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Aspirin-Associated Iron Loss: An Anticancer Mechanism Even in the Short Term?

      To the Editor:
      Mills et al
      • Mills E.J.
      • Wu P.
      • Alberton M.
      • Kanters S.
      • Lanas A.
      • Lester R.
      Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials.
      demonstrated that the benefits of low-dose aspirin on cancer mortality protection seem to begin in the short term (∼4 years). The authors suggested that these benefits likely were based on pleiotropic effects, rather than only on antithrombotic action. Indeed, these data confirm a previous suggestion that an anticarcinogenic mechanism of prolonged aspirin use may be related to aspirin-induced chronic iron loss.
      • Mascitelli L.
      • Pezzetta F.
      • Sullivan J.L.
      Aspirin-associated iron loss as an anticancer mechanism.
      Losses of stored iron are possible even in aspirin users with clinically undetectable occult gastric bleeding. In iron depletion, less iron may be available for carcinogenesis through free radical–mediated mechanisms and for promotion of tumor growth. Although in the short term, duration of use is an important factor in the cancer-preventive action of aspirin.
      • Mills E.J.
      • Wu P.
      • Alberton M.
      • Kanters S.
      • Lanas A.
      • Lester R.
      Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials.
      This is compatible with a chronic iron-loss mechanism, because continual losses have a cumulative effect on stored iron load.
      Observational studies suggest the magnitude of aspirin-mediated iron loss. The Framingham Study
      • Fleming D.J.
      • Jacques P.F.
      • Massaro J.M.
      • D'Agostino Sr, R.B.
      • Wilson P.W.
      • Wood R.J.
      Aspirin intake and the use of serum ferritin as a measure of iron status.
      found that mean serum ferritin was lower among categories of regular aspirin users by 21% to 50%. In a Danish population,
      • Milman N.
      • Ovesen L.
      • Byg K.
      • Graudal N.
      Iron status in Danes updated 1994 I: prevalence of iron deficiency and iron overload in 1332 men aged 40-70 years. Influence of blood donation, alcohol intake, and iron supplementation.
      aspirin use was associated with serum ferritin values 20% lower than those of nonusers. Postmenopausal women in the Nurses' Health Study
      • Liu J.M.
      • Hankinson S.E.
      • Stampfer M.J.
      • Rifai N.
      • Willett W.C.
      • Ma J.
      Body iron stores and their determinants in healthy postmenopausal US women.
      who used aspirin 15 to 30 times per month had a 19% lower mean serum ferritin value than nonusers.
      A protective effect of iron loss against cancer mortality has been confirmed in a randomized trial with subjects randomized to reduction in iron stores or observation.
      • Zacharski L.R.
      • Chow B.K.
      • Howes P.S.
      • et al.
      Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.
      The iron reduction group experienced a 35% decrease in mean serum ferritin, that is, of the same order of magnitude reported with aspirin use.
      • Fleming D.J.
      • Jacques P.F.
      • Massaro J.M.
      • D'Agostino Sr, R.B.
      • Wilson P.W.
      • Wood R.J.
      Aspirin intake and the use of serum ferritin as a measure of iron status.
      • Milman N.
      • Ovesen L.
      • Byg K.
      • Graudal N.
      Iron status in Danes updated 1994 I: prevalence of iron deficiency and iron overload in 1332 men aged 40-70 years. Influence of blood donation, alcohol intake, and iron supplementation.
      • Liu J.M.
      • Hankinson S.E.
      • Stampfer M.J.
      • Rifai N.
      • Willett W.C.
      • Ma J.
      Body iron stores and their determinants in healthy postmenopausal US women.
      Over just 4.5 years, the risk of new visceral malignancy was significantly lower in the iron reduction group than in controls; among patients with new cancers, those with iron reduction had highly significantly lower cancer-specific and all-cause mortality. Of note, cumulative risk curves for the intervention and control groups began to separate at 6 months, that is, after only 1 phlebotomy.
      • Zacharski L.R.
      • Chow B.K.
      • Howes P.S.
      • et al.
      Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.
      Therefore, progressive iron loss from mucosal microbleeding, previously considered only as an undesirable side effect, could be a mechanism of cancer prevention from prolonged aspirin use, even in the relatively short term.

      References

        • Mills E.J.
        • Wu P.
        • Alberton M.
        • Kanters S.
        • Lanas A.
        • Lester R.
        Low-dose aspirin and cancer mortality: a meta-analysis of randomized trials.
        Am J Med. 2012; 125: 560-567
        • Mascitelli L.
        • Pezzetta F.
        • Sullivan J.L.
        Aspirin-associated iron loss as an anticancer mechanism.
        Med Hypotheses. 2010; 74: 78-80
        • Fleming D.J.
        • Jacques P.F.
        • Massaro J.M.
        • D'Agostino Sr, R.B.
        • Wilson P.W.
        • Wood R.J.
        Aspirin intake and the use of serum ferritin as a measure of iron status.
        Am J Clin Nutr. 2001; 74: 219-226
        • Milman N.
        • Ovesen L.
        • Byg K.
        • Graudal N.
        Iron status in Danes updated 1994.
        Ann Hematol. 1999; 78: 393-400
        • Liu J.M.
        • Hankinson S.E.
        • Stampfer M.J.
        • Rifai N.
        • Willett W.C.
        • Ma J.
        Body iron stores and their determinants in healthy postmenopausal US women.
        Am J Clin Nutr. 2003; 78: 1160-1167
        • Zacharski L.R.
        • Chow B.K.
        • Howes P.S.
        • et al.
        Decreased cancer risk after iron reduction in patients with peripheral arterial disease: results from a randomized trial.
        J Natl Cancer Inst. 2008; 100: 996-1002

      Linked Article

      • Low-dose Aspirin and Cancer Mortality: A Meta-analysis of Randomized Trials
        The American Journal of MedicineVol. 125Issue 6
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          Low-dose aspirin is a common strategy for preventing cardiovascular disease and associated mortality. A recent individual patient data meta-analysis of 8 trials of low- and high-dose aspirin, with long-term follow-up, found important reductions in cancer mortality. We aimed to determine whether cancer mortality also is reduced by low-dose aspirin in the shorter term.
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