Abstract
Background:
Liver cancer remains a significant global health concern, with hepatitis B virus (HBV) as the leading cause. This study aims to systematically evaluate the global epidemiological burden, risk factors, and long-term trends of HBV-related liver cancer.
Methods:
Data from the Global Burden of Disease (GBD) study 2021 were used to analyze incidence, deaths, and prevalence rates of HBV-related liver cancer across 204 countries and territories. Age-period-cohort (APC) models were applied to assess age-specific trends, period effects, and cohort impacts on age-standardized disease burden. Pearson correlation analyses examined the relationship between liver cancer burden, the socio-demographic index (SDI), and the universal health coverage (UHC) index. We also evaluated the influence of other concomitant risk factors on HBV-related liver cancer deaths. Projections for future death trends were generated using Bayesian APC models.
Results:
In 2021, there were 206,365.7 new cases of HBV-related liver cancer and 181,194.3 deaths worldwide. Between 1990 and 2021, both the global age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) showed an upward trend. The age-standardized death rate (ASDR) declined, particularly in middle SDI countries, where the ASDR dropped by 21.7%. Incidence rates decreased among individuals under 70 years old, while death rates dropped for those under 75 years. Period trends revealed an increase in incidence and deaths from 1995 to 2000, followed by a sharp decline from 2000 to 2010, with death reductions being more pronounced. The downward trend was most notable among birth cohorts from the 1970s onward. A negative correlation was found between the SDI, the UHC, and liver cancer burden. The number of deaths attributable to risk factors increased by 97.8% from 1990 to 2021. Projections indicate a 30.2% reduction in HBV-related liver cancer deaths globally by 2040.
Conclusions:
The global burden of HBV-related liver cancer showed significant regional disparities and presented ongoing global health challenges. Socioeconomic factors and healthcare access are closely associated with disease burden. Effective, region-specific interventions are essential to mitigate future HBV-related liver cancer burdens.
Keywords: Liver cancer, Hepatitis B virus, Global, Age-period-cohort, Risk factors, Burden, Incidence, Mortality, Prevalence, SDI
Introduction
Liver cancer remains a significant global health concern, with an estimated 866,136 new cases and 758,725 deaths reported worldwide in 2022, making it the sixth most commonly diagnosed cancer and the third leading cause of cancer-related death globally.[1] Hepatitis B virus (HBV) is widely recognized as the primary cause of liver cancer, accounting for approximately one-third of liver cancer fatalities worldwide.[2]
Currently, significant geographic disparities exist in HBV prevalence, with higher case concentrations in developing countries compared with developed countries, particularly in Eastern Asia and Sub-Saharan Africa, where the disease exhibits strong geographical aggregation.[3] With the immigration from endemic countries, the burden of HBV-related liver cancer showed ethnic variation in the United States and Europe, with migrant populations over-represented.[4] Consistently, this significant disparity is associated with certain social determinants.[5] Some studies have explained the inequalities in liver cancer incidence and development based on indicators related to socioeconomic development, emphasizing that many individuals still lack access to quality healthcare.[6] In 2015, the World Health Organization (WHO) set a common target to eliminate viral hepatitis as a public health threat by 2030. However, most regions remain far from achieving this goal. Chronic HBV infection continues to be significantly underdiagnosed and undertreated, even in high-income countries, with the situation further exacerbated in low-income regions.[7] Most studies on the disease burden of HBV-related liver cancer have been conducted in high-burden regions, and there is a lack of studies comparing different global regions across various levels of the socio-demograohic index (SDI). Moreover, the disease burden does not always align with the SDI, which serves as an indicator of socioeconomic development. The lack of comparable cross-national estimates that provide a multidimensional comparison of population burdens has hindered efforts to implement appropriate prevention measures.
To better understand the current trends of HBV-related liver cancer globally as well as the distribution of disease burden and the necessity of implementing effective intervention measures, this study systematically evaluates the latest epidemiological burden, risk factors, and long-term trends of HBV-related liver cancer by analyzing the most recent data from the Global Burden of Disease (GBD) study.
Methods
Data source and estimations
The data used in our study were derived from the 2021 GBD study. It provided a comprehensive and up-to-date repository of epidemiological data covering 371 diseases and injuries, as well as 88 risk factors. Notably, it includes comparative statistics spanning the years from 1990 to 2021 across 204 countries and territories worldwide. The general methodology of GBD 2021 has been described in previous publications.[8,9] In our analysis, we adhered to the methodological framework and analytical strategies used in the GBD 2021. The GBD 2021 introduced an innovative comparative risk assessment (CRA) approach based on a causal framework and a hierarchy of risk factors. Our focus was on evaluating risk factors attributable to HBV-related liver cancer deaths in 1990 and 2021, as well as the percentage change in the number of deaths over this period.
SDI and universal health coverage (UHC) index
Two established indices were used to assess potential associations with disease burden, capturing aspects of social and economic development as well as health system performance. SDI is a composite indicator that incorporates a country’s or territory’s lag-distributed income per capita, average years of schooling, and the total fertility rate for females under 25 years old. These estimates are derived from the GBD SDI index. The UHC service coverage index combines 14 tracer indicators of service coverage into a single summary measure, reflecting the Sustainable Development Goals (SDGs) in Goal 3, which focuses on health (target 3.8). The UHC index is scored on a scale from 0 (worst) to 100 (best), based on the average coverage of essential services, including reproductive, maternal, newborn, and child health; infectious diseases; non-communicable diseases; and service capacity and access. The UHC index data were obtained from the Global Health Observatory data repository by the WHO (https://data.who.int/).
Statistical analyses
This study aimed to analyze trends in the HBV-related liver cancer burden from 1990 to 2021 by using various epidemiological metrics, including the number or rate of incidence, deaths, and prevalence across regions and countries. Data were obtained from the Global Health Data Exchange query tool, accessible at https://vizhub.healthdata.org/gbd-results/. Furthermore, all estimates from the GBD are presented with 95% uncertainty intervals (UIs), derived from the 25th and 975th ordered values drawn from 1000 samples of the posterior distribution.
To explore potential trends in incidence and death rates across age, period, and birth cohort, we used the APC models, aiming to unveil the interplay between age-related biological factors and the influence of technological and societal elements on disease tendencies.[10] This multifaceted analysis, often elusive with traditional epidemiological approaches, has found wide application in the study of various chronic diseases.[11–13] Generally, the APC model fits a log-linear Poisson model over a Lexis diagram of observed rates and quantifies the additive effects of age, period, and birth cohorts. As the relationship between age, period, and cohort is perfectly linear (birth cohort = period − age), it is statistically impossible to estimate their independent effects, a challenge known as the identification problem. To address this, we derived estimable APC parameters and functions without imposing arbitrary constraints on model parameters.
Pearson correlation analyses were conducted to examine the strength of relationships between incidence, deaths, and the SDI and UHC index. Pearson’s correlation coefficient (r) was used to determine the correlation between two variables. Subsequently, leveraging the world’s population data in GBD spanning from 1990 to 2019, we projected HBV-related death burdens from 2020 to 2040, using a Bayesian APC (BAPC) model with the Integrated Nested Laplace Approximation (INLA) approach. All statistical tests were two-tailed, with statistical significance defined as P <0.05. The data analysis was conducted using R Software (version 4.3.0; R Foundation, Vienna, Austria).
Results
Global, regional, and national burden of HBV-related liver cancer
In 2021, the global incidence number of HBV-related liver cancer was 206,365.7 cases, with 181,194.3 deaths and 288,105.9 prevalent individuals [Table 1]. Between 1990 and 2021, both the global age-standardized incidence rate (ASIR) and age-standardized prevalence rate (ASPR) showed an upward trend, while the age-standardized death rate (ASDR) declined. The ASPR rose across all SDI levels, with the most significant increase in ASIR observed in high-middle and low-middle SDI countries. The middle SDI countries bore the heaviest death burden, with the highest ASDR at 2.9 per 100,000, representing a 21.7% decrease between 1990 and 2021. The high-middle SDI countries also experienced an increase in the ASIR, ASDR, and ASPR, with ASPR showing a prominent 46.6% rise. The lowest burden was observed in countries with low SDI. The most significant increase in age-standardized rates (ASR) was observed in North Africa and the Middle East, followed by South Asia and Central Europe. The most notable decline occurred in Southern Latin America, followed by Central Latin America and Tropical Latin America. At the national level, Mongolia had the highest incidence, followed by Gambia and Mali, whereas Morocco and Argentina had the lowest. In most countries, the burden of deaths was closely aligned with incidence, but some developed nations, such as the United States and countries in Europe, showed relatively lower deaths. South Korea had a significantly higher prevalence compared with other countries, followed by Singapore and China in the Western Pacific region.
Table 1.
Incidence, deaths, prevalent cases for liver cancer burden due to hepatitis B in 2021, and percentage change in ASR per 100,000, by Global Burden of Disease region, from 1990 to 2021.
| Location | Incidence | Deaths | Prevalence | ||||||
|---|---|---|---|---|---|---|---|---|---|
| Number (95% CI) | ASIR per 100,000 (95% CI) | Percentage change in ASR from 1990 to 2021 (95% CI) | Number (95% CI) | ASDR per 100,000 (95% CI) | Percentage change in ASR from 1990 to 2021 (95% CI) | Number (95% CI) | ASPR per 100,000 (95% CI) | Percentage change in ASR from 1990 to 2021 (95% CI) | |
| Global | 206,365.7 (169,400.9, 252,049.9) | 2.4 (2.0, 2.9) | 4.2 (−9.0, 19.2) | 181,194.3 (148,896.5, 221,685.3) | 2.1 (1.7, 2.6) | −3.7 (−15.7, 10.1) | 288,105.9 (237,812.5, 349,750.4) | 3.3 (2.7, 4.0) | 11.9 (−1.4, 27.8) |
| High SDI | 28,989.2 (23,731.9, 34,829.6) | 1.6 (1.3, 1.9) | −6.7 (−23.9, 14.7) | 22,541.5 (18,388.1, 27,201.7) | 1.2 (1.0, 1.4) | −16.4 (−31.2, 3.0) | 50,880.7 (41,694.7, 60,880.5) | 2.9 (2.4, 3.4) | 5.6 (−13.9, 29.6) |
| High-middle SDI | 55,363.3 (43,590.3, 70,055.1) | 2.9 (2.3, 3.7) | 19.8 (11.8, 27.4) | 47,895.2 (37,909.5, 60,439.7) | 2.5 (2.0, 3.2) | 5.7 (−1.7, 12.7) | 76,539.7 (60,527.6, 96,593.8) | 4.1 (3.3, 5.2) | 46.6 (37.5, 55.4) |
| Middle SDI | 92 418.9 (73 620.8, 117 265.3) | 3.3 (2.6, 4.1) | −5.2 (−18.3, 9.6) | 81,086.9 (64,898.2, 101,640.6) | 2.9 (2.4, 3.6) | −21.7 (−33.2, −9.1) | 124,473.1 (99,281.0, 157,936.5) | 4.4 (3.5, 5.5) | 26.3 (8.2, 45.4) |
| Low-middle SDI | 18,219.6 (14,528.8, 22,911.2) | 1.2 (0.9, 1.5) | 2.0 (−17.6, 26.3) | 18,248.8 (14,602.6, 23,064.3) | 1.2 (0.9, 1.5) | −8.3 (−25.4, 12.6) | 22,172.2 (17,782.6, 27,797.0) | 1.3 (1.1, 1.7) | 9.8 (−10.8, 36.0) |
| Low SDI | 11,303.3 (8431.4, 14,885.1) | 1.9 (1.4, 2.5) | 0 (−25.6, 34.5) | 11,351.6 (8478.5, 14,986.0) | 2.0 (1.5, 2.6) | −12.6 (−34.5, 17.1) | 13,951.7 (10,532.1, 18,464.8) | 2.2 (1.6, 2.8) | 13.4 (−15.8, 53.6) |
| High-income Asia Pacific | 14,818.3 (11,974.0, 18,162.6) | 4.0 (3.2, 4.8) | −6.3 (−22.9, 15.4) | 10,738.8 (8624.7, 13,128.5) | 2.7 (2.2, 3.3) | −14.2 (−28.8, 4.7) | 28,834.0 (23,517.6, 35,026.8) | 8.1 (6.7, 10.0) | −3.7 (−21.2, 18.8) |
| High-income North America | 3795.4 (3138.1, 4501.9) | 0.6 (0.5, 0.8) | −14.7 (−33.6, 9.9) | 2839.4 (2330.4, 3358.6) | 0.5 (0.4, 0.5) | −24.4 (−40.8, –3.5) | 6207.5 (5192.6, 7352.3) | 1.1 (1.0, 1.3) | −4.8 (−26.3, 23.9) |
| Western Europe | 5487.1 (4017.1, 7391.6) | 0.7 (0.5, 0.9) | 6.7 (−13.5, 28.5) | 4637.8 (3414.1, 6338.1) | 0.6 (0.4, 0.7) | 6.5 (−14.4, 28.3) | 9016.7 (6621.0, 12,081.9) | 1.2 (0.9, 1.7) | 2.5 (−12.9, 24.5) |
| Australasia | 377.3 (264.1, 528.7) | 0.8 (0.6, 1.1) | −6.6 (−23.6, 18.7) | 305.4 (212.1, 430.7) | 0.6 (0.4, 0.9) | −7.1 (−24.2, 17.4) | 640.8 (446.9, 879.5) | 1.5 (1.1, 2.0) | −4.8 (−21.8, 21.6) |
| Andean Latin America | 565.5 (400.2, 777.4) | 0.9 (0.7, 1.3) | −20.3 (−34.2, 10.5) | 587.5 (411.5, 817.0) | 1.0 (0.7, 1.4) | −19.8 (−34.1, 11.7) | 649.0 (462.6, 875.1) | 1.1 (0.8, 1.4) | −22.5 (−34.9, 4.3) |
| Tropical Latin America | 915.0 (763.6, 1081.2) | 0.3 (0.3, 0.4) | −29.1 (−42.7, 5.7) | 924.9 (771.2, 1095.2) | 0.4 (0.3, 0.4) | −29.4 (−43.0, 4.9) | 1086.6 (911.3, 1281.0) | 0.4 (0.3, 0.5) | −27.1 (−41.2, 7.1) |
| Central Latin America | 869.3 (648.2, 1159.3) | 0.3 (0.3, 0.5) | −28.4 (−36.0, −20.1) | 885.3 (655.4, 1190.1) | 0.3 (0.3, 0.5) | −40.4 (−47.1, −33.0) | 1033.3 (780.5, 1362.7) | 0.4 (0.3, 0.5) | −4.3 (−14.5, 7.1) |
| Southern Latin America | 272.7 (188.9, 389.6) | 0.3 (0.2, 0.5) | −26.9 (−41.8, −7.6) | 272.6 (187.7, 392.1) | 0.3 (0.2, 0.5) | −44.7 (−56.4, −29.6) | 321.8 (227.7, 449.8) | 0.4 (0.3, 0.5) | 8.4 (−12.7, 35.6) |
| Caribbean | 234.4 (164.8, 317.4) | 0.4 (0.3, 0.6) | 103.9 (94.7, 112.4) | 236.0 (166.2, 319.3) | 0.4 (0.3, 0.6) | 112.7 (106.4, 118.5) | 280.2 (199.1, 376.7) | 0.5 (0.4, 0.7) | 167.0 (158.4, 175.9) |
| Central Europe | 1277.1 (900.8, 1745.3) | 0.6 (0.5, 0.8) | 136.0 (129.0, 142.7) | 1312.0 (924.7, 1810.8) | 0.6 (0.5, 0.9) | 80.9 (72.3, 88.1) | 1433.1 (1008.0, 1928.6) | 0.7 (0.5, 1.0) | 141.8 (130.3, 152.3) |
| Eastern Europe | 1646.4 (1353.3, 2004.6) | 0.5 (0.4, 0.6) | 49.0 (40.7, 57.4) | 1655.2 (1365.6, 2007.0) | 0.5 (0.4, 0.6) | 29.9 (23.0, 36.8) | 1919.0 (1580.5, 2322.5) | 0.6 (0.5, 0.7) | 93.4 (82.0, 104.9) |
| Central Asia | 1398.9 (971.2, 1939.1) | 1.5 (1.1, 2.1) | 43.8 (34.5, 54.2) | 1405.1 (966.1, 1956.9) | 1.6 (1.1, 2.2) | 22.6 (14.4, 31.4) | 1671.1 (1174.5, 2317.0) | 1.8 (1.2, 2.4) | 91.7 (79.6, 106.0) |
| North Africa and Middle East | 6303.7 (4749.0, 8154.2) | 1.3 (0.9, 1.6) | 197.7 (163.8, 235.0) | 6219.2 (4680.6, 8079.0) | 1.3 (1.0, 1.7) | 163.1 (131.9, 197.5) | 7733.8 (5904.1, 9871.1) | 1.5 (1.1, 1.9) | 257.9 (218.0, 305.6) |
| South Asia | 14,004.2 (11,808.4, 16,799.7) | 0.9 (0.7, 1.1) | 147.0 (115.2, 183.4) | 14,172.2 (11,904.0, 16,996.1) | 0.9 (0.8, 1.1) | 110.3 (81.6, 142.3) | 16,611.9 (14,071.8, 19,676.3) | 1.0 (0.9, 1.2) | 220.0 (174.0, 271.8) |
| Southeast Asia | 17,700.8 (12,864.2, 24,371.2) | 2.5 (1.8, 3.4) | −1.4 (−25.1, 26.3) | 17,131.5 (12,363.6, 23,545.5) | 2.4 (1.8, 3.3) | −0.9 (−24.5, 27.1) | 22,294.6 (16,418.8, 30,338.5) | 3.0 (2.2, 4.1) | −11.5 (−31.8, 16.5) |
| East Asia | 122,179.5 (95,828.7, 157,144.4) | 5.7 (4.5, 7.3) | −15.1 (−35.5, 10.7) | 103,357.9 (80,924.5, 132,256.4) | 4.8 (3.8, 6.1) | −15.7 (−35.9, 9.4) | 170,204.2 (134,132.1, 220263.9) | 8.0 (6.4, 10.4) | –14.4 (–35.5, 11.7) |
| Oceania | 149.4 (91.4, 296.8) | 1.7 (1.0, 3.3) | 8.9 (3.1, 15.3) | 147.4 (89.9, 294.0) | 1.7 (1.0, 3.4) | 8.2 (2.4, 14.2) | 185.3 (114.4, 364.4) | 1.9 (1.2, 3.8) | 2.3 (–5.8, 14.9) |
| Western Sub-Saharan Africa | 8892.1 (6801.9, 11252.1) | 3.8 (2.9, 4.7) | 1.8 (–4.8, 8.9) | 8912.3 (6855.6, 11345.6) | 3.9 (3.0, 4.9) | 0.7 (–5.9, 7.7) | 11141.9 (8563.2, 14101.1) | 4.3 (3.3, 5.4) | 2.9 (–3.7, 10.0) |
| Eastern Sub-Saharan Africa | 3086.6 (2121.4, 4672.5) | 1.5 (1.0, 2.3) | –1.2 (–10.2, 9.2) | 3089.5 (2114.6, 4707.9) | 1.6 (1.1, 2.4) | –1.6 (–10.2, 8.5) | 3811.9 (2641.8, 5670.1) | 1.7 (1.2, 2.6) | –5.6 (–16.0, 7.6) |
| Central Sub-Saharan Africa | 730.7 (325.8, 1738.8) | 1.0 (0.5, 2.4) | –22.0 (–30.0, –12.6) | 724.0 (321.1, 1761.3) | 1.1 (0.5, 2.6) | –22.9 (–31.2, –13.7) | 936.6 (420.0, 2266.0) | 1.2 (0.5, 2.9) | –19.5 (–27.9, –9.8) |
| Southern Sub-Saharan Africa | 1661.3 (1330.6, 2098.3) | 2.5 (2.0, 3.1) | 121.2 (88.0, 155.5) | 1640.6 (1309.4, 2072.5) | 2.5 (2.0, 3.1) | 115.1 (83.4, 147.6) | 2092.7 (1676.9, 2626.4) | 2.9 (2.4, 3.7) | 127.3 (91.9, 165.1) |
ASR: Age-standardized rates; ASIR: Age-standardized incidence rate; ASDR: Age-standardized death rates; ASPR: Age-standardized prevalence rate; SDI: Socio-demographic index.
The age–period–cohort effects on HBV-related liver cancer
The overall local drift revealed an annual percentage change in disease rates across different age groups. The incidence rates decreased among individuals under 70 years old, and the death rate dropped for those under 75 years. The decline in deaths was more pronounced than the decline in incidence among individuals aged 45–55 years. Across different SDI categories, the reduction in deaths was most significant in high SDI countries, followed by middle SDI and high-middle SDI countries. Similarly, younger age groups, particularly those aged 30–44 years in high SDI countries, exhibited the most substantial decline. In contrast, low-middle SDI and low SDI countries experienced a more stable decline across all age groups. The downward trend in all age groups was also more pronounced among males than females [Figure 1 and Supplementary Figure 1, http://links.lww.com/CM9/C588].
Figure 1.
Local drifts with net drift for ASDR of HBV-related liver cancer in global and five SDI regions by (A) both, (B) male, and (C) female. The colour indicates the value of the local drifts (% per year). ASDR: Age-standardized death rate; HBV: Hepatitis B virus; SDI: Socio-demographic index.
The age-specific rates showed an upward trend, with males consistently having higher rates than females. The peak age for liver cancer incidence has been progressively increasing. Global period effects also varied by gender. The period trend of incidence and deaths showed an upward trend from 1995 to 2000 compared to the period from 1990 to 1995, but declined sharply from 2000 to 2010, with the decrease in deaths being more pronounced. From 2010 onward, the period trend in deaths continued to decline at a slower pace, while the trend in incidence showed a slight rebound. However, the overall risk remained lower than during 1995–2000. Post-2010 trends varied across SDI levels: high-middle and middle SDI countries showed signs of stabilization, whereas other regions continued to experience a decline [Figure 2, Supplementary Table 1, and Supplementary Figure 2, http://links.lww.com/CM9/C588].
Figure 2.
The age-period-cohort analysis of ASDR of HBV-related liver cancer in global and five SDI regions. (A) Longitudinal age curve; (B) Period rate ratio; (C) Cohort rate ratio. ASDR: Age-standardized death rate; HBV: Hepatitis B virus; SDI: Socio-demographic index.
Global cohort effects on both incidence and deaths have shown a long-term declining trend since the 1930s, with the decline becoming particularly evident among birth cohorts from the 1970s onward. Compared to the disease rates in the 1960s, the risk was higher for cohorts born between 1920 and 1960, but gradually decreased for those born after the 1970s, with the reduction in deaths being more significant. Trends in high-middle SDI and middle SDI regions closely mirrored global patterns, while the decline was most pronounced across different birth cohorts in low SDI regions [Figure 2 and Supplementary Figure 2, http://links.lww.com/CM9/C588].
Burden of HBV-related liver cancer by SDI and UHC
At the regional level, significant negative correlations were found between ASIR and SDI, as well as between ASDR and SDI, with the correlation coefficients of −0.18 (95% confidence interval [CI]: −0.25 to −0.11) and −0.28 (95% CI: −0.35 to −0.21), respectively. The lowest ASIR and ASDR rates occurred at an SDI of approximately 0.75, followed by intermittent increases with further SDI improvements. Western Sub-Saharan Africa, East Asia, Southeast Asia, Southern Sub-Saharan Africa, Central Asia, and the high-income Asia Pacific had higher than expected ASIR and ASDR levels between 1990 and 2021 [Figure 3].
Figure 3.
The relationship between SDI levels, UHC levels, and ASIR, ASDR of HBV-related liver cancer in GBD regions from 1990 to 2021. (A) SDI levels and ASIR. (B) SDI levels and ASDR. (C) UHC levels and ASIR. (D) UHC levels and ASDR. ASIR: Age-standardized incidence rate; ASDR: Age-standardized death rate; GBD: Global Burden of Disease; HBV: Hepatitis B virus; SDI: Socio-demographic index; UHC: Universal health coverage index.
At the national level, significant negative correlations were also found between the ASIR, ASDR rates, and the UHC index, with correlation coefficients of −0.34 (−0.46 to −0.21) for ASIR and −0.38 (−0.49 to −0.25) for ASDR. The highest ASIR and ASDR rates were observed at a UHC level of around 40, whereas the lowest rates were seen at a UHC level of approximately 80. Countries with lower UHC indices generally experienced a higher disease burden. Several typical developed and developing countries, such as Singapore, South Korea, Turkey, China, and Thailand, demonstrated higher-than-expected ASIR and ASDR levels from 1990 to 2021 [Figure 3].
Concomitant risk factors for HBV-related liver cancer
In 2021, the number of deaths attributable to all concomitant risk factors for HBV-related liver cancer was 42,171.3, accounting for 23.2% of all HBV-related liver cancer deaths. Among all age groups, high BMI and tobacco use contributed the highest proportions, at 8.6% and 13.5%, respectively. Alcohol consumption was a more prominent risk factor in the 15–49 years age group, accounting for 2.3% of deaths. In the 50–74 years age group, the proportion of HBV-related liver cancer attributable to risk factors was the highest, with tobacco use being the most prominent factor. From 1990 to 2021, the number of deaths attributable to risk factors for HBV-related liver cancer increased by 97.8%, with the largest increase observed for high BMI, which rose by 360.6%, followed by drug use, which increased by 282.9% [Table 2].
Table 2.
Liver cancer burden due to hepatitis B with concomitant risk factors stratified by age group in 1990 and 2021, and percentage change from 1990 to 2021.
| Age groups | Risk factors | 1990 | 2021 | Percentage change in number of deaths (%), 1990–2021 | ||
|---|---|---|---|---|---|---|
| Absolute number, thousand (n [95% confidence interval]) | Proportion (%) | Absolute number, thousand (n [95% confidence interval]) | Proportion (%) | |||
| All ages | ||||||
| All risk factors | 21,316.4 (10,714.5, 31201.5) | 20.0 (10.4, 28.8) | 42,171.3 (24,788.9, 62,371.4) | 23.2 (14.6, 31.9) | 97.8 | |
| High body-mass index | 3408.5 (1325.4, 5502.0) | 3.2 (1.4, 5.2) | 15,697.9 (6009.6, 26,907.0) | 8.6 (3.6, 14.0) | 360.6 | |
| Alcohol use | 1276.0 (22.6, 3609.1) | 1.2 (0, 3.5) | 1389.3 (39.5, 4318.8) | 0.8 (0.0, 2.4) | 8.9 | |
| Drug use | 967.3 (584.2, 1473.8) | 0.9 (0.6, 1.4) | 3703.6 (2422.0, 5252.3) | 2.1 (1.4, 2.8) | 282.9 | |
| Tobacco | 16,626.1 (6069.0, 26,870.8) | 15.6 (5.5, 25.0) | 24,612.9 (8093.3, 42,003.8) | 13.5 (4.8, 22.1) | 48.0 | |
| 15–49 years | ||||||
| All risk factors | 21,316.4 (10,714.5, 31,201.5) | 20.0 (10.4, 28.8) | 9285.4 (5674.9, 13,633.7) | 23.4 (14.8, 31.6) | 41.4 | |
| High body-mass index | 922.2 (362.5, 1452.5) | 2.8 (1.2, 4.5) | 3482.9 (1390.8, 6079.0) | 8.8 (3.6, 14.3) | 277.7 | |
| Alcohol use | 897.4 (12.2, 2287.3) | 2.7 (0, 6.8) | 905.0 (29.6, 2421.3) | 2.3 (0.1, 5.7) | 0.9 | |
| Drug use | 269.9 (157.1, 408.2) | 0.8 (0.5, 1.2) | 761.6 (498.6, 1072.2) | 1.9 (1.3, 2.8) | 182.2 | |
| Tobacco | 4833.9 (1656.5, 7883.5) | 14.5 (5.3, 23.1) | 4941.4 (1662.3, 8315.6) | 12.4 (4.3, 20.0) | 2.2 | |
| 50–74 years | ||||||
| All risk factors | 12,190.9 (5470.6, 18,406.5) | 23.8 (11.4, 35.0) | 24,027.5 (13,081.0, 36,576.6) | 26.3 (16.0, 36.3) | 106.3 | |
| High body-mass index | 1510.1 (593.9, 2502.4) | 3.0 (1.3, 4.8) | 7404.8 (2784.3, 13,062.8) | 8.1 (3.4, 13.2) | 366.5 | |
| Alcohol use | 372.2 (1.9, 1465.5) | 0.7 (0.0, 2.8) | 470.7 (0.9, 2044.7) | 0.5 (0, 2.1) | 26.0 | |
| Drug use | 548.6 (313.5, 857.7) | 1.1 (0.6, 1.6) | 2105.5 (1319.7, 2997.9) | 2.3 (1.6, 3.2) | 285.0 | |
| Tobacco | 10,276.6 (3758.4, 16,625.5) | 20.0 (7.3, 31.8) | 16,005.9 (5137.7, 27,846.8) | 17.5 (6.3, 28.4) | 54.9 | |
| 75+ years | ||||||
| All risk factors | 1412.9 (675.9, 2237.5) | 14.9 (7.4, 22.1) | 5370.6 (3072.5, 8149.3) | 18.0 (10.8, 25.0) | 280.1 | |
| High body-mass index | 310.1 (119.4, 545.3) | 3.3 (1.4, 5.3) | 2064.3 (809.0, 3598.5) | 6.9 (2.8, 11.1) | 565.6 | |
| Alcohol use | 4.7 (0, 23.5) | 0.1 (0, 0.2) | 13.0 (0, 63.5) | 0 (0, 0.2) | 179.5 | |
| Drug use | 69.0 (36.7, 121.2) | 0.7 (0.4, 1.2) | 522.9 (326.3, 811.1) | 1.8 (1.2, 2.4) | 657.6 | |
| Tobacco | 1070.6 (351.1, 1824.1) | 11.3 (3.7, 18.8) | 3066.5 (990.7, 5561.3) | 10.3 (3.5, 17.4) | 186.4 | |
Projections of HBV-related liver cancer with concomitant risk factors
From 2019 to 2040, global HBV-related liver cancer deaths will continue to decline, with a more pronounced decrease in males. The ASDR is expected to decrease by 30.2%, from 4.56 per 100,000 in 2019 to 3.18 per 100,000 in 2040. The burden of HBV-related liver cancer deaths with concomitant risk factors is also expected to decline globally and among males, whereas the burden among females is projected to increase [Supplementary Figure 3, http://links.lww.com/CM9/C588].
Discussion
The burden of HBV-related liver cancer exhibited significant regional differences and an overall long-term decline on a global scale. The reduction in death rates has been most pronounced in high SDI countries, followed by middle SDI and high-middle SDI countries. The highest disease burden was observed in individuals over 75 years old and in males. The APC analysis revealed that while incidence rates remained high globally and among males since 2000, death rates have declined significantly among birth cohorts since the 1970s. Analysis of socioeconomic indicators showed a significant negative correlation between the burden of HBV-related liver cancer and both the SDI and UHC. This study is the first, to our knowledge, to estimate the impact of concomitant risk factors for HBV-related liver cancer, identifying high BMI as the most significant contributor. In addition, an increase in alcohol consumption has been observed among individuals aged 15–29 years. Given current trends, global HBV-related liver cancer deaths are expected to continue declining in the coming decades.
Despite the WHO calling for all countries to work toward eliminating viral hepatitis as a public health threat by 2030, mortality caused by viral hepatitis has continued to rise over the past decade.[14] The prevalence of chronic hepatitis B (CHB) varied across geographic regions and populations, with the Western Pacific and African regions exhibiting the highest prevalence of hepatitis B surface antigen (HBsAg).[7] The African region accounted for 63% of all new HBV infections, whereas an additional 22% occurred in the South-East Asia region. The Western Pacific region contributed to 47% of nearly 1.1 million deaths from hepatitis B.[3] This regional distribution is consistent with the burden of HBV-related liver cancer. Although a series of measures have been implemented to control HBV infection, projections indicate that between 2015 and 2030, the incidence of HBV-related hepatocellular carcinoma (HCC) and HBV-related mortality in the Asia-Pacific region will increase by approximately 30%.[15] Therefore, rapid expansion of screening, surveillance, and efficient treatment remains crucial in this region to reduce HBV-related liver cancer cases and associated deaths.
The GBD study categorized the etiologies of liver cancer primarily as HBV, hepatitis C virus (HCV), alcohol, and non-alcoholic steatohepatitis (NASH). Although HBV-related liver cancer remains a significant burden, the incidence and mortality of liver cancer due to NASH are rising in most high-SDI countries. Although HBV infection rates have decreased in younger birth cohorts, the high prevalence of CHB and the long latency period of HCC suggest that HBV-related HCC incidence will continue to rise.[16] Between 2010 and 2015, liver cancer mortality remained stable in high-middle SDI countries, in contrast to the downward trend observed elsewhere, making these regions significant contributors to the global disease burden. With increasing global migration, the prevalence of CHB in North America is estimated to rise by 2030.[7] In Australia, traditionally considered a low-risk country, liver cancer has become the fastest-growing cause of cancer-related mortality, driven primarily by non-viral factors such as NASH.[17,18] Therefore, implementing region-specific prevention and control strategies tailored to key etiologies is essential for effective liver cancer management.
Prevention and treatment efforts targeting HBV-related liver cancer have shown promising results, particularly in East Asia. The widespread implementation of neonatal hepatitis B vaccination has substantially reduced the disease burden among recent birth cohorts.[19] In China, high coverage of timely birth-dose vaccination to prevent mother-to-child transmission has led to a remarkable decline in HBsAg prevalence among children under 5 years, dropping from 9.67% in 1992 to 0.3% in 2016, with a reduction of 97%.[20,21] Correspondingly, the age-standardized incidence of liver cancer in China has also shown a declining trend. However, in densely populated and economically underdeveloped regions of Africa, HBV vaccination coverage remains relatively low.[22] In high-endemic areas, expanding vaccination programs beyond neonatal immunization is recommended, including targeted catch-up campaigns for adolescents and young adults (15–35 years), particularly in regions with coverage gaps. Given the long latency period of liver cancer development, the impact on liver cancer burden in these regions will take longer to materialize.
In 2024, the WHO expanded the indications for antiviral treatment to support the goal of eliminating hepatitis B by 2030, prompting many countries to enhance their HBV management policies.[23–25] The increasing age of peak incidence of HBV-related liver cancer reflects a delayed onset following the widespread use of antiviral drugs. The broad promotion of hepatitis B vaccination, which began in the early 1990s, likely had a limited immediate impact on mortality due to the time lag between vaccination and its effects on liver cancer incidence. The rapid decline in mortality rates between 2000 and 2010 is likely attributable to widespread antiviral therapy and improved liver cancer treatments, which directly improve clinical outcomes by reducing viral replication and preventing progression in HBV-infected individuals. These findings underscore the importance of combining both interventions in future public health policies. Many countries recommend HBV screening in regions with a prevalence greater than 2%, a widely accepted threshold. In 2023, the U.S. Centers for Disease Control and Prevention issued guidelines advocating for universal screening of individuals aged 18 years and older.[26] Cost-effectiveness analysis also indicated that universal HBsAg screening in the U.S. adult population would be cost-saving compared to current chronic HBV screening practices.[27] Professional guidelines in the United States, Europe, and the Asia-Pacific region recommend liver cancer screening for patients with CHB.[28] However, current surveillance efforts in these countries remain inadequate, highlighting the urgent need to establish population-based surveillance programs.[29,30]
Socioeconomic disparities significantly influence HBV-related liver cancer incidence and mortality. Vertical transmission of HBV remains the most common route of infection in developing countries. Administering the HBV vaccine and antiviral medications during late pregnancy can significantly reduce vertical transmission, yet lower socioeconomic populations often face barriers in accessing these preventive measures.[4] Socioeconomic conditions impact various aspects of health, including household living standards, access to healthcare, and health literacy, which in turn affect the timely diagnosis and treatment of HBV-related liver cancer. The UHC index consists of several indicators that reflect a country’s overall healthcare system development, accessibility, and equity of healthcare services, showing a significant negative correlation with HBV-related liver cancer burden. Since 2000, the greatest improvements have been seen in infectious disease indicators, whereas those for non-communicable diseases and other areas showed gradual progress until 2015, followed by minimal or no improvements through 2021. Further efforts are required to expand vaccine coverage, strengthen HBV screening measures, and improve healthcare accessibility, particularly in less developed regions.[31]
Few studies have analyzed the burden of HBV-related liver cancer with risk factors, especially on a global scale. The proportion of liver cancer deaths attributable to risk factors is 47.7%, and among HBV-related liver cancer deaths, 23.2% are specifically attributable to risk factors.[8] This suggests that patients with CHB should enhance the management of risk factors, particularly diabetes, while undergoing antiviral treatment. Some studies indicate that CHB patients with modifiable risk factors, such as alcohol consumption and high BMI, face an increased progression to severe conditions such as cirrhosis and liver cancer.[32,33] Previous research shows that the differences in liver cancer burden between men and women are linked to various risk factors. For liver cancer caused by hepatitis C and non-alcoholic steatohepatitis (NASH), the number of cases in women exceeded that in men, whereas HBV-related liver cancer was more prevalent in men.[34] This study indicated an increasing future burden of liver cancer in women attributable to risk factors, likely due to the rising influence of NASH and obesity. In high-HBV prevalence regions, strengthening risk factor control for individuals with multiple risk factors, such as weight reduction and reduced alcohol intake, could lower liver cancer mortality risk. Furthermore, individuals with multiple risk factors should undergo more frequent liver cancer screenings to facilitate early detection and intervention.
Given the complex interplay between HBV prevalence, socioeconomic disparities, and risk factors, targeted policy strategies are essential. In high-endemic regions such as Sub-Saharan Africa and East Asia, priority should be given to scaling up antiviral therapy and improving HBV screening accessibility. Investment in affordable generic antiviral drugs and strengthening healthcare infrastructure to deliver these treatments should be a key focus. Strengthening hepatitis B vaccination programs remains essential for long-term prevention, particularly in ensuring high coverage among newborns and high-risk populations. Gradual implementation of liver cancer screening can be considered, starting with high-risk groups such as individuals with cirrhosis, as resources allow. For middle- and low-HBV prevalence regions, a balanced approach combining continued vaccination efforts, expanded antiviral treatment, and targeted liver cancer screening programs is recommended. Establishing national HBV elimination funding and incorporating hepatitis B prevention into universal health coverage policies could significantly improve outcomes. A phased implementation roadmap, from short-term vaccination scale-up to long-term integration into universal health systems, will be essential to meet WHO 2030 targets.
Several limitations should be acknowledged. First, data quality and availability varied significantly between countries, with particular restrictions in resource-limited regions, potentially compromising the accuracy of estimates in these areas. Second, the GBD study analyzing models relied on available data, which was sometimes insufficient for estimating risk factor exposures. Many data sources lacked sufficient information to account for potential measurement errors or biases. Third, the prediction relies on the assumption that past trends will continue, failing to account for unforeseen changes like global events or shifts in public health interventions, which may affect projection accuracy. In addition, the burden of HBV-related liver cancer was estimated within the GBD cause hierarchy, making it impossible to isolate the precise population-attributable fraction of HBV. Last, the risk factors of liver cancer in GBD’s analysis were constrained by current knowledge and data availability, preventing the analysis of certain synergistic risk factors, such as aflatoxin exposure.
In summary, HBV-related liver cancer continues to pose a significant global burden despite progress in vaccination and antiviral treatment. Although incidence remains high in certain regions, particularly among older populations and males, mortality rates have shown an overall decline. Strengthening prevention and treatment strategies—such as vaccination expansion, antiviral accessibility, and risk factor management—alongside targeted public health interventions tailored to regional needs will be critical to achieving HBV elimination goals.
Acknowledgment
We thank Professor Michael David for his proofread of this paper before final acceptance.
Funding
This study was supported by a grant from the Capital’s Funds for Health Improvement and Research (No. 2024-1G-4023).
Conflicts of interest
None.
Supplementary Material
Footnotes
How to cite this article: Cao MD, Xia CF, Zhou JH, Teng Y, Li QR, Tan NP, Wang JC, Zuo TT, Li TY, Zheng YJ, Chen WQ. Global epidemiology of liver cancer burden due to hepatitis B virus: A comprehensive estimate based on Global Burden of Disease Study 2021. Chin Med J 2025;138:3457–3466. doi: 10.1097/CM9.0000000000003787
References
- 1.Bray F Laversanne M Sung H Ferlay J Siegel RL Soerjomataram I, et al. Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2024;74:229–263. doi: 10.3322/caac.21834. [DOI] [PubMed] [Google Scholar]
- 2.Abdelhamed W, El-Kassas M. Hepatitis B virus as a risk factor for hepatocellular carcinoma: There is still much work to do. Liver Res 2024;8:83–90. doi: 10.1016/j.livres.2024.05.004. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.World Health Organization . Global hepatitis report 2024: Action for access in low- and middle-income countries. Geneva: World Health Organization, 2024. Available from: https://www.who.int/publications/i/item/9789240091672. [Last accessed on March 24, 2025]. [Google Scholar]
- 4.Gnyawali B, Pusateri A, Nickerson A, Jalil S, Mumtaz K. Epidemiologic and socioeconomic factors impacting hepatitis B virus and related hepatocellular carcinoma. World J Gastroenterol 2022;28:3793–802. doi: 10.3748/wjg.v28.i29.3793. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Flores YN Datta GD Yang L Corona E Devineni D Glenn BA, et al. Disparities in hepatocellular carcinoma incidence, stage, and survival: A large population-based study. Cancer Epidemiol Biomarkers Prev 2021;30:1193–1199. doi: 10.1158/1055-9965.Epi-20-1088. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Kondili LA Lazarus JV Jepsen P Murray F Schattenberg JM Korenjak M, et al. Inequities in primary liver cancer in Europe: The state of play. J Hepatol 2024;80:645–660. doi: 10.1016/j.jhep.2023.12.031. [DOI] [PubMed] [Google Scholar]
- 7.Hsu YC, Huang DQ, Nguyen MH. Global burden of hepatitis B virus: Current status, missed opportunities and a call for action. Nat Rev Gastroenterol Hepatol 2023;20:524–537. doi: 10.1038/s41575-023-00760-9. [DOI] [PubMed] [Google Scholar]
- 8.GBD 2021 Risk Factors Collaborators . Global burden and strength of evidence for 88 risk factors in 204 countries and 811 subnational locations, 1990-2021: A systematic analysis for the Global Burden of Disease Study 2021. Lancet 2024;403:2162–2203. doi: 10.1016/s0140-6736(24)00933-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.GBD 2021 Diseases and Injuries Collaborators . 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;403:2133–2161. doi: 10.1016/s0140-6736(24)00757-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Rosenberg PS, Anderson WF. Age-period-cohort models in cancer surveillance research: Ready for prime time? Cancer Epidemiol Biomarkers Prev 2011;20:1263–1268. doi: 10.1158/1055-9965.Epi-11-0421. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Bell A. Age period cohort analysis: A review of what we should and shouldn’t do. Ann Hum Biol 2020;47:208–217. doi: 10.1080/03014460.2019.1707872. [DOI] [PubMed] [Google Scholar]
- 12.Su Z Zou Z Hay SI Liu Y Li S Chen H, et al. Global, regional, and national time trends in mortality for congenital heart disease, 1990-2019: An age-period-cohort analysis for the Global Burden of Disease 2019 study. EClinicalMedicine 2022;43:101249. doi: 10.1016/j.eclinm.2021.101249. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Falcaro M Castañon A Ndlela B Checchi M Soldan K Lopez-Bernal J, et al. The effects of the national HPV vaccination programme in England, UK, on cervical cancer and grade 3 cervical intraepithelial neoplasia incidence: A register-based observational study. Lancet 2021;398:2084–2092. doi: 10.1016/s0140-6736(21)02178-4. [DOI] [PubMed] [Google Scholar]
- 14.Al Awaidy ST, Ezzikouri S. Moving towards hepatitis B elimination in Gulf Health Council states: From commitment to action. J Infect Public Health 2020;13:221–227. doi: 10.1016/j.jiph.2019.08.004. [DOI] [PubMed] [Google Scholar]
- 15.Mak LY Liu K Chirapongsathorn S Yew KC Tamaki N Rajaram RB, et al. Liver diseases and hepatocellular carcinoma in the Asia-Pacific region: Burden, trends, challenges and future directions. Nat Rev Gastroenterol Hepatol 2024;21:834–851. doi: 10.1038/s41575-024-00967-4. [DOI] [PubMed] [Google Scholar]
- 16.Nguyen VT, Law MG, Dore GJ. Hepatitis B-related hepatocellular carcinoma: Epidemiological characteristics and disease burden. J Viral Hepat 2009;16:453–463. doi: 10.1111/j.1365-2893.2009.01117.x. [DOI] [PubMed] [Google Scholar]
- 17.Cocker F, Chien Yee K, Palmer AJ, de Graaff B. Increasing incidence and mortality related to liver cancer in Australia: Time to turn the tide. Aust N Z J Public Health 2019;43:267–273. doi: 10.1111/1753-6405.12889. [DOI] [PubMed] [Google Scholar]
- 18.Yang J Pan G Guan L Liu Z Wu Y Liu Z, et al. The burden of primary liver cancer caused by specific etiologies from 1990 to 2019 at the global, regional, and national levels. Cancer Med 2022;11:1357–1370. doi: 10.1002/cam4.4530. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.de Villiers MJ, Nayagam S, Hallett TB. The impact of the timely birth dose vaccine on the global elimination of hepatitis B. Nat Commun 2021;12:6223. doi: 10.1038/s41467-021-26475-6. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Xia GL Liu CB Cao HL Bi SL Zhan MY Su CA, et al. Prevalence of hepatitis B and C virus infections in the general Chinese population. Results from a nationwide cross-sectional seroepidemiologic study of hepatitis A, B, C, D, and E virus infections in China, 1992. Int Hepatol Commun 1996;5:62–73. doi: 10.1016/S0928-4346(96)82012-3. [Google Scholar]
- 21.Cui F Shen L Li L Wang H Wang F Bi S, et al. Prevention of chronic hepatitis b after 3 decades of escalating vaccination policy, China. Emerg Infect Dis 2017;23:765–772. doi: 10.3201/eid2305.161477. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22.Polaris Observatory Collaborators . Global prevalence, treatment, and prevention of hepatitis B virus infection in 2016: A modelling study. Lancet Gastroenterol Hepatol 2018;3:383–403. doi: 10.1016/s2468-1253(18)30056-6. [DOI] [PubMed] [Google Scholar]
- 23.Bagcchi S. WHO’s 2024 guidelines to combat hepatitis B. The Lancet Infectious Diseases 2024;24:e360. doi: 10.1016/S1473-3099(24)00308-6. [DOI] [PubMed] [Google Scholar]
- 24.Easterbrook PJ Luhmann N Bajis S Min MS Newman M Lesi O, et al. WHO 2024 hepatitis B guidelines: An opportunity to transform care. Lancet Gastroenterol Hepatol 2024;9:493–495. doi: 10.1016/S2468-1253(24)00089-X. [DOI] [PubMed] [Google Scholar]
- 25.Freeland C Lo W Kabagambe K Wang S Adda D Graham CS, et al. Urgent need for lived experience in hepatitis B guideline development. Lancet Gastroenterol Hepatol 2024;9:282–284. doi: 10.1016/s2468-1253(23)00455-7. [DOI] [PubMed] [Google Scholar]
- 26.Conners EE Panagiotakopoulos L Hofmeister MG Spradling PR Hagan LM Harris AM, et al. Screening and testing for hepatitis B virus infection: CDC recommendations - United States, 2023. MMWR Recomm Rep 2023;72:1–25. doi: 10.15585/mmwr.rr7201a1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Toy M, Hutton D, Harris AM, Nelson N, Salomon JA, So S. Cost-effectiveness of 1-time universal screening for chronic hepatitis b infection in adults in the United States. Clin Infect Dis 2022;74:210–217. doi: 10.1093/cid/ciab405. [DOI] [PubMed] [Google Scholar]
- 28.Singal AG Sanduzzi-Zamparelli M Nahon P Ronot M Hoshida Y Rich N, et al. International Liver Cancer Association (ILCA) white paper on hepatocellular carcinoma risk stratification and surveillance. J Hepatol 2023;79:226–239. doi: 10.1016/j.jhep.2023.02.022. [DOI] [PubMed] [Google Scholar]
- 29.Qurashi M, Sharma R. Improving hepatocellular carcinoma surveillance in the United Kingdom: Challenges and solutions. Lancet Reg Health Eur 2024;43:100963. doi: 10.1016/j.lanepe.2024.100963. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Singal AG Yopp AC Gupta S Skinner CS Halm EA Okolo E, et al. Failure rates in the hepatocellular carcinoma surveillance process. Cancer Prev Res (Phila) 2012;5:1124–1130. doi: 10.1158/1940-6207.Capr-12-0046. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Lee A, Hilmers D, Russell T. A new hepatitis B elimination strategy for remote populations is needed. Lancet Reg Health West Pac 2024;48:101129. doi: 10.1016/j.lanwpc.2024.101129. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 32.Rehm J Patra J Brennan A Buckley C Greenfield TK Kerr WC, et al. The role of alcohol use in the aetiology and progression of liver disease: A narrative review and a quantification. Drug Alcohol Rev 2021;40:1377–1386. doi: 10.1111/dar.13286. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Wang CC, Tseng TC, Kao JH. Hepatitis B virus infection and metabolic syndrome: Fact or fiction? J Gastroenterol Hepatol 2015;30:14–20. doi: 10.1111/jgh.12700. [DOI] [PubMed] [Google Scholar]
- 34.Cao M Xia C Cao M Yang F Yan X He S, et al. Attributable liver cancer deaths and disability-adjusted life years in China and worldwide: Profiles and changing trends. Cancer Biol Med 2024;21:679–691. doi: 10.20892/j.issn.2095-3941.2024.0149. [DOI] [PMC free article] [PubMed] [Google Scholar]