Increased Risk of Early-Onset Endometrial Cancer in Women Aged 20–39 Years with Non-Alcoholic Fatty Liver Disease: A Nationwide Cohort Study

<b>Background/Objectives</b>: Given the rising incidence of early-onset endometrial cancer diagnosed before the age of 50 years, this study examined whether non-alcoholic fatty liver disease (NAFLD) served as an independent risk factor for early-onset endometrial cancer, irrespective of obesity status. <b>Methods</b>: This nationwide cohort study included 2,311,949 Korean women aged 20-39 years who underwent health screenings from 2009 to 2012. NAFLD severity was classified based on the fatty liver index: none (<30), moderate (30-59), and severe (≥60). Multivariable-adjusted Cox proportional hazards models were applied to estimate adjusted hazard ratios (aHRs) for early-onset endometrial cancer. <b>Results</b>: During a median follow-up of 7.6 years, 1289 women developed early-onset endometrial cancer. The cumulative incidence of early-onset endometrial cancer was significantly higher in women with NAFLD than in those without (log-rank <i>p</i> < 0.001). A dose-dependent association was observed, with increased risk corresponding to greater NAFLD severity (aHR [95% confidence interval (CI)]: moderate NAFLD, 2.38 [1.99-2.85]; severe NAFLD, 5.39 [4.44-6.53]; <i>p</i> for trend < 0.01). Compared with non-obese women without NAFLD, the aHRs for early-onset endometrial cancer were 2.53 [2.11-3.05] in non-obese women with NAFLD, 1.66 [1.10-2.52] in obese women without NAFLD, and 4.30 [3.60-5.13] in obese women with NAFLD (synergy index = 1.50, <i>p</i> < 0.01). <b>Conclusions</b>: NAFLD was independently associated with increased risk of early-onset endometrial cancer in both non-obese and obese women. Furthermore, young women with both NAFLD and obesity exhibited a synergistically elevated risk. Early identification and management of NAFLD may help mitigate the rapidly growing burden of early-onset endometrial cancer.