Metabolic Risk Factors for Hepatocellular Carcinoma in Patients with Nonalcoholic Fatty Liver Disease: A Prospective Study

SIMPLE SUMMARY: About 30% of Americans have nonalcoholic fatty liver disease (NAFLD), and some of these individuals may develop hepatocellular carcinoma (HCC), a frequently fatal cancer. A major current challenge is how to identify those NAFLD patients who are likely to progress to HCC. Metabolic conditions such as obesity and diabetes may drive the progression of NAFLD to HCC, but the extent of risks associated with these conditions is unknown. The aim of this study was to assess the magnitudes of risk and population-attributable risk fractions associated with various metabolic conditions regarding HCC risk. Our study shows that NAFLD patients with diabetes have the highest risk for developing HCC, followed by those with metabolic syndrome and then obesity. Because the incidence of NAFLD is expected to increase further, these results are important for designing targeted strategies to prevent HCC development in NAFLD patients with high-risk metabolic conditions. ABSTRACT: Non-alcoholic fatty liver disease (NAFLD) is a fast-growing public health problem and predisposes to hepatocellular carcinoma (HCC) in a significant proportion of patients. Metabolic alterations might underlie the progression of NAFLD to HCC, but the magnitudes of risk and population-attributable risk fractions (PAFs) for various metabolic conditions that are associated with HCC risk in patients with NAFLD are unknown. We investigated the associations between metabolic conditions and HCC development in individuals with a prior history of NAFLD. The study included 11,245 participants in the SEER-Medicare database, comprising 1310 NAFLD-related HCC cases and 9835 NAFLD controls. We excluded individuals with competing liver diseases (e.g., alcoholic liver disease and chronic viral hepatitis). Baseline pre-existing diabetes mellitus, dyslipidemia, obesity, hypertension, hypothyroidism, and metabolic syndrome were assessed. Multivariable-adjusted logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs). PAFs were also calculated for each metabolic condition. The results show that diabetes (OR = 2.39, 95% CI: 2.04–2.79), metabolic syndrome (OR = 1.73, 95% CI: 1.49–2.01), and obesity (OR = 1.62, 95% CI: 1.43–1.85) were associated with a higher HCC risk in individuals with NAFLD. The highest PAF for HCC was observed for pre-existing diabetes (42.1%, 95% CI: 35.7–48.5), followed by metabolic syndrome (28.8%, 95% CI: 21.7–35.9) and obesity (13.2%, 95% CI: 9.6–16.8). The major predisposing factors for HCC in individuals with NAFLD are diabetes mellitus, metabolic syndrome, and obesity, and their control would be critically important in mitigating the rising incidence of NAFLD-related HCC.