Background 
Higher dietary iron intake, particularly heme iron, has been hypothesized to increase hepatocellular carcinoma (HCC) risk through iron-mediated oxidative stress and chronic liver injury, but evidence remains limited and inconsistent. Existing studies have rarely distinguished between heme and non-heme iron subtypes and there are few data on anatomically related biliary tract cancers.
Objectives 
To investigate the associations between dietary total, heme and non-heme iron intakes and the risk of HCC and other hepatobiliary cancers in a large prospective European cohort. 
Methods 
Within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, we included 367,517 men and women with baseline dietary and lifestyle data from validated questionnaires. Intakes of total, heme and non-heme iron were derived from food composition databases and energy-adjusted using the residual method. First incident HCC, intrahepatic bile duct cancer (IBD), extrahepatic bile duct cancer (EBD), gallbladder cancer (GBC) and ampulla of Vater cancer (AOV) were ascertained through cancer registries and active follow-up. Cox proportional hazards models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) per 1-standard deviation (SD) increase in iron intakes, stratified by study center, sex and age at recruitment, and adjusted for major lifestyle, anthropometric, socioeconomic and dietary factors. Sensitivity analyses were conducted excluding the first two years of follow-up.
Results
During a median follow-up of 14.9 years, 211 HCC, 69 IBD, 70 EBD, 70 GBC and 53 AOV cases were identified with available data. For HCC, higher total and non-heme iron intakes were associated with lower risk. In multivariable models, the HRs per 1-SD increase were 0.81 (95% CI: 0.70–0.94; p=0.005) for total iron and 0.82 (95% CI: 0.71–0.96; p=0.011) for non-heme iron. Heme iron intake was not significantly associated with HCC (HR: 0.95; 95% CI: 0.82–1.10; p=0.504). For IBD, higher non-heme iron intake was associated with a lower risk (HR: 0.72; 95% CI: 0.55–0.95; p=0.022) and total iron showed a similar association (HR: 0.75; 95% CI: 0.57–0.98; p=0.036), whereas heme iron did not (HR: 0.95; 95% CI: 0.73–1.23; p=0.705). For EBD, heme iron was positively associated with risk (HR: 1.25; 95% CI: 1.00–1.55; p=0.048), while non-heme iron (HR: 0.99; 95% CI: 0.74–1.32; p=0.937) and total iron (HR: 1.05; 95% CI: 0.81–1.37; p=0.690) were not. For GBC, the corresponding HRs were 0.81 (95% CI: 0.57–1.13; p=0.215) for heme, 1.03 (95% CI: 0.77–1.39; p=0.831) for non-heme, and 0.96 (95% CI: 0.71–1.29; p=0.794) for total iron; for AOV, the HRs were 0.72 (95% CI: 0.49–1.05; p=0.086), 0.81 (95% CI: 0.58–1.12; p=0.199), and 0.81 (95% CI: 0.59–1.11; p=0.184), respectively. Results were similar after excluding the first two years of follow-up.
Conclusions  
In this large European cohort, higher dietary intakes of total and non-heme iron were associated with lower risk of HCC and were suggestive of a lower risk of IBD. Higher heme iron intake showed no clear association with risks of HCC, IBD, GBC or AOV, whereas a suggestive positive association with EBD was observed.