The aetiopathogenesis of colorectal carcinoma (CRC) remains the holy grail for researchers in the field. CRC arises from benign neoplasms and evolves into adenocarcinoma through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations are associated with specific steps in this polyp-adenocarcinoma sequence and are believed to drive the histological progression towards colon cancer. Approximately 50% of CRCs are attributed to dietary factors and about 15–20% to genetic factors, including the high risk familial syndromes.¹ Large prospectively collected epidemiological data have suggested that iron may confer an increased risk for CRC.²

WHAT ARE THE MECHANISMS BY WHICH IRON CONFERS AN INCREASED RISK OF CRC?

An apparent dose-response for serum ferritin level and adenoma risk suggests that exposure to dietary iron may be involved in the development of colorectal adenomas (and particularly proximal adenomas).³ Dietary haem iron (through its effect on epithelial proliferation) is associated with an increased risk of proximal colon cancer, especially in women who drink alcohol.⁴ In the dextran sodium sulphate model of mouse colitis, a twofold increase in dietary iron increased iron accumulation in colonic luminal contents at the colonic mucosal surface and in superficial epithelial cells with a concomitant increase in colitis associated CRC incidence.⁵ High dietary iron decreases tocopherol levels in rat colonocytes, promotes oxidative stress (through generation of lipid peroxides and reactive oxygen species (ROS)) in faeces and colonocytes,^6–,⁸ and decreases the activity of the colonic antioxidant enzyme manganese superoxide dismutase.⁹ ROS activation of activator protein 1 and nuclear factor κB signal transduction pathways leads to transcription of genes involved in cell growth regulatory pathways.¹⁰

In addition, some studies suggest that possession of HFE gene mutations are statistically associated with increased rates of CRC, …