Re: Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer.

Shaheen et al. (1) recently reported that carriers of hemochromatosis (HFE) gene mutations have a statistically significantly increased risk of colon cancer. Taken together with other recent findings (2), these results suggest that heterozygosity for hemochromatosis confers increased risk of both colon cancer and cardiovascular disease in the approximately 15% of the U.S. population who are HFE gene mutation carriers. However, Shaheen et al. (1) may have underestimated the strength of the association between colon cancer risk and HFE gene mutations because of the potential for delayed diagnosis of colon cancer among HFE gene mutation carriers who often have elevated levels of stored iron. Increased stored iron may delay the diagnostic sign of anemia because, for a given rate of microbleeding, a subject with more stored iron will require more time to exhaust iron stores and then compromise erythropoiesis. Because HFE gene mutation carriers tend to have elevated levels of stored iron, they might be less likely than agematched control subjects without HFE gene mutations to be diagnosed with an existing colon cancer because they would require more time to develop anemia. Healthy subjects without any stored iron, i.e., iron-depleted subjects, might not only be protected from the potentially prooxidant and carcinogenic effects of excessive iron, as suggested by Shaheen et al. (1), but would also be more likely to develop anemia early if they did develop a microbleeding colon cancer. Blood contains approximately 0.5 mg of iron per mL. Typical, middleaged North American men have approximately 1000 mg of stored elemental iron. For a colonic lesion that sheds 2 mL of blood per day, 1000 days of bleeding would have to pass before iron deficiency anemia would appear. A period of 1000 days would often be enough for a cancer to progress to an inoperable stage. In an iron-depleted subject with essentially no stored iron, an excess iron loss of 1 mg per day would produce anemia in a matter of days to weeks rather than over months to years. An effect of stored iron in delaying cancer diagnosis argues against the traditional view that stored iron is benign. Recommendations that iron depletion be avoided are not based on controlled clinical trials, but rather, on long-standing, customary practices. Stored iron is iron in excess of that needed to maximize hemoglobin levels. There is no good evidence that stored iron has any beneficial function except to prevent anemia from chronic blood loss. (Clearly, no amount of stored iron can prevent anemia in the event of sudden blood loss.) However, this “protective” effect of stored iron may also function to defer symptoms and delay diagnosis of colon