Fatty liver index and AST/ALT ratio for hepatocellular carcinoma prediction in low-risk Korean men: Results from the HEXA-G cohort

Background: The prognostic utility of the fatty liver index (FLI, a steatosis index derived from BMI, waist circumference, triglycerides, and GGT) and AST/ALT (De Ritis) ratio for hepatocellular carcinoma (HCC) risk in low-risk Asian populations is not well defined. We evaluated their independent and incremental predictive value in a large Korean cohort. Methods: We analyzed 43,981 Korean men (376 HCC cases) from the Health Examinees-Gem (HEXA-G) cohort (2004-2013). A low-risk subcohort (n = 39,033) was defined by excluding individuals with diabetes or chronic hepatitis. Multivariable Cox models assessed associations with log-transformed FLI and the AST/ALT ratio after adjusting for demographic, lifestyle, socioeconomic, and metabolic factors. Incremental predictive value was evaluated using likelihood ratio tests (LRTs), changes in C-statistics, and Bayesian Information Criterion (BIC). Sensitivity analyses using penalized regression produced similar results. Results: In univariable analyses, the AST/ALT ratio showed crude associations with HCC, whereas FLI did not. After adjustment, this pattern reversed: the AST/ALT ratio became non-predictive-consistent with confounding by age, alcohol consumption, smoking, and metabolic factors-while log(FLI) emerged as a modest independent predictor in the low-risk subcohort (adjusted HR 1.08; 95% CI, 1.01-1.16; p = 0.04). Discrimination improved minimally (C-statistic 0.715 to 0.719), and conventional FLI categories failed to stratify risk. In the full cohort, log(FLI) remained independently associated with HCC (adjusted HR 1.11; 95% CI, 1.03-1.20; p = 0.009) and modestly improved model fit (LRT p = 0.011) without meaningfully improving discrimination (C-statistic 0.795 to 0.797). The De Ritis ratio added no independent or incremental value in any model. Conclusions: Across low-risk and mixed-risk Korean men, FLI remained an independent predictor of HCC after adjustment, although the effect size was modest. In contrast, the AST/ALT ratio lost all prognostic value after accounting for demographic, lifestyle, and metabolic confounding. The reversal of crude versus adjusted associations underscores substantial confounding for AST/ALT and a small, metabolically related signal for FLI. Overall, these findings highlight that FLI provides some independent information in low-risk settings, but substantial improvement in HCC risk prediction will require more robust biomarkers.