Global trends in metabolic-associated hepatocellular carcinoma: genetic and socio-demographic drivers

Metabolic dysfunction-associated steatotic liver disease (MASLD) has emerged as a primary driver of hepatocellular carcinoma (HCC). However, the synergistic impact of ancestral genetic susceptibility and socio-demographic transitions on the global MASLD-HCC landscape remains insufficiently quantified.

Using GBD 2021 data, we analyzed MASLD-HCC mortality and DALYs across 204 countries (1990-2021). Temporal trends were quantified using Joinpoint-derived average annual percent change (AAPC). We integrated ancestry-weighted risk allele frequencies (RAF) for five high-impact SNPs (PNPLA3, TM6SF2, MBOAT7, GCKR, HSD17B13) into GBD regions and utilized frontier and inequality analyses to evaluate socio-demographic drivers and 2050 projections.

In 2021, sub-Saharan Africa exhibited the highest mortality age-standardized rates (up to 1.09/100,000), while high-income super regions and Southern Latin America showed the most rapid historical increases (AAPC: 2.88% to 4.19%). Genetic-epidemiological mapping revealed that regional mortality burden was strongly correlated with PNPLA3 (ρ = 0.663, p = 0.001) and GCKR (ρ = 0.662, p = 0.001) risk frequencies, while HSD17B13 exerted a protective effect (ρ = -0.562, p = 0.008). The concentration index shifted toward zero (from - 0.0752 to - 0.0459), indicating an epidemiological convergence and global homogenization of the MASLD-HCC epidemic. By 2050, high-income super regions are projected to experience a disproportionate 52.11% surge in mortality, reflecting a significant delayed burden of cumulative metabolic risk exposure.

The MASLD-HCC landscape is transitioning toward global prevalence, driven by genetic architecture and metabolic shifts. This narrowing inequality gap and impending mortality surge necessitate genetically-informed precision prevention and re-evaluation of metabolic-oncology surveillance.