The changing etiology of liver cancer: A comparative study of global and Chinese burden trends from hepatitis dominance to metabolic risks (1990-2021) and forecasts to 2035.

Background and aims: Liver cancer remains a major global health burden with a complex and shifting epidemiology. While viral hepatitis continues to drive significant morbidity, metabolic risk factors are increasingly contributing to the incidence of liver cancer. Utilizing data from the Global Burden of Disease (GBD) Study 2021, this analysis examines China's incidence, prevalence, and age-standardized disability-adjusted life year (DALY) rates for liver cancer from 1990 to 2021, comparing these trajectories against global and regional patterns. This study further analyzed the correlations between liver cancer burden and socioeconomic development, aiming to provide evidence for targeted intervention strategies and health policy formulation. Methods: This study utilized data from the Global Burden of Disease Study 2021 to analyze the burden of liver cancer from 1990 to 2021 across 204 countries and territories. Standardized methodologies were used to estimate prevalence, incidence and DALYs. The Socio-demographic index (SDI) was applied to evaluate Socioeconomic disparities. Joinpoint regression was employed to analyze temporal trends, and age-period-cohort modeling was applied to estimate drivers of disease burden. Age-standardized rates were projected to 2035 using statistical modeling techniques. Results: Globally, the absolute number of liver cancer cases increased continuously, whereas age-standardized rates declined from 1990 to 2021. Prevalent cases increased by 113.7% (from 345,912.7 to 739,299.5), incident cases increased by 116.2% (from 244,689.4 to 529,202.5), and total DALYs grew by 70.6% (from 7,553,666.8 to 12,887,652.4); the age-standardized DALY rate (ASDR) declined with an estimated annual percentage change (EAPC) of -0.6 (95% CI -0.72 to -0.48). Hepatitis B-related DALYs decreased significantly, while non-alcoholic steatohepatitis (NASH) and alcohol-related cases increased. China achieved marked reductions in age-standardized rates: the age-standardized incidence rate (ASIR) decreased from 10.6 to 9.5 per 100,000 (EAPC -0.28, 95% CI -0.42 to -0.13), and the ASDR fell from 334.5 to 239.9 per 100,000 (EAPC -1.16, 95% CI -1.34 to -0.98), especially in hepatitis B, though metabolic-related burdens grew. Prevalent cases in China doubled (from 132,779.2 to 265,539.4) and incident cases rose by 104.0% (from 96,434.3 to 196,636.6). Gender and age disparities were evident, with males and older adults bearing higher burdens. High-income regions saw rising metabolic-related rates, whereas low- and middle-income areas faced persistent viral hepatitis burdens. Projections suggest a continued rise in metabolic-related liver cancer globally, with NASH-related rates accelerating fastest in China, underscoring the need for dual preventive strategies targeting both infection and lifestyle factors. Conclusions: The global burden of liver cancer is undergoing an epidemiological transition, marked by declining viral hepatitis-related rates but rising metabolic- and alcohol-related cases. Significant reductions in age-standardized rates were observed in China, though absolute case number increased. Socioeconomic and geographic disparities persist, with high-income regions facing growing metabolic burdens. Future trends emphasize the need for integrated strategies addressing both infectious and lifestyle-related risk factors.