CORRESPONDENCE

Re: Association Between Hemochromatosis (HFE) Gene Mutation Carrier Status and the Risk of Colon Cancer

Jerome L. Sullivan

Affiliation of author: Department of Pathology, Immunology and Laboratory Medicine, University of Florida, College of Medicine, Gainesville, FL.

Correspondence to: Jerome L. Sullivan, M.D., Ph.D., 315 Salvador Square, Winter Park, FL 32789 (e-mail: jlsullivan{at}pol.net).

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 age-matched 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, middle-aged 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 cancer or other diseases associated with slow chronic bleeding. Given the emerging role of iron in cardiovascular diseases (2,35), carcinogenesis (1), diabetes (6), and infectious diseases (7), as well as its potential for delaying cancer diagnosis, the burden of proof should rest with those who believe that stored iron is safe. Shaheen et al. (1) state that limiting iron intake as a way to lower cancer risk is "highly speculative." However, this idea is not unreasonable considering that the safety of stored iron has not been established in scientifically objective studies.

REFERENCES

1 Shaheen NJ, Silverman LM, Keku T, Lawrence LB, Rohlfs EM, Martin CF, et al. Association between hemochromatosis (HFE) gene mutation carrier status and the risk of colon cancer. J Natl Cancer Inst 2003;95:154–9.[Abstract/Free Full Text]

2 Sullivan JL, Zacharski LR. Hereditary haemochromatosis and the hypothesis that iron depletion protects against ischemic heart disease. Eur J Clin Invest 2001;31:375–7.[CrossRef][ISI][Medline]

3 Sullivan JL. Iron and the sex difference in heart disease risk. Lancet 1981;1:1293–4.[ISI][Medline]

4 de Valk B, Marx JJ. Iron, atherosclerosis, and ischemic heart disease. Arch Intern Med 1999;159:1542–8.[Abstract/Free Full Text]

5 Sullivan JL. Are menstruating women protected from heart disease because of, or in spite of, estrogen? Relevance to the iron hypothesis. Am Heart J 2003;145:190–4.[CrossRef][ISI][Medline]

6 Facchini FS, Saylor KL. Effect of iron depletion on cardiovascular risk factors: studies in carbohydrate-intolerant patients. Ann N Y Acad Sci 2002;967:342–51.[Abstract/Free Full Text]

7 Sullivan JL, Weinberg ED. Iron and the role of Chlamydia pneumoniae in heart disease. Emerg Infect Dis 1999;5:724–6.[ISI][Medline]


This article has been cited by other articles in HighWire Press-hosted journals:


             
Copyright © 2003 Oxford University Press (unless otherwise stated)
Oxford University Press Privacy Policy and Legal Statement