability in incidence, prevalence, mortality, and risk factors contributes to the uneven distribution of PLA's impact worldwide[ 6 , 7 ]. Our review of the literature indicates that previous studies on PLA have often concentrated on specific etiologies like HBV and HCV infections or alcohol consumption, or they have been confined to single countries or regions, and have not captured temporal trends over a single year[ 6 , 8 – 10 ]. No study to date has conducted diverse comprehensive analysis of the worldwide burden of liver cancer, including decomposition of disease burden drivers, cross-country inequality, and frontier analysis. Decomposition analysis helps to elucidate the key factors contributing to changes in disease burden[ 11 ]. Cross-country inequality analysis, utilizing tools like the slope index of inequality (SII) and concentration index, assesses disparities in health outcomes between nations[ 12 ]. Frontier analysis estimates the potential for optimal health outcomes based on socio-demographic index (SDI) levels[ 13 ]. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides an opportunity to delve into the nuances of liver cancer's impact on the middle-aged and elderly. Unlike previous studies, the GBD categorizes age into 5-year intervals and examines the long-term effects of specific etiologies across various countries and regions. In this study, leveraging data from GBD 2021, we employ diverse methodologies to explore the multifaceted burden of liver cancer among middle-aged and elderly individuals from 1990 to 2021. Methods Data source Our study draws on data from the Global Burden of Disease (GBD) 2021, a meticulous and extensive initiative that estimates the impact of 371 diseases and 88 risk factors across 204 nations and territories. The dateset includes annual incidence and mortality rates of liver cancer, standardized by age, and spans from 2010 to 2021. It is stratified by gender, age, geographical region, and country. These figures were sourced from the Global Health Data Exchange (GHDx), an online repository managed by the Institute for Health Metrics and Evaluation (IHME). Access to the GHDx can be found at http://ghdx.healthdata.org/ . For our analysis, we had chosen disability-adjusted life years (DALYs) data from GBD 2021 as the primary metric. DALYs, which amalgamate years lived with disability (YLDs) and years of life lost (YLLs), offered a holistic view of disease burden by accounting for premature mortality and diminished quality of life. This metric wass instrumental for comparing various health conditions and populations, thus serving as a benchmark for health disparities. Furthermore, we had incorporated the Socio-demographic Index (SDI) as a gauge of societal development. The SDI was a composite index derived from the geometric mean of three normalized indicators: fertility rates among those under 25, average years of education for individuals 15 and older, and income per capita on a lag-distributed basis. This index, calculated nationally, provides an accurate reflection of the social development statues across different countries and territories[ 14 ]. Based on SDI values, the 204 countries and territories in GBD 2021 were categorized into five developmental tiers, scaling from low to high. The SDI ranges from 0 to 1, with higher values signifying a higher socioeconomic status. To maintain precision and clarity, we had rounded the SDI threshold values for classification. The nations and territories are thus grouped into development levels using the following SDI thresholds: low SDI [0–0.4658), low-middle SDI [0.4658–0.6188), middle SDI [0.6188–0.7120), high-middle SDI [0.7120–0.8103), and high SDI [0.8103–1.0000]. This stratification facilitated a more methodical examination of how varying levels of socioeconomic development influenced health outcomes. Cross-country inequality analysis These indices were instrumental in quantifying the disparities in liver cancer distribution across various countries and territories, providing an in-depth assessment of health inequalities. The Slope Index of Inequality (SII) was derived by regressing the DALYs rate against the Socio-demographic Index (SDI), utilizing the midpoint of the cumulative population distribution, which was sorted by SDI. This method allowed for a detailed examination of health inequality changes by comparing data from 204 countries and territories over the period from 1990 to 2021. To enhance the control over bias and heterogeneity in our analysis, we employed a robust regression model (rlm) for the health inequality analysis. This model was less sensitive to outliers, thereby reducing the bias that could be introduced by data heterogeneity or extreme values. As a result, it provided a more accurate depiction of health inequality. Furthermore, the Concentration Index was calculated by aligning the cumulative proportion of DALYs with the cumulative population distribution, ranked by SDI, and numerically integrating the area under the Lorenz curve. Decomposition Analysis In this study, we employed decomposition analysis to elucidate the intricate interplay of factors contributing to the burden of liver cancer. This analytical approached dissects the variations in disease-related mortality and disability-adjusted life years (DALYs) into components attributable to population aging, population growth, and epidemiological shifts. The decomposition analysis yielded both the absolute and relative contributions of each factor to the alterations in disease-related deaths or DALYs. By leveraging decomposition techniques, we were able to isolate the impacts of demographic changes on incidence and mortality rates. This isolation provided valuable insights into the fundamental drivers behind the observed trends in liver cancer burden. Frontier analysis This study utilized frontier analysis to develop an age-standardized DALYs rate (ASDR)-based frontier model, leveraging the Socio-demographic Index (SDI) to evaluate the correlation between liver cancer burden and sociodemographic development levels. Frontier analysis was designed to ascertain the theoretical minimum ASDR that each country or territory could achieve, given its current development status, thus establishing a benchmark for optimal health outcomes.This methodology quantified the disparity between a country’s or territory’s actual liver cancer burden and its potential minimum burden, pinpointing areas for potential improvement. To generate smooth frontier lines that capture the non-linear relationship between SDI and ASDR, we employed locally weighted regression (LOESS) in conjunction with local polynomial regression, utilizing varying smoothing spans of 0.3, 0.4, and 0.5. To reinforce the robustness of our analysis, we executed 1000 bootstrap samples and computed the average ASDR for each SDI value. By calculating the absolute distance between each country’s or territory’s 2021 ASDR and the frontier line, we were able to gauge the improvement potential for each country or territory. Statistics To evaluate the burden of liver cancer, we utilized both the rate and the count of disability-adjusted life years (DALYs). The DALYs rate, expressed as estimates per 100,000 individuals, provided a relative measure of the disease burden, while the number of cases offered an absolute measure, reflecting the total burden in terms of incident cases. Each metric was accompanied by its 95% uncertainty intervals (UI), which were crucial for understanding the precision of our estimates. All analyses were performed using statistically sound models, with a p-value threshold of less than 0.05 indicating statistical significance. Comprehensive descriptions of the specific methodologies employed, including the slope index of inequality, concentration index, frontier analysis, and decomposition analysis, were detailed in subsequent sections of our study. For the execution of all analyses and the generation of visualizations, we relied on the World Health Organization’s Health Equity Assessment Toolkit and R Software (version 4.3.2), ensuring that our methods were both rigorous and in line with established health equity assessment practices. Results Global level Globally, in 2021, the prevalent number of liver cancer was 739299.54 (95% UI 673114.25, 821948.24), with age standardized prevalence rate of 26.33 (95% UI 23.26, 29.73) per 100000, an increase of 0.72 (0.53, 0.90) since 1990. The incident number of liver cancer was 529202.46 (95% UI 480339.46, 593849.10), with age standardized incidence rate of 20.33 (95% UI 17.96, 22.89) per 100000, an increase of 0.20 (95% UI 0.09, 0.33) since 1990. The deaths number of liver cancer was 483875.13 (95% UI 440400.32, 540177.12), with age standardized rate of 18.98 (95% UI 16.78, 21.33) per 100000, a decrease of 0.05 (95% UI -0.17, 0.08) since 1990. The DALYs of liver cancer was 12887652.41 (95% UI 11673532.55, 4472227.99), with age standardized rate of 451.26 (95% UI 400.35, 511.09) per 100000, a decrease of 0.31 (95% UI -0.430, -0.191) since 1990 (Table s1 ). Among five developmental tiers, the highest prevalent number of liver cancer was 235057.51 (95% UI 213883.81, 249189.79) in High SDI region since 1990, with age standardized prevalence rate of 39.62 (95% UI 35.23, 43.69) per 100000, a decrease of 0.50 (95% UI -0.751, -0.245). The highest incident, deaths and DALYs number of liver cancer were 160138.35 (95% UI 134420.32, 193407.02), 151642.25 (95% UI 128320.31, 181621.80) and 3925890.51 (95% UI 3305552.18, 4742009.53) respectively, in Middle SDI region since 1990, with age standardized incidence rate of 21.31 (95% UI 17.90, 25.69), 20.59 (95% UI 17.42, 24.61) and 504.57 (95% UI 425.14, 608.19)per 100000, respectively. An increased of 0.13 (95% UI 0.00, 0.25) of incidence rate occurred in Middle SDI since 1990. A decreased of 0.20 (95% UI -0.31, -0.08) and 0.37 (95% UI -0.31, -0.25) of deaths and DALYs rate occurred in Middle SDI since 1990 (Table s1 , Fig. 1 ). In 2021, the global prevalent, incident and deaths number of liver cancer started to increase in 45–49 years group and peaked in 65–69 years group, then decreased with increasing age both in men and women. The global DALYs of liver cancer started to increase in 45–49 years group and peaked in 55–59 years group, then decreased with increasing age in men, but peaked in 65–69 group in women. The numbers of prevalent, incident, deaths and DALYs cases of liver cancer were higher in men from 45–49 years group to 85–89 years group expect 90–94 years group and 95 + years group in women. The prevalence, incidence rate of liver cancer started to increase in 45–49 years group and peaked in 85–89 years group, then decreased with increasing age both in men and women. The deaths and DALYs rate of liver cancer started to increase in 45–49 years group and peaked in 90–94 years and 65–69 years group, respectively, then decreased with increasing age in men. Whereas for women, the deaths and DALY rate increased up to the oldest age group (95 + years) (Fig. 2 ). Regional level In 2021, among 21 regions, the highest prevalent, incident, deaths and DALYs number of liver cancer were 275114.25 (95% UI 222236.65, 340133.39 ), 203596.96 (95% UI 165109.85, 250430.69), 178494.83(95% UI 145380.74, 218906.75) and 5063799.90 (95% UI 4074239.52, 6285122.10) in East Asia, respectively. The highest age standardized prevalence, incidence and deaths of rates were 85.27 (95% UI 68.83, 103.00), 44.10 (95% UI 36.64, 51.81) and 32.60 (95% UI 27.27, 37.67) per 100000, respectively, in High-income Asia Pacific since 1990. The highest age standardized DALYs rate was 735.85 (95% UI 594.17, 895.07) per 100000, respectively, in Western Sub-Saharan Africa since 1990. An increase of 0.57 (95% UI 0.43, 0.71) of prevalence rate occurred in East Asia since 1990. A decrease of 0.02 (95% UI -0.16, 0.11), 0.51 (95% UI -0.66, -0.36) and 0.75 (95% UI -0.90, -0.59) of incidence, deaths and DALYs rate occurred in East Asia since 1990, respectively (Table s1 ). We found approximate V shaped association between the SDI and the age standardized DALY rate of liver cancer (r=-0.1648, p = 0.00001802), from 1990 to 2021. The age standardized prevalence, incidence deaths and DALY rate decreased exponentially with increases in SDI, down to a SDI of about 0.7, before increasing again. High-income Asia Pacific, East Asia,Central Asia, Southeast Asia, Western Sub − Saharan Africa, Southern Sub − Saharan Africa had higher than expected DALY rates. In contrast, High − Income North America, Western Europe, Oceania, Australasia, Andean Latin America, Tropical Latin America, Central Latin America, Southern Latin America, Caribbean, Central Europe, Eastern Europe, Central Asia and South Asia had lower than expected DALY rates (Fig. 3 ). In 2021, among 21 regions, the prevalence, incidence deaths and DALYs rates of liver cancer in men were all higher than in women. High-income Asia Pacific had the highest prevalence rate both in men and women. High-income Asia Pacific had the highest incidence, deaths and DALYs rates in men. Western Sub-Saharan Africa had the highest incidence deaths and DALYs rates in women(Figure s1 ). National level In 2021, among 204 nations, Mongolia (252.77 [95% UI 179.92, 339.30]), Republic of Korea (126.62 [95% UI 87.80, 175.48]) and Gambia (105.60 [95% UI 57.68, 172.91]) had the highest age standardized prevalence rate of liver cancer. In contrast, Morocco (1.77 [95% UI 1.06, 2.71]), Mauritius (2.59 [95% UI 2.22, 2.97]) and Argentina (3.91 [95% UI 3.17, 4.76]) had the lowest rate. Mongolia (259.60 [95% UI 183.74, 349.89]), Gambia (103.75 [95% UI 56.70, 169.54]) and Mali (90.30 [95% UI 56.22, 136.46]) had the highest age standardized incidence rate. In contrast, Argentina (3.75 [95% UI 3.05, 4.56]), Mauritius (2.38 [95% UI 2.04, 2.72]) and Morocco (1.73 [95% UI 1.04, 2.63]) had the lowest rate. Mongolia (284.04 [95% UI 199.87, 383.83]), Gambia (110.90 [95% UI 60.45, 180.91]) and Mali (98.40 [95% UI 61.20, 149.41]) had the highest age standardized deaths rate. In contrast, Morocco (1.85 [95% UI 1.11, 2.79]), Mauritius (2.45 [95% UI 2.12, 2.80]) and Argentina (3.98 [95% UI 3.22, 4.83]) had the lowest rate. The highest age standardized DALYs rates of liver cancer were seen in Mali (2396.87 [95% UI 1481.38, 3665.39]), Gambia (2852.35 [95% UI 1551.69, 4663.82]), and Mongolia (6626.982183 [95% UI 4712.97, 8904.30]). Whereas the lowest rate were in Morocco (45.08 [95% UI 26.93, 68.76]), Mauritius (60.11 [95% UI 51.83, 68.74]) and Kuwait (85.71 [95% UI 64.00, 110.76]) (Table s1 ). The largest increases of age standardized prevalence rate were found in United Kingdom (5.65 [95% UI 5.30, 6.00]), Australia (5.26 [95% UI 4.88, 5.63]) and Poland (4.748 [95% UI 4.08, 5.43). In contrast, the largest decreases were found in Kuwait (-3.012 [95% UI -3.465, -2.557]), Kazakhstan (-3.361 (95% UI -3.680, -3.040]) and Zambia (-3.748 [95% UI -4.375, -3.117)]). Similarly, the largest increases of age standardized incidence rate were also found in Australia (3.995 [95% UI 3.803, 4.186]), Poland (4.429 [95% UI 3.758, 5.104]) and United Kingdom (4.655 [95% UI 4.398, 4.913]). In contrast, the largest decreases were found in Zambia (-3.665 [95% UI -4.297, -3.030]), Kazakhstan (-3.264 [95% UI -3.598, -2.928]) and Kuwait (-3.126 [95% UI -3.569, -2.682]). The largest increases of age standardized deaths rate were found in Uruguay ( 3.603 [95% UI 3.295, 3.912]), United Kingdom (4.145 [95% UI 3.893, 4.398]) and Poland (4.359 [95% UI 3.668, 5.055]). In contrast, the largest decreases were found in Zambia (-3.575 [95% UI-4.220, -2.925]), Kuwait (-3.264 [95% UI -4.312, -2.204]) and Kazakhstan(-3.237 [95% UI -3.566, -2.907]). Similarly, the largest increases of age standardized DALYs rate were also found in Uruguay (3.497 [95% UI 3.199, 3.795]), United Kingdom (3.953 [95% UI 3.695,4.213]) and Poland (4.696 [95% UI 3.984, 5.412]). In contrast, the largest decreases were found in Zambia (-3.971 [95% UI -4.680, -3.257]), Kuwait( -3.789 [95% UI -4.807, -2.760]) and Kazakhstan (-3.693 [95% UI -4.044, -3.340]) (Fig. 4 , s 2 ). There was a significance negative correlation between the SDI and the age standardized DALY rate of liver cancer (r=-0.2506, p = 0.0003136). Nations such as Mongolia, Gambia and Mali had much higher than expected burden (Fig. 5 ). Decomposition analysis Overall, the DALYs difference showed a upward trend globally and in all SDI regions. Population growth was the most primary contribution to the increase of liver cancer burden both in globe and all SDI regions. Aging contributed to 15.94% and 33.14% to the reduction of liver cancer burden in high and high-middle SDI regions. Whereas for low, low-middle and middle SDI regions and globe, aging contributed to 8.74%, 10.01%, 25.91% and 1.54% respectively to the increase of liver cancer burden. Epidemiological changes contributed to 4.49%, 18.37%, 23.6%, 48.5% and 13.89% respectively to the reduction of liver cancer burden in high, high-middle, middle and low SDI regions and globe, while epidemiological changes was linked to an increase of liver cancer burden in low-middle SDI region(Fig. 6 ). Cross-country inequality analysis In terms of the burden of liver cancer, we observed significant absolute inequalities associated with SDI ( Figure and Table, p > 0.05), while relative inequalities was no statistical significance. As shown by the slope, the discrepancy in DALYs rate between the highest and lowest SDI countries and territories decreased from − 389.165041 (95% UI -535.26, -243.07) in 1990 to -167.29 (95% UI -261.08, -73.50) in 2021. The result suggested that absolute health inequalities in liver cancer burden decreased from1990 to 2021(Fig. 7 ). Frontier analysis The 15 countries and territories with the largest actual differences in potential improvement included Mongolia (1983.54), Gambia (964.83), Mali (746.10), Eswatini (587.86), Tonga (587.17), Mozambique (545.07), Guinea (523.63), Mauritania (516.94), Guinea-Bissau (509.98), Lesotho (469.76), Egypt (466.90), Burkina Faso (463.29), Liberia (448.26), Zimbabwe (393.76), Republic of Korea (345.01). Frontier analysis revealed the potential improvement space in reducing liver cancer burden across countries and territories(Fig. 8 ). Discussion The current study outlined the global burden of liver cancer across middle-aged and elderly people from 1990–2021 based on the results of GBD 2021. Our study indicated that the number of global liver cancer cases and the incidence rate had both risen compared to 1990, increasing by 0.72 and 0.20, respectively. This trend was likely closely related to several factors. First, With the improvement of global medical conditions and living standards, life expectancy had been extended, leading to a higher proportion of elderly people[ 15 , 16 ]. Liver cancer was a disease highly associated with age, with its incidence rate significantly increasing after the age of 45, peaking in the 65–69 age group. The increase in the elderly population directly led to a rise in the number of liver cancer patients. Second, HBV and HCV infections were among the primary causes of liver cancer[ 17 , 18 ]. Although vaccination and antiviral treatments had achieved some success in certain areas, there was still a large number of chronic liver disease patients worldwide. As these patients' liver diseases progress over time, the risk of developing liver cancer increases. Third, Unhealthy lifestyle practices, such as long-term heavy drinking, high-fat diets, and obesity, were becoming increasingly prevalent globally[ 19 ]. The incidence rates of alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) were continuously rising compared with previous studies[ 9 , 20 ], and these diseases also increased the risk of liver cancer. Despite the increase in incidence and prevalence, the mortality rate and DALYs of liver cancer had shown a downward trend, decreasing by 0.05 and 0.31, respectively. This could be attributed to the following factors: Firstly, significant progress has been made in the diagnosis and treatment of liver cancer. The widespread use of imaging technologies such as magnetic resonance imaging (MRI) and computed tomography (CT) enables earlier detection of liver cancer, providing patients with more treatment opportunities[ 21 ]. Additionally, improvements in therapeutic techniques[ 22 , 23 ], the development of new drugs[ 24 , 25 ], and the application of liver transplantation had greatly increased the survival rate of liver cancer patients. Secondly, Some countries and regions had increased their investment in liver cancer prevention, such as promoting HBV vaccination[ 26 ], conducting liver cancer screening programs, and raising public awareness of liver cancer prevention and treatment. Thirdly, With the development of the economy, people's health awareness was enhanced, and the accessibility and affordability of medical resources had improved. More patients sought medical attention and receive standardized treatment in a timely manner, thereby reducing the mortality rate of liver cancer. Globally, the prevalence, incidence, mortality, and DALYs of liver cancer were all higher in males than in females. In different age groups, the prevalence and incidence of liver cancer in males were higher than in females from the age group of 45–49, and this difference gradually expanded with increasing age, reaching the highest in the 85–89 age group. For males, the mortality and DALYs of liver cancer also started to be higher than females from the age group of 45–49, and reached the peak in the 65–69 age group. In contrast, in females, the mortality and DALYs continued to rise with increasing age, reaching the highest in the 95 + age group. There were biological differences between males and females, such as different hormone levels. Androgen promoted the proliferation of liver cells, increasing the risk of liver cancer[ 27 ]. In addition, males' livers may have weaker metabolic capabilities for certain carcinogens[ 28 ], leading to higher incidence and mortality rates of liver cancer. Males were more susceptible to the influence of unhealthy lifestyles compared to females, such as long-term heavy drinking, smoking, and high-fat diets. The proportion of chronic liver disease patients in males was usually higher than in females, with higher infection rates of chronic hepatitis B and C in males, and these chronic liver diseases are important causes of liver cancer[ 29 ]. This results indicated that we should enhance the screening and management of high-risk male populations while pay attention to the prevention and treatment of liver cancer in elderly female populations. The study found that there was a significant negative correlation between SDI and the age standardized DALYs rate of liver cancer, showing a near "V" shape relationship. This indicated that the level of socioeconomic development has a complex impact on the burden of liver cancer. Taking the high-income Asia-Pacific region (High SDI region) as an example, the prevalence, incidence, mortality, and DALYs of liver cancer were all high, but these indicators had shown a downward trend since 1990. This was likely due to the high socioeconomic level, well-developed medical systems, and high emphasis on liver cancer prevention and control in these regions. However, the liver cancer burden in these regions was still high, possibly due to factors such as population aging, a large population of chronic liver disease patients, and unhealthy lifestyles. Middle SDI regions, such as East Asia, had the highest number of liver cancer cases, incidence, mortality, and DALYs globally since 1990, the incidence was shown an upward trend, while the mortality and DALYs was shown a downward trend. This might be related to the large population base, high hepatitis virus infection rate[ 30 ] and improvement in medical conditions. Taking the Western Sub-Saharan Africa region (Low SDI region) as an example, the incidence, mortality, and DALYs of liver cancer were high. Although the mortality and DALYs was shown a downward trend since 1990, the decrease was relatively small. This was likely due to the relatively backward medical and health conditions, scarce medical resources, and insufficient awareness of liver cancer prevention and control in these regions. Despite some improvements in medical conditions in recent years, the limited socioeconomic level restricted the treatment opportunities and effects for liver cancer patients, resulting in a still heavy disease burden. Manifestations of differences in liver cancer burden also were vary among different nations. High burden nations, such as Mongolia, South Korea, and The Gambia, had high the age-standardized prevalence, incidence, mortality, and DALYs of liver cancer. Low burden nations, such as Morocco, Mauritius, and Argentina, had the age standardized prevalence, incidence, mortality, and DALYs of liver cancer. The discrepancy was linked to socioeconomic levels, hepatitis virus infection, and lifestyles. For example, alcohol use as a primary cause of liver cancer mortality, particularly affecting men and significantly impacting the disease burden in Mongolia[ 31 ]. Our study conducted decomposition analysis of disease burden. Overall, there was an increasing trend in the global DALYs disparities for liver cancer, with population growth being the primary factor contributing to the increased burden of liver cancer, which was consistent with previous study[ 32 ]. Aging had made a significant contribution to the reduction of liver cancer burden in high SDI and high-middle SDI regions, while it had also contributed to the increase in liver cancer burden in low SDI, low-middle SDI, and middle SDI regions as well as globally, which was similar result with previous study[ 8 ]. Additionally, epidemiological changes had significantly contributed to the reduction of liver cancer burden in high SDI, high-middle SDI, middle SDI, and low SDI regions, but were associated with an increase in liver cancer burden in low-middle SDI regions. This indicated that factors influencing the burden of liver cancer vary across regions with different levels of development, necessitating the adoption of differentiated prevention and control strategies. The study found that there was a significant absolute inequality in the burden of liver cancer between countries, while relative inequality was not statistically significant. From 1990 to 2021, the difference in DALYs rates between the highest and lowest SDI countries and regions had shown a downward trend, indicating a reduction in absolute health inequality for the burden of liver cancer, which was similar with previous study[ 33 ]. However, the differences in the burden of liver cancer between different countries and regions were still considered, requiring further strengthening of international cooperation and promoting the fair distribution of medical resources. Frontier analysis showed that there was considerable potential for improvement in reducing the burden of liver cancer in 15 countries and regions, including Mongolia, Gambia, Mali, et al. This suggested that these countries and regions had significant potential for improvement in the prevention and control of liver cancer, necessitating the strengthening of medical system construction, improving the level of risk factor control, and promoting effective preventive measures. Some limitations of our study must be acknowledged. First, The data utilized in this study may possess certain limitations. The liver cancer data from some countries and regions may not be sufficiently complete and accurate. Particularly in areas with poor medical and health conditions and inadequate data collection and reporting systems, the incidence and mortality rates of liver cancer may be underestimated or under reported. Second, In the estimation and analysis of the burden of liver cancer, some simplified methods and assumptions may have been employed. For instance, the predictive models for liver cancer incidence and mortality may have certain limitations and may not have fully considered all possible influencing factors and complex interrelationships. Third, In analyzing the influencing factors of the burden of liver cancer, it may not have been possible to comprehensively cover all relevant factors, such as environmental and genetic factors, as well as the interactions among different factors. Conclusion The trend of the disease burden of liver cancer has significant implications for global public health. Although the incidence of liver cancer is still rising, the decline in mortality and DALYs suggests that effective medical interventions and public health measures can significantly reduce the lethality of liver cancer. This suggests that countries should focus their prevention and control efforts on early screening, early diagnosis, and standardized treatment to further improve patient survival rates and quality of life. Despite continuous advancements in treatment technologies, the high incidence of liver cancer remains a severe challenge. This underscores the importance of preventive work, necessitating further strengthening of preventive measures such as hepatitis vaccination, alcohol control, and improvement of dietary habits to reduce the occurrence of liver cancer at the source. The global trend in the disease burden of liver cancer also highlights the necessity of strengthening global health cooperation. Countries should share experiences and technologies in prevention and treatment, jointly address the global public health issue of liver cancer, and promote the improvement of global liver cancer prevention and control levels. Abbreviations Age-standardized rate (ASR), Estimated annual percentage change (EAPC), disability-adjusted life years (DALYs), Primary liver cancer (PLA), Hepatocellular carcinoma (HCC), Intrahepatic cholangiocarcinoma (ICC), socio-demographic index (SDI) The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), The Slope Index of Inequality (SII) Declarations Ethics approval and consent to participate: Not applicable Consent for publication: Not applicable Availability of data and material: Not applicable Competing interests: None Funding: None Authors' contributions Weifan Sui designed the study, performed the statistical analysis, drafted the manuscript. Yunxin Fuan, Zefeng Cai, Yimao Xia, Jianyun Li and Jianhua Fu participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript. Acknowledgements: None References Sung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. 2021;71(3):209–49. Bray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin. 2018;68(6):394–424. McGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. Hepatology. 2021;73:4–13. Huang DQ, Mathurin P, Cortez-Pinto H, et al. Global epidemiology of alcohol-associated cirrhosis and HCC: trends, projections and risk factors. Nat reviews Gastroenterol Hepatol. 2023;20(1):37–49. Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77(6):1598–606. Cao G, Liu J, Liu M. Global, Regional, and National trends in Incidence and Mortality of Primary Liver Cancer and its underlying etiologies from 1990 to 2019: results from the global burden of Disease Study 2019. J Epidemiol Global Health. 2023;13(2):344–60. Murray CJL, Aravkin AY, et al. Global burden of 87 risk factors in 204 countries and territories, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. lancet. 2020;396(10258):1223–49. Li J, Bai H, Gao Z et al. Global, regional, and national temporal trends in incidence and mortality for liver cancer due to hepatitis B, 1990–2021: a decomposition and age-period-cohort analysis for the Global Burden of Disease Study 2021. Hep Intl 2024: 1–16. Wang Q, Jia W, Liu J et al. Global, regional, and national burden of liver cancer due to alcohol use, 1990–2021: results from the Global Burden of Disease study 2021. Eur J Gastroenterol Hepatol. 2024: 10–1097. Danpanichkul P, Suparan K et al. Global Trend of MASH-associated Liver Cancer A Systematic Analysis from the Global Burden of Disease 2021. Clin Gastroenterol Hepatol. 2024. Liu C, Zhu S, Zhang J, et al. Global, regional, and national burden of liver cancer due to non-alcoholic steatohepatitis, 1990–2019: a decomposition and age–period–cohort analysis. J Gastroenterol. 2023;58(12):1222–36. Organization WH. Handbook on health inequality monitoring: with a special focus on low-and middle-income countries. World Health Organization; 2013. Xie Y, Bowe B, Mokdad AH, et al. Analysis of the Global Burden of Disease study highlights the global, regional, and national trends of chronic kidney disease epidemiology from 1990 to 2016. Kidney Int. 2018;94(3):567–81. Ferrari AJ, Santomauro DF, Aali A, et al. Global incidence, prevalence, years lived with disability (YLDs), disability-adjusted life-years (DALYs), and healthy life expectancy (HALE) for 371 diseases and injuries in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the global burden of disease study 2021. Lancet. 2024;403(10440):2133–61. Rumgay H, Arnold M, Ferlay J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77(6):1598–606. Kocarnik JM, Compton K, Dean FE, et al. Cancer Incidence, Mortality, Years of Life Lost, Years Lived With Disability, and Disability-Adjusted Life Years for 29 Cancer Groups From 2010 to 2019: A Systematic Analysis for the Global Burden of Disease Study 2019. JAMA Oncol. 2022;8(3):420–44. World Orgnization Health, Hepatitis B. Available from https://www.who.int/en/news-room/fact-sheets/detail/hepatitis-b World Orgnization Health, Hepatitis C. Available from https://www.who.int/news-room/fact-sheets/detail/hepatitis-c Xie J, Lin X, Fan X, et al. Global Burden and Trends of Primary Liver Cancer Attributable to Comorbid Type 2 Diabetes Mellitus Among People Living with Hepatitis B: An Observational Trend Study from 1990 to 2019. J Epidemiol Glob Health. 2024;14(2):398–410. Wang D, Xu Y, Zhu Z, et al. Changes in the global, regional, and national burdens of NAFLD from 1990 to 2019: A systematic analysis of the global burden of disease study 2019. Front Nutr. 2022;21(9):1047129–41. Cai Y, Wang W, Jiao Q, et al. Nanotechnology for the Diagnosis and Treatment of Liver Cancer. Int J Nanomed. 2024;24(19):13805–21. Llovet JM, Real MI, Montana X, et al. Arterial embolisation or chemoembolisation versus symptomatic treatment in patients with unresectable hepatocellular carcinoma: a randomised controlled trial. Lancet. 2002;359(9319):1734–9. Feng K, Yan J, Li X, et al. A randomized controlled trial of radiofrequency ablation and surgical resection in the treatment of small hepatocellular carcinoma. J Hepatol. 2012;57(4):794–802. Finn RS, Qin S, Ikeda M, et al. Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma. N Engl J Med. 2020;382(20):1894–905. Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet. 2017;389(10064):56–66. World Health Organization. Hepatitis B vaccines:WHO position paper, July 2017 - Recommendations. Vaccine. 2019;37(2):223–5. Ma WL, Lai HC, Yeh S, et al. Androgen receptor roles in hepatocellular carcinoma, fatty liver, cirrhosis and hepatitis. Endocr Relat Cancer. 2014;21(3):R165–82. Jiang C, Li P, Ma Y, et al. Comprehensive gene profiling of the metabolic landscape of humanized livers in mice. J Hepatol. 2024;80(4):622–33. Xiao J, Wang F, Yuan Y et al. Epidemiology of liver diseases: global disease burden and forecasted research trends. Sci China Life Sci. 2024. Global progress report on HIV. viral hepatitis and sexually transmitted infections,2021. Accountability for the global health sector strategies 2016–2021: actions for impact. https://apps.who.int/iris/bitstream/handle/10665/342808/ 9789240030985-eng. Batsaikhan O, Chimed-Ochir O, Kubo Tc, et al. The burden of liver cancer in Mongolia from 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019. Front Oncol. 2024;3(14):1381173–83. Tan EY, Danpanichkul P, Yong JN, et al. Liver cancer in 2021: Global burden of disease study. J Hepatol. 2024;S0168–8278(24):02652–7. Song Y, Wang X, Shen Y et al. Trends and cross-country inequality in the incidence of GI cancers among the working-age population from 1990 to 2021: a Global Burden of Disease 2021 analysis. Gut. 2024;333932. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-5913454","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":411200999,"identity":"50594ce5-34a6-495b-8035-2740ac908051","order_by":0,"name":"Weifan Sui","email":"","orcid":"","institution":"Zhenjiang First People’s Hospital","correspondingAuthor":false,"prefix":"","firstName":"Weifan","middleName":"","lastName":"Sui","suffix":""},{"id":411201000,"identity":"e6306916-d68f-416d-90bf-486202087a01","order_by":1,"name":"Yuxin Duan","email":"","orcid":"","institution":"Zhenjiang First People’s 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2","display":"","copyAsset":false,"role":"figure","size":256627,"visible":true,"origin":"","legend":"\u003cp\u003eThe global trends of age standardized prevalence (A), incidence (B), deaths (C) and disability-adjusted life years (D) of gender with different age groups in 2021.\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/bc11608709445614fb8e9f66.png"},{"id":75638495,"identity":"026f69fd-3837-4044-9ab9-d40d0452f607","added_by":"auto","created_at":"2025-02-06 14:59:24","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":73353,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation between regions and age standardized disability-adjusted life years rate in 2021.\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/9a5986b2c4d10d1274f58f5b.png"},{"id":75638921,"identity":"695d7033-3bc7-4833-a328-993ebb82e8a9","added_by":"auto","created_at":"2025-02-06 15:07:25","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":137497,"visible":true,"origin":"","legend":"\u003cp\u003eThe national trends of age standardized disability-adjusted life years in 2021.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/b5ca79b40e0799f344985494.png"},{"id":75638497,"identity":"ab797da7-35a2-44a8-9b86-03d5fcbbaf2d","added_by":"auto","created_at":"2025-02-06 14:59:25","extension":"png","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":121987,"visible":true,"origin":"","legend":"\u003cp\u003eThe correlation between nations and age standardized disability-adjusted life years rate in 2021.\u003c/p\u003e","description":"","filename":"5.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/60e35c1fd10461b032d51702.png"},{"id":75638505,"identity":"1fa04792-bf9d-4ad3-985f-a547072cfedb","added_by":"auto","created_at":"2025-02-06 14:59:25","extension":"png","order_by":6,"title":"Figure 6","display":"","copyAsset":false,"role":"figure","size":214019,"visible":true,"origin":"","legend":"\u003cp\u003eDecomposition analysis of age standardized prevalence (A), incidence (B), disability-adjusted life years (C) and deaths (D) in global, five Socio-demographic Index regions.\u003c/p\u003e","description":"","filename":"6.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/5c7468c0f4641697dff8bcc0.png"},{"id":75638919,"identity":"c3400a15-b65a-4b2b-93a8-3abcb7afd4f7","added_by":"auto","created_at":"2025-02-06 15:07:25","extension":"png","order_by":7,"title":"Figure 7","display":"","copyAsset":false,"role":"figure","size":506911,"visible":true,"origin":"","legend":"\u003cp\u003eCross-country inequality analysis of incidence (A, B), prevalence (C, D), disability-adjusted life years (E, F) and deaths(G, H) in five Socio-demographic Index regions.\u003c/p\u003e","description":"","filename":"7.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/d39e07ac411b5ed737f1a5a1.png"},{"id":75638503,"identity":"30a03de6-c931-4a31-a754-9930d27db9f4","added_by":"auto","created_at":"2025-02-06 14:59:25","extension":"png","order_by":8,"title":"Figure 8","display":"","copyAsset":false,"role":"figure","size":309030,"visible":true,"origin":"","legend":"\u003cp\u003eFrontier analysis of age standardized incidence (A, B), age standardized prevalence (C, D), age standardized disability-adjusted life years (E, F) and age standardized deaths(G, H) among 204 nations.\u003c/p\u003e","description":"","filename":"8.png","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/c4e90b506ac2c48080aeefd3.png"},{"id":75751552,"identity":"9808955a-e40c-4d7b-8338-5f98615b0565","added_by":"auto","created_at":"2025-02-07 20:46:34","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":2280563,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-5913454/v1/0d9e3dbc-c4f7-4b21-8d65-3494be235319.pdf"},{"id":75638498,"identity":"9d471b64-bd3d-4598-987e-0ac54c329230","added_by":"auto","created_at":"2025-02-06 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These subtypes exhibit significant differences in their etiology, biological characteristics, histological features, therapeutic approaches, and prognoses. HCC predominates, constituting 75\u0026ndash;85% of cases, followed by ICC, which accounts for 10\u0026ndash;15%[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Risk factors for PLA encompass chronic infections with HBV, HCV, and HIV, as well as lifestyle factors such as excessive alcohol intake, smoking, liver flukes, aflatoxin exposure through contaminated food, and conditions like diabetes, obesity, and non-alcoholic fatty liver disease[\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The geographical variability in incidence, prevalence, mortality, and risk factors contributes to the uneven distribution of PLA's impact worldwide[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur review of the literature indicates that previous studies on PLA have often concentrated on specific etiologies like HBV and HCV infections or alcohol consumption, or they have been confined to single countries or regions, and have not captured temporal trends over a single year[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan additionalcitationids=\"CR9\" citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. No study to date has conducted diverse comprehensive analysis of the worldwide burden of liver cancer, including decomposition of disease burden drivers, cross-country inequality, and frontier analysis. Decomposition analysis helps to elucidate the key factors contributing to changes in disease burden[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. Cross-country inequality analysis, utilizing tools like the slope index of inequality (SII) and concentration index, assesses disparities in health outcomes between nations[\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Frontier analysis estimates the potential for optimal health outcomes based on socio-demographic index (SDI) levels[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eThe Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) provides an opportunity to delve into the nuances of liver cancer's impact on the middle-aged and elderly. Unlike previous studies, the GBD categorizes age into 5-year intervals and examines the long-term effects of specific etiologies across various countries and regions. In this study, leveraging data from GBD 2021, we employ diverse methodologies to explore the multifaceted burden of liver cancer among middle-aged and elderly individuals from 1990 to 2021.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eData source\u003c/h2\u003e \u003cp\u003eOur study draws on data from the Global Burden of Disease (GBD) 2021, a meticulous and extensive initiative that estimates the impact of 371 diseases and 88 risk factors across 204 nations and territories. The dateset includes annual incidence and mortality rates of liver cancer, standardized by age, and spans from 2010 to 2021. It is stratified by gender, age, geographical region, and country. These figures were sourced from the Global Health Data Exchange (GHDx), an online repository managed by the Institute for Health Metrics and Evaluation (IHME). Access to the GHDx can be found at \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ghdx.healthdata.org/\u003c/span\u003e\u003cspan address=\"http://ghdx.healthdata.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e.\u003c/p\u003e \u003cp\u003eFor our analysis, we had chosen disability-adjusted life years (DALYs) data from GBD 2021 as the primary metric. DALYs, which amalgamate years lived with disability (YLDs) and years of life lost (YLLs), offered a holistic view of disease burden by accounting for premature mortality and diminished quality of life. This metric wass instrumental for comparing various health conditions and populations, thus serving as a benchmark for health disparities. Furthermore, we had incorporated the Socio-demographic Index (SDI) as a gauge of societal development. The SDI was a composite index derived from the geometric mean of three normalized indicators: fertility rates among those under 25, average years of education for individuals 15 and older, and income per capita on a lag-distributed basis. This index, calculated nationally, provides an accurate reflection of the social development statues across different countries and territories[\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. Based on SDI values, the 204 countries and territories in GBD 2021 were categorized into five developmental tiers, scaling from low to high. The SDI ranges from 0 to 1, with higher values signifying a higher socioeconomic status. To maintain precision and clarity, we had rounded the SDI threshold values for classification. The nations and territories are thus grouped into development levels using the following SDI thresholds: low SDI [0\u0026ndash;0.4658), low-middle SDI [0.4658\u0026ndash;0.6188), middle SDI [0.6188\u0026ndash;0.7120), high-middle SDI [0.7120\u0026ndash;0.8103), and high SDI [0.8103\u0026ndash;1.0000]. This stratification facilitated a more methodical examination of how varying levels of socioeconomic development influenced health outcomes.\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eCross-country inequality analysis\u003c/h3\u003e\n\u003cp\u003eThese indices were instrumental in quantifying the disparities in liver cancer distribution across various countries and territories, providing an in-depth assessment of health inequalities. The Slope Index of Inequality (SII) was derived by regressing the DALYs rate against the Socio-demographic Index (SDI), utilizing the midpoint of the cumulative population distribution, which was sorted by SDI. This method allowed for a detailed examination of health inequality changes by comparing data from 204 countries and territories over the period from 1990 to 2021. To enhance the control over bias and heterogeneity in our analysis, we employed a robust regression model (rlm) for the health inequality analysis. This model was less sensitive to outliers, thereby reducing the bias that could be introduced by data heterogeneity or extreme values. As a result, it provided a more accurate depiction of health inequality. Furthermore, the Concentration Index was calculated by aligning the cumulative proportion of DALYs with the cumulative population distribution, ranked by SDI, and numerically integrating the area under the Lorenz curve.\u003c/p\u003e\n\u003ch3\u003eDecomposition Analysis\u003c/h3\u003e\n\u003cp\u003eIn this study, we employed decomposition analysis to elucidate the intricate interplay of factors contributing to the burden of liver cancer. This analytical approached dissects the variations in disease-related mortality and disability-adjusted life years (DALYs) into components attributable to population aging, population growth, and epidemiological shifts. The decomposition analysis yielded both the absolute and relative contributions of each factor to the alterations in disease-related deaths or DALYs. By leveraging decomposition techniques, we were able to isolate the impacts of demographic changes on incidence and mortality rates. This isolation provided valuable insights into the fundamental drivers behind the observed trends in liver cancer burden.\u003c/p\u003e\n\u003ch3\u003eFrontier analysis\u003c/h3\u003e\n\u003cp\u003eThis study utilized frontier analysis to develop an age-standardized DALYs rate (ASDR)-based frontier model, leveraging the Socio-demographic Index (SDI) to evaluate the correlation between liver cancer burden and sociodemographic development levels. Frontier analysis was designed to ascertain the theoretical minimum ASDR that each country or territory could achieve, given its current development status, thus establishing a benchmark for optimal health outcomes.This methodology quantified the disparity between a country\u0026rsquo;s or territory\u0026rsquo;s actual liver cancer burden and its potential minimum burden, pinpointing areas for potential improvement. To generate smooth frontier lines that capture the non-linear relationship between SDI and ASDR, we employed locally weighted regression (LOESS) in conjunction with local polynomial regression, utilizing varying smoothing spans of 0.3, 0.4, and 0.5. To reinforce the robustness of our analysis, we executed 1000 bootstrap samples and computed the average ASDR for each SDI value. By calculating the absolute distance between each country\u0026rsquo;s or territory\u0026rsquo;s 2021 ASDR and the frontier line, we were able to gauge the improvement potential for each country or territory.\u003c/p\u003e\n\u003ch3\u003eStatistics\u003c/h3\u003e\n\u003cp\u003eTo evaluate the burden of liver cancer, we utilized both the rate and the count of disability-adjusted life years (DALYs). The DALYs rate, expressed as estimates per 100,000 individuals, provided a relative measure of the disease burden, while the number of cases offered an absolute measure, reflecting the total burden in terms of incident cases. Each metric was accompanied by its 95% uncertainty intervals (UI), which were crucial for understanding the precision of our estimates. All analyses were performed using statistically sound models, with a p-value threshold of less than 0.05 indicating statistical significance. Comprehensive descriptions of the specific methodologies employed, including the slope index of inequality, concentration index, frontier analysis, and decomposition analysis, were detailed in subsequent sections of our study. For the execution of all analyses and the generation of visualizations, we relied on the World Health Organization\u0026rsquo;s Health Equity Assessment Toolkit and R Software (version 4.3.2), ensuring that our methods were both rigorous and in line with established health equity assessment practices.\u003c/p\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eGlobal level\u003c/h2\u003e \u003cp\u003eGlobally, in 2021, the prevalent number of liver cancer was 739299.54 (95% UI 673114.25, 821948.24), with age standardized prevalence rate of 26.33 (95% UI 23.26, 29.73) per 100000, an increase of 0.72 (0.53, 0.90) since 1990. The incident number of liver cancer was 529202.46 (95% UI 480339.46, 593849.10), with age standardized incidence rate of 20.33 (95% UI 17.96, 22.89) per 100000, an increase of 0.20 (95% UI 0.09, 0.33) since 1990. The deaths number of liver cancer was 483875.13 (95% UI 440400.32, 540177.12), with age standardized rate of 18.98 (95% UI 16.78, 21.33) per 100000, a decrease of 0.05 (95% UI -0.17, 0.08) since 1990. The DALYs of liver cancer was 12887652.41 (95% UI 11673532.55, 4472227.99), with age standardized rate of 451.26 (95% UI 400.35, 511.09) per 100000, a decrease of 0.31 (95% UI -0.430, -0.191) since 1990 (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003es1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAmong five developmental tiers, the highest prevalent number of liver cancer was 235057.51 (95% UI 213883.81, 249189.79) in High SDI region since 1990, with age standardized prevalence rate of 39.62 (95% UI 35.23, 43.69) per 100000, a decrease of 0.50 (95% UI -0.751, -0.245). The highest incident, deaths and DALYs number of liver cancer were 160138.35 (95% UI 134420.32, 193407.02), 151642.25 (95% UI 128320.31, 181621.80) and 3925890.51 (95% UI 3305552.18, 4742009.53) respectively, in Middle SDI region since 1990, with age standardized incidence rate of 21.31 (95% UI 17.90, 25.69), 20.59 (95% UI 17.42, 24.61) and 504.57 (95% UI 425.14, 608.19)per 100000, respectively. An increased of 0.13 (95% UI 0.00, 0.25) of incidence rate occurred in Middle SDI since 1990. A decreased of 0.20 (95% UI -0.31, -0.08) and 0.37 (95% UI -0.31, -0.25) of deaths and DALYs rate occurred in Middle SDI since 1990 (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003es1\u003c/span\u003e, Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn 2021, the global prevalent, incident and deaths number of liver cancer started to increase in 45\u0026ndash;49 years group and peaked in 65\u0026ndash;69 years group, then decreased with increasing age both in men and women. The global DALYs of liver cancer started to increase in 45\u0026ndash;49 years group and peaked in 55\u0026ndash;59 years group, then decreased with increasing age in men, but peaked in 65\u0026ndash;69 group in women. The numbers of prevalent, incident, deaths and DALYs cases of liver cancer were higher in men from 45\u0026ndash;49 years group to 85\u0026ndash;89 years group expect 90\u0026ndash;94 years group and 95\u0026thinsp;+\u0026thinsp;years group in women. The prevalence, incidence rate of liver cancer started to increase in 45\u0026ndash;49 years group and peaked in 85\u0026ndash;89 years group, then decreased with increasing age both in men and women. The deaths and DALYs rate of liver cancer started to increase in 45\u0026ndash;49 years group and peaked in 90\u0026ndash;94 years and 65\u0026ndash;69 years group, respectively, then decreased with increasing age in men. Whereas for women, the deaths and DALY rate increased up to the oldest age group (95\u0026thinsp;+\u0026thinsp;years) (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e\n\u003ch3\u003eRegional level\u003c/h3\u003e\n\u003cp\u003eIn 2021, among 21 regions, the highest prevalent, incident, deaths and DALYs number of liver cancer were 275114.25 (95% UI 222236.65, 340133.39 ), 203596.96 (95% UI 165109.85, 250430.69), 178494.83(95% UI 145380.74, 218906.75) and 5063799.90 (95% UI 4074239.52, 6285122.10) in East Asia, respectively. The highest age standardized prevalence, incidence and deaths of rates were 85.27 (95% UI 68.83, 103.00), 44.10 (95% UI 36.64, 51.81) and 32.60 (95% UI 27.27, 37.67) per 100000, respectively, in High-income Asia Pacific since 1990. The highest age standardized DALYs rate was 735.85 (95% UI 594.17, 895.07) per 100000, respectively, in Western Sub-Saharan Africa since 1990. An increase of 0.57 (95% UI 0.43, 0.71) of prevalence rate occurred in East Asia since 1990. A decrease of 0.02 (95% UI -0.16, 0.11), 0.51 (95% UI -0.66, -0.36) and 0.75 (95% UI -0.90, -0.59) of incidence, deaths and DALYs rate occurred in East Asia since 1990, respectively (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003es1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eWe found approximate V shaped association between the SDI and the age standardized DALY rate of liver cancer (r=-0.1648, p\u0026thinsp;=\u0026thinsp;0.00001802), from 1990 to 2021. The age standardized prevalence, incidence deaths and DALY rate decreased exponentially with increases in SDI, down to a SDI of about 0.7, before increasing again. High-income Asia Pacific, East Asia,Central Asia, Southeast Asia, Western Sub\u0026thinsp;\u0026minus;\u0026thinsp;Saharan Africa, Southern Sub\u0026thinsp;\u0026minus;\u0026thinsp;Saharan Africa had higher than\u003c/p\u003e \u003cp\u003eexpected DALY rates. In contrast, High\u0026thinsp;\u0026minus;\u0026thinsp;Income North America, Western Europe, Oceania, Australasia, Andean Latin America, Tropical Latin America, Central Latin America, Southern Latin America, Caribbean, Central Europe, Eastern Europe, Central Asia and South Asia had lower than expected DALY rates (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn 2021, among 21 regions, the prevalence, incidence deaths and DALYs rates of liver cancer in men were all higher than in women. High-income Asia Pacific had the highest prevalence rate both in men and women. High-income Asia Pacific had the highest incidence, deaths and DALYs rates in men. Western Sub-Saharan Africa had the highest incidence deaths and DALYs rates in women(Figure \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003es1\u003c/span\u003e).\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eNational level\u003c/h2\u003e \u003cp\u003eIn 2021, among 204 nations, Mongolia (252.77 [95% UI 179.92, 339.30]), Republic of Korea (126.62 [95% UI 87.80, 175.48]) and Gambia (105.60 [95% UI 57.68, 172.91]) had the highest age standardized prevalence rate of liver cancer. In contrast, Morocco (1.77 [95% UI 1.06, 2.71]), Mauritius (2.59 [95% UI 2.22, 2.97]) and Argentina (3.91 [95% UI 3.17, 4.76]) had the lowest rate. Mongolia (259.60 [95% UI 183.74, 349.89]), Gambia (103.75 [95% UI 56.70, 169.54]) and Mali (90.30 [95% UI 56.22, 136.46]) had the highest age standardized incidence rate. In contrast, Argentina (3.75 [95% UI 3.05, 4.56]), Mauritius (2.38 [95% UI 2.04, 2.72]) and Morocco (1.73 [95% UI 1.04, 2.63]) had the lowest rate. Mongolia (284.04 [95% UI 199.87, 383.83]), Gambia (110.90 [95% UI 60.45, 180.91]) and Mali (98.40 [95% UI 61.20, 149.41]) had the highest age standardized deaths rate. In contrast, Morocco (1.85 [95% UI 1.11, 2.79]), Mauritius (2.45 [95% UI 2.12, 2.80]) and Argentina (3.98 [95% UI 3.22, 4.83]) had the lowest rate. The highest age standardized DALYs rates of liver cancer were seen in Mali (2396.87 [95% UI 1481.38, 3665.39]), Gambia (2852.35 [95% UI 1551.69, 4663.82]), and Mongolia (6626.982183 [95% UI 4712.97, 8904.30]). Whereas the lowest rate were in Morocco (45.08 [95% UI 26.93, 68.76]), Mauritius (60.11 [95% UI 51.83, 68.74]) and Kuwait (85.71 [95% UI 64.00, 110.76]) (Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003es1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe largest increases of age standardized prevalence rate were found in United Kingdom (5.65 [95% UI 5.30, 6.00]), Australia (5.26 [95% UI 4.88, 5.63]) and Poland (4.748 [95% UI 4.08, 5.43). In contrast, the largest decreases were found in Kuwait (-3.012 [95% UI -3.465, -2.557]), Kazakhstan (-3.361 (95% UI -3.680, -3.040]) and Zambia (-3.748 [95% UI -4.375, -3.117)]). Similarly, the largest increases of age standardized incidence rate were also found in Australia (3.995 [95% UI 3.803, 4.186]), Poland (4.429 [95% UI 3.758, 5.104]) and United Kingdom (4.655 [95% UI 4.398, 4.913]). In contrast, the largest decreases were found in Zambia (-3.665 [95% UI -4.297, -3.030]), Kazakhstan (-3.264 [95% UI -3.598, -2.928]) and Kuwait (-3.126 [95% UI -3.569, -2.682]). The largest increases of age standardized deaths rate were found in Uruguay ( 3.603 [95% UI 3.295, 3.912]), United Kingdom (4.145 [95% UI 3.893, 4.398]) and Poland (4.359 [95% UI 3.668, 5.055]). In contrast, the largest decreases were found in Zambia (-3.575 [95% UI-4.220, -2.925]), Kuwait (-3.264 [95% UI -4.312, -2.204]) and Kazakhstan(-3.237 [95% UI -3.566, -2.907]). Similarly, the largest increases of age standardized DALYs rate were also found in Uruguay (3.497 [95% UI 3.199, 3.795]), United Kingdom (3.953 [95% UI 3.695,4.213]) and Poland (4.696 [95% UI 3.984, 5.412]). In contrast, the largest decreases were found in Zambia (-3.971 [95% UI -4.680, -3.257]), Kuwait( -3.789 [95% UI -4.807, -2.760]) and Kazakhstan (-3.693 [95% UI -4.044, -3.340]) (Fig.\u0026nbsp;\u003cspan refid=\"Fig4\" class=\"InternalRef\"\u003e4\u003c/span\u003e, s\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThere was a significance negative correlation between the SDI and the age standardized DALY rate of liver cancer (r=-0.2506, p\u0026thinsp;=\u0026thinsp;0.0003136). Nations such as Mongolia, Gambia and Mali had much higher than expected burden (Fig.\u0026nbsp;\u003cspan refid=\"Fig5\" class=\"InternalRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eDecomposition analysis\u003c/h2\u003e \u003cp\u003eOverall, the DALYs difference showed a upward trend globally and in all SDI regions. Population growth was the most primary contribution to the increase of liver cancer burden both in globe and all SDI regions. Aging contributed to 15.94% and 33.14% to the reduction of liver cancer burden in high and high-middle SDI regions. Whereas for low, low-middle and middle SDI regions and globe, aging contributed to 8.74%, 10.01%, 25.91% and 1.54% respectively to the increase of liver cancer burden. Epidemiological changes contributed to 4.49%, 18.37%, 23.6%, 48.5% and 13.89% respectively to the reduction of liver cancer burden in high, high-middle, middle and low SDI regions and globe, while epidemiological changes was linked to an increase of liver cancer burden in low-middle SDI region(Fig.\u0026nbsp;\u003cspan refid=\"Fig6\" class=\"InternalRef\"\u003e6\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCross-country inequality analysis\u003c/h2\u003e \u003cp\u003eIn terms of the burden of liver cancer, we observed significant absolute inequalities associated with SDI ( Figure and Table, p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), while relative inequalities was no statistical significance. As shown by the slope, the discrepancy in DALYs rate between the highest and lowest SDI countries and territories decreased from \u0026minus;\u0026thinsp;389.165041 (95% UI -535.26, -243.07) in 1990 to -167.29 (95% UI -261.08, -73.50) in 2021. The result suggested that absolute health inequalities in liver cancer burden decreased from1990 to 2021(Fig.\u0026nbsp;\u003cspan refid=\"Fig7\" class=\"InternalRef\"\u003e7\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eFrontier analysis\u003c/h2\u003e \u003cp\u003eThe 15 countries and territories with the largest actual differences in potential improvement included Mongolia (1983.54), Gambia (964.83), Mali (746.10), Eswatini (587.86), Tonga (587.17), Mozambique (545.07), Guinea (523.63), Mauritania (516.94), Guinea-Bissau (509.98), Lesotho (469.76), Egypt (466.90), Burkina Faso (463.29), Liberia (448.26), Zimbabwe (393.76), Republic of Korea (345.01). Frontier analysis revealed the potential improvement space in reducing liver cancer burden across countries and territories(Fig.\u0026nbsp;\u003cspan refid=\"Fig8\" class=\"InternalRef\"\u003e8\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe current study outlined the global burden of liver cancer across middle-aged and elderly people from 1990\u0026ndash;2021 based on the results of GBD 2021. Our study indicated that the number of global liver cancer cases and the incidence rate had both risen compared to 1990, increasing by 0.72 and 0.20, respectively. This trend was likely closely related to several factors. First, With the improvement of global medical conditions and living standards, life expectancy had been extended, leading to a higher proportion of elderly people[\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e]. Liver cancer was a disease highly associated with age, with its incidence rate significantly increasing after the age of 45, peaking in the 65\u0026ndash;69 age group. The increase in the elderly population directly led to a rise in the number of liver cancer patients. Second, HBV and HCV infections were among the primary causes of liver cancer[\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. Although vaccination and antiviral treatments had achieved some success in certain areas, there was still a large number of chronic liver disease patients worldwide. As these patients' liver diseases progress over time, the risk of developing liver cancer increases. Third, Unhealthy lifestyle practices, such as long-term heavy drinking, high-fat diets, and obesity, were becoming increasingly prevalent globally[\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. The incidence rates of alcoholic liver disease and non-alcoholic fatty liver disease (NAFLD) were continuously rising compared with previous studies[\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], and these diseases also increased the risk of liver cancer.\u003c/p\u003e \u003cp\u003eDespite the increase in incidence and prevalence, the mortality rate and DALYs of liver cancer had shown a downward trend, decreasing by 0.05 and 0.31, respectively. This could be attributed to the following factors: Firstly, significant progress has been made in the diagnosis and treatment of liver cancer. The widespread use of imaging technologies such as magnetic resonance imaging (MRI) and computed tomography (CT) enables earlier detection of liver cancer, providing patients with more treatment opportunities[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e]. Additionally, improvements in therapeutic techniques[\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e], the development of new drugs[\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], and the application of liver transplantation had greatly increased the survival rate of liver cancer patients. Secondly, Some countries and regions had increased their investment in liver cancer prevention, such as promoting HBV vaccination[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], conducting liver cancer screening programs, and raising public awareness of liver cancer prevention and treatment. Thirdly, With the development of the economy, people's health awareness was enhanced, and the accessibility and affordability of medical resources had improved. More patients sought medical attention and receive standardized treatment in a timely manner, thereby reducing the mortality rate of liver cancer.\u003c/p\u003e \u003cp\u003eGlobally, the prevalence, incidence, mortality, and DALYs of liver cancer were all higher in males than in females. In different age groups, the prevalence and incidence of liver cancer in males were higher than in females from the age group of 45\u0026ndash;49, and this difference gradually expanded with increasing age, reaching the highest in the 85\u0026ndash;89 age group. For males, the mortality and DALYs of liver cancer also started to be higher than females from the age group of 45\u0026ndash;49, and reached the peak in the 65\u0026ndash;69 age group. In contrast, in females, the mortality and DALYs continued to rise with increasing age, reaching the highest in the 95\u0026thinsp;+\u0026thinsp;age group. There were biological differences between males and females, such as different hormone levels. Androgen promoted the proliferation of liver cells, increasing the risk of liver cancer[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. In addition, males' livers may have weaker metabolic capabilities for certain carcinogens[\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], leading to higher incidence and mortality rates of liver cancer. Males were more susceptible to the influence of unhealthy lifestyles compared to females, such as long-term heavy drinking, smoking, and high-fat diets. The proportion of chronic liver disease patients in males was usually higher than in females, with higher infection rates of chronic hepatitis B and C in males, and these chronic liver diseases are important causes of liver cancer[\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. This results indicated that we should enhance the screening and management of high-risk male populations while pay attention to the prevention and treatment of liver cancer in elderly female populations.\u003c/p\u003e \u003cp\u003eThe study found that there was a significant negative correlation between SDI and the age standardized DALYs rate of liver cancer, showing a near \"V\" shape relationship. This indicated that the level of socioeconomic development has a complex impact on the burden of liver cancer. Taking the high-income Asia-Pacific region (High SDI region) as an example, the prevalence, incidence, mortality, and DALYs of liver cancer were all high, but these indicators had shown a downward trend since 1990. This was likely due to the high socioeconomic level, well-developed medical systems, and high emphasis on liver cancer prevention and control in these regions. However, the liver cancer burden in these regions was still high, possibly due to factors such as population aging, a large population of chronic liver disease patients, and unhealthy lifestyles. Middle SDI regions, such as East Asia, had the highest number of liver cancer cases, incidence, mortality, and DALYs globally since 1990, the incidence was shown an upward trend, while the mortality and DALYs was shown a downward trend. This might be related to the large population base, high hepatitis virus infection rate[\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e] and improvement in medical conditions. Taking the Western Sub-Saharan Africa region (Low SDI region) as an example, the incidence, mortality, and DALYs of liver cancer were high. Although the mortality and DALYs was shown a downward trend since 1990, the decrease was relatively small. This was likely due to the relatively backward medical and health conditions, scarce medical resources, and insufficient awareness of liver cancer prevention and control in these regions. Despite some improvements in medical conditions in recent years, the limited socioeconomic level restricted the treatment opportunities and effects for liver cancer patients, resulting in a still heavy disease burden.\u003c/p\u003e \u003cp\u003eManifestations of differences in liver cancer burden also were vary among different nations. High burden nations, such as Mongolia, South Korea, and The Gambia, had high the age-standardized prevalence, incidence, mortality, and DALYs of liver cancer. Low burden nations, such as Morocco, Mauritius, and Argentina, had the age standardized prevalence, incidence, mortality, and DALYs of liver cancer. The discrepancy was linked to socioeconomic levels, hepatitis virus infection, and lifestyles. For example, alcohol use as a primary cause of liver cancer mortality, particularly affecting men and significantly impacting the disease burden in Mongolia[\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eOur study conducted decomposition analysis of disease burden. Overall, there was an increasing trend in the global DALYs disparities for liver cancer, with population growth being the primary factor contributing to the increased burden of liver cancer, which was consistent with previous study[\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. Aging had made a significant contribution to the reduction of liver cancer burden in high SDI and high-middle SDI regions, while it had also contributed to the increase in liver cancer burden in low SDI, low-middle SDI, and middle SDI regions as well as globally, which was similar result with previous study[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Additionally, epidemiological changes had significantly contributed to the reduction of liver cancer burden in high SDI, high-middle SDI, middle SDI, and low SDI regions, but were associated with an increase in liver cancer burden in low-middle SDI regions. This indicated that factors influencing the burden of liver cancer vary across regions with different levels of development, necessitating the adoption of differentiated prevention and control strategies.\u003c/p\u003e \u003cp\u003eThe study found that there was a significant absolute inequality in the burden of liver cancer between countries, while relative inequality was not statistically significant. From 1990 to 2021, the difference in DALYs rates between the highest and lowest SDI countries and regions had shown a downward trend, indicating a reduction in absolute health inequality for the burden of liver cancer, which was similar with previous study[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e]. However, the differences in the burden of liver cancer between different countries and regions were still considered, requiring further strengthening of international cooperation and promoting the fair distribution of medical resources. Frontier analysis showed that there was considerable potential for improvement in reducing the burden of liver cancer in 15 countries and regions, including Mongolia, Gambia, Mali, et al. This suggested that these countries and regions had significant potential for improvement in the prevention and control of liver cancer, necessitating the strengthening of medical system construction, improving the level of risk factor control, and promoting effective preventive measures.\u003c/p\u003e \u003cp\u003eSome limitations of our study must be acknowledged. First, The data utilized in this study may possess certain limitations. The liver cancer data from some countries and regions may not be sufficiently complete and accurate. Particularly in areas with poor medical and health conditions and inadequate data collection and reporting systems, the incidence and mortality rates of liver cancer may be underestimated or under reported. Second, In the estimation and analysis of the burden of liver cancer, some simplified methods and assumptions may have been employed. For instance, the predictive models for liver cancer incidence and mortality may have certain limitations and may not have fully considered all possible influencing factors and complex interrelationships. Third, In analyzing the influencing factors of the burden of liver cancer, it may not have been possible to comprehensively cover all relevant factors, such as environmental and genetic factors, as well as the interactions among different factors.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe trend of the disease burden of liver cancer has significant implications for global public health. Although the incidence of liver cancer is still rising, the decline in mortality and DALYs suggests that effective medical interventions and public health measures can significantly reduce the lethality of liver cancer. This suggests that countries should focus their prevention and control efforts on early screening, early diagnosis, and standardized treatment to further improve patient survival rates and quality of life. Despite continuous advancements in treatment technologies, the high incidence of liver cancer remains a severe challenge. This underscores the importance of preventive work, necessitating further strengthening of preventive measures such as hepatitis vaccination, alcohol control, and improvement of dietary habits to reduce the occurrence of liver cancer at the source. The global trend in the disease burden of liver cancer also highlights the necessity of strengthening global health cooperation. Countries should share experiences and technologies in prevention and treatment, jointly address the global public health issue of liver cancer, and promote the improvement of global liver cancer prevention and control levels.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eAge-standardized rate (ASR), Estimated annual percentage change (EAPC), disability-adjusted life years (DALYs), Primary liver cancer (PLA), Hepatocellular carcinoma (HCC), Intrahepatic cholangiocarcinoma (ICC), socio-demographic index (SDI) \u0026nbsp;The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD), The Slope Index of Inequality (SII)\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: Not applicable \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: Not applicable \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAvailability of data and material: Not applicable \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eCompeting interests: None \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding: None \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAuthors\u0026apos; contributions Weifan Sui designed the study, performed the statistical analysis, drafted the manuscript. Yunxin Fuan, Zefeng Cai, Yimao Xia, Jianyun Li and Jianhua Fu participated in its design and coordination and helped to draft the manuscript. All authors read and approved the final manuscript. \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgements: None\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eSung H, Ferlay J, Siegel RL, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA. 2021;71(3):209\u0026ndash;49.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBray F, Ferlay J, Soerjomataram I, et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries[J]. CA Cancer J Clin. 2018;68(6):394\u0026ndash;424.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMcGlynn KA, Petrick JL, El-Serag HB. Epidemiology of hepatocellular carcinoma. 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Gut. 2024;333932.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"liver cancer, global burden disease, disability-adjusted life years, incidence, prevalence","lastPublishedDoi":"10.21203/rs.3.rs-5913454/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-5913454/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e \u003cp\u003eLiver cancer is a significant contributor to the global disease burden. we first provide estimates of the worldwide burden of liver cancer from 2000 to 2021 in middle-aged and elderly people with decomposition, cross-country inequality and frontier analysis.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe age-standardized rate (ASR) and estimated annual percentage change (EAPC) were utilized for measuring prevalence, incidence, deaths and disability-adjusted life years (DALYs) rate trends. Decomposition, cross country inequalities and frontier analysis to estimate the burden.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eIn 2021, the number of liver cancer prevalence and the incidence was increased compared to 1990, while the number of deaths and DALYs slightly decreased. The burden of liver cancer was higher in males than in females. Population growth led to an increase in the burden. Aging and epidemiological changes made significant contributions to the reduction of the liver cancer burden. There was a V-shaped relationship between the DALYs rate and SDI regions. There was a significant absolute inequality across countries. 15 countries and regions had considerable potential for improvement in reducing the burden .\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThis study reveals the complex dynamic changes in the global burden of liver cancer across middle-aged and elderly people. In the future, it is necessary to strengthen international cooperation, promote the fair distribution of medical resources, and formulate and implement differentiated strategies.\u003c/p\u003e","manuscriptTitle":"Worldwide burden of liver cancer across middle-aged and elderly people, 1990-2021: a decomposition, cross-country inequality and frontier analysis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-02-06 14:59:20","doi":"10.21203/rs.3.rs-5913454/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"d656e1e7-0ddf-4025-b691-3679cbe11606","owner":[],"postedDate":"February 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-02-07T20:38:21+00:00","versionOfRecord":[],"versionCreatedAt":"2025-02-06 14:59:20","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-5913454","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-5913454","identity":"rs-5913454","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}