Causal Relationship Between Liver Iron Content, Liver Fat Percentage, Liver Volume, and Hepatocellular Carcinoma: A Mendelian Randomization Study

Objective: To investigate the causal relationship between liver iron content, percent liver fat, liver volume, and hepatocellular carcinoma (HCC), using Mendelian randomization (MR). Methods Tools from public databases were utilized as instrumental variables to analyze the links between the exposure factors (liver iron content, percent liver fat, and liver volume) and the outcome (HCC) through two-sample Mendelian randomization analysis. The inverse-variance weighted method (IVW) was employed for the primary analysis, with MR-Egger regression, weighted median, simple mode, and weighted mode as the supplementary methods. The causal relationship among liver iron content, percent liver fat, liver volume, and HCC was evaluated using the effect indicator odds ratio (OR) and 95% confidence interval (CI). Leave-one-out analysis, heterogeneity tests, and horizontal pleiotropy tests were performed to validate the stability and reliability of the results. Results The IVW for liver iron content was OR = 1.0009, 95% CI: 1.0005–1.0013, using 10 single nucleotide polymorphisms (SNPs) as instrumental variables. The IVW for percent liver fat with 10 SNPs as instrumental variables was OR = 1.0015, 95% CI: 1.0012–1.0019. The IVW for liver volume was OR = 1.0009, 95% CI: 0.9996–1.0023, using 11 SNPs as instrumental variables. The IVW p-values for liver iron content and percent liver fat were less than 0.05, indicating a causal relationship with HCC. However, the IVW p-value for liver volume was greater than 0.05, suggesting no causal relationship between liver volume and HCC. Conclusion This study revealed that higher liver iron content and percent liver fat were associated with an increased risk of hepatocellular carcinoma. However, no causal relationship was established between liver volume and HCC.