Iron supplementation? Ferritin screening? Why questions persist

Studies on donor iron nutrition have enjoyed a long history. In 1958 a publication in the Scandinavian Journal of Clinical and Laboratory Investigation suggested, based on increases in serum iron after oral iron administration to blood donors, that their stores were reduced.1 This observation prompted the investigators to recommend "that blood donors should be given additional iron from the very first donation." Over the next 60 years, the association between blood donation and reduced iron stores has been, and continues to be, confirmed enthusiastically. Many of the contributing publications have appeared in this journal, and the current edition, in adding to the accumulating literature, is no exception. While some will question why it is necessary to continue funding donor iron research, part of the answer might be that it is only recently, at least in the United States, that guidelines have been proposed to more comprehensively address the extensively documented consequences of blood donation on iron balance. These guidelines appeared in the AABB Donor Iron Deficiency Risk-Based Decision-Making Assessment Report of 2018.2 The report favored iron supplementation and ferritin testing as the preferred options for risk management. Granted, there have been occasional earlier appeals to mitigate donor iron depletion. For example, in 2002 a workshop looked at programs to prevent iron deficiency in female blood donors of childbearing age.3 At that time, a panel of blood bankers included some who favored iron replacement, provided it was safe, but the panel decided that more research was necessary. The US Food and Drug Administration has also set the stage on a number of occasions for discussions about donor iron balance. In 2008, the agency's Blood Products Advisory Committee (BPAC) voted unanimously that iron depletion was a concern, but no consensus recommendations for management strategies emerged.4 Then again, in 2016, the agency asked their Advisory Committee to consider "if teenage blood donors are more susceptible to developing iron deficiency and the resulting short- and long-term effects."5 In an opening address at this meeting, the speaker from the Office of Blood Research and Review reported "… we also know that iron deficiency impacts cognition, even in the absence of anemia. Therefore, iron-deficient adolescents are at risk of impaired executive functioning." To this writer, it seemed that the agency had already made up its mind, albeit prematurely, about perilous intellectual risks for young donors. However, the apparent confidence implicit in the opening statements was not shared by all the committee members, one of whom characterized the briefing information on cognitive achievement as "weak." Others have similarly criticized studies associating iron deficiency, alone, with neurocognitive sequelae. The authors of a systematic review and meta-analysis on the topic, for example, lamented that published studies were "generally small, short, and methodically weak."6 Convincing evidence of damaging intellectual sequelae due to storage iron deficiency was also disputed by the AABB Donor Iron Deficiency Assessment Working Group. In their report, risk for cognitive performance in adolescents, as well as risk for ongoing brain development, adverse pregnancy outcomes, and fetal development, was described as "theoretical."2 A similarly judicious assessment appears in the current paper by Spencer and coworkers7 concerning the risk for iron depletion in high school blood donors, which notes that any clinical impact "may be subtle and challenging to detect." If detection is difficult, it is not because populations allegedly at risk are limited in numbers. Iron deficiency anemia is the commonest nutritional deficiency in the world. Even in ostensibly healthy teenagers, the Spencer paper reports that some 18% of 16- to 18-year-old females, with no history of donation, have ferritin levels less than 12 ng/mL. Against this background, while there has been ample opportunity to reveal storage iron deficiency–related health morbidities, confirmation has not been realized, neither in populations at large nor in teenage blood donors. Nonetheless, lack of evidence has not tempered the opinions of the study authors, who urge precaution in the face of a potential for "more serious health consequences." This is not to say that cognitive performance as an adult escapes any influence of risk factors encountered during youth. For example, the Young Finns study followed a cohort of more than 3000 children for 31 years.8 In follow-up, their cognitive ability in midlife was associated with earlier cardiovascular risk factors, such as hypertension and hypercholesterolemia, and impaired cognitive performance was independent of any events as adults. Investigations of this caliber are a rarity, but they are a reminder that the threat of cognitive impairment, if indeed real, but subtle, might demand decades-long studies, as well as decades-long funding, which could be difficult to secure against competing studies with much shorter turnaround times. They are also a reminder that scale is an essential contributor to confidence in results. Lack of scale in some studies, especially in studies concerning neurocognitive disability, weakens evidence and is another reason why questions linger about the interventions favored in the Donor Iron Deficiency Assessment Report. An example of scale inadequate to justify conclusions comes from the two articles that the report cited as "some of the strongest evidence" for iron supplementation of iron deficient women in improving cognitive function.9, 10 The combined number of women who were iron supplemented and completed the studies was 62. Such studies are valuable in generating hypotheses, but they are no substitute for large-scale studies that would determine if interventions that are successful in small research settings are equally applicable to the donor base at large (or, to quote a phrase used at a BPAC meeting, once they are "exported to the population at large").4 A similarly cautionary reminder emerged in a letter to the editor of the Lancet, which had published one of the two papers the report cited as evidence confirming a role for iron supplementation. Readers were reminded that the study "should not be mistaken for a pragmatic trial designed to confirm whether any potential benefit could be realized in practice."11 It is disappointing that no definitive trial has yet been conducted. Suitably scaled studies of donor health are few, but there are examples. The Interval Study looked at the effects on donor safety when interdonation intervals for volunteers presenting at blood centers in England were reduced over a 2-year period.12 Analysis of responses to health survey questionnaires given to more than 25,000 participating donors did not show any effect on quality of life or cognitive function despite increases in the frequency of donation above standard practice. In another study conducted at an appropriate scale on more than 16,000 Danish donors, there was no evidence for an association between reduced iron stores, as measured by serum ferritin, and self-reported health-related quality of life.13 Another suitably scaled study from Rigas and colleagues14 appears in this edition. Using national data, they report that scholastic achievement was not influenced by the frequency of donation before pregnancy. Ethical considerations also contribute to reluctance to embrace the preferred interventions recommended in the Donor Iron Deficiency Assessment Report. The report failed to comment on how implementing iron supplementation and ferritin testing would change the relationships between some donors and their blood program to relationships more akin to those between patients and physicians. One of the co-authors of the paper by Spencer and colleagues7 had expressed this opinion at the earlier BPAC meeting when studies on donor iron supplementation were being discussed. He remarked "I don't think we do donors a service when we turn them into patients."4 With a change in the relationship between the donor and the blood program, new responsibilities emerge. For those invoking the precautionary principle in the belief that there is evidence for adverse sequelae, such as cognitive deficiency, attributable to iron deficiency alone, then the presence of adequate iron stores, as measured by serum ferritin, should become a qualifying test for donors, lest individuals who pass the hemoglobin threshold but have reduced stores are accepted as donors. This will be inconvenient. There is currently no suitable point-of-care ferritin assay, and donors would have to return later, once their ferritin results become available, before being allowed to donate. Inconvenience, however, has never been a strong argument against ethically responsible conduct. The ethical responsibility on the part of blood programs to ensure that storage iron–deficient donors are not drawn extends to how best to manage those individuals who return to donate but, upon being asked, say that they decided not to take supplemental iron or, for whatever reason, did not complete the recommended course. If primum non nocere applies, these individuals should also be deferred. The argument that they have been given medical advice, which they have chosen to ignore, in whole or in part, does not permit the blood program to go ahead and draw the donor regardless, unless the blood program takes the unethical approach of capitalizing on donors who, in effect, are now patients who have decided to refuse treatment. A slightly different ethical dilemma would arise for donors who said they were compliant with iron supplementation but whose ferritin values did not budge. While measuring ferritins was the other preferred option recommended in the Donor Iron Deficiency Assessment Report, there will inevitably be circumstances where additional investigation is indicated. Although ferritin is a convenient measure of storage iron, its behavior as an acute-phase protein imposes sensitivity and specificity shortcomings when it is used as the only marker of iron status.15 For donors with iron deficiency in conjunction with a comorbidity, such as inflammation, additional screening by hepcidin assay might be indicated for select individuals who would respond to intravenous rather than oral iron.16 An interesting role for hepcidin has been postulated that might explain why it was necessary to concede that neurocognitive sequelae of storage iron deficiency might be subtle and difficult to detect. A ferroportin blocker, hepcidin acts at a number of levels, including the erythroblast.17 During iron deficiency, hepcidin levels are reduced and erythroblast iron is exported, making iron available to other tissues, such as brain. This mechanism, in which erythropoietic activity is reduced, protects nonerythropoietic tissues from iron depletion.18 For some, another reason for hesitation in accepting iron supplementation as a preferred option has to do with concern for the side effects of oral iron, which the Donor Iron Deficiency Assessment Report regarded as "tolerable." This safety assumption, which possibly reflects a confidence in iron supplement preparations since they are easily available without a prescription, could be premature. The reason why more comprehensive concern for untoward sequelae of supplemental iron administration has not been expressed in blood banking circles, could be related to the fact that relevant discussion is found in publications—Free Radical Biology and Medicine is an example—which seldom, if ever, cross our desks. There is increasing evidence of a role for iron in the pathogenesis of epithelial malignancies. Particular attention has been paid to colorectal cancer, one of the commonest malignancies in the Western world. In a review of 33 human studies exploring an iron–colorectal neoplasia link, 8 of 10 studies that were graded best for strength of data analysis were confirmatory.19 The author of the review commented on extensive dietary iron supplementation in the United States, as well as the popularity of self-medication with iron-containing preparations. He warned that benefits from iron supplements should be balanced against the risks of chronic increased iron exposure, "one of which might be increased risk of colorectal cancer." It is not difficult to postulate mechanisms for iron's promotion of tumorigenesis. Because only 10% to 15% of dietary iron is absorbed, high levels of the metal can be expected in the colonic lumen. Although iron absorption in the colon is inefficient, it is not absent, and intracellular ferrous iron can cause oxidative damage to DNA, as the metal catalyzes the production of hydroxyl radicals.20 There is laboratory evidence to support this hypothesis. In a rodent colitis model, a diet enriched in iron significantly increased the instance of colorectal malignancy.21 A genetic model of colonic neoplasia also confirmed that dietary iron contributes to the promotion of intestinal tumor development.22 The authors of the study cautioned individuals with colorectal adenomas against oral iron to avoid increasing risk for colorectal carcinoma. The relevance this might have for ostensibly healthy donors is that during screening colonoscopy, high-grade lesions are found in 2% of asymptomatic individuals, and invasive disease is present in 1%.23 Given the epidemiologic evidence for a link between dietary iron intake and colorectal cancer risk, as well as potential explanations from animal studies, it is reasonable to ask if reduced exposure to iron is protective. Results from a long-term Veterans Affairs study of phlebotomized individuals throw some light on this question. In a large, randomized control clinical trial, enrollees were compared with an "iron reduction group" who were phlebotomized at 6 monthly intervals for an average follow-up period of 4.5 years.24 This group developed significantly fewer malignancies, and their cancer-specific and all-cause mortality were significantly lower than the control group. The authors concluded that reducing iron levels decreased cancer risk. When discussing the appropriateness of invoking the precautionary principle, the Iron Deficiency Assessment Working Group commented on the importance of reviewing their decision in the light of additional information, which is certainly needed. Suitably scaled studies to reveal the presence or absence of any of the currently "theoretical" storage iron deficiency morbidities are needed. Until there is evidence that giving iron to nonanemic donors who have low ferritin levels is associated with the relief of symptoms from these morbidities, the recommended interventions risk being regarded as no more than treating laboratory values. A more extensive review of the ethical responsibilities of blood programs, especially those electing ferritin screening and iron supplements, would also be valuable, as would a review of iron's potential role in colorectal tumorigenesis. These comments should not be interpreted as disparagement of precaution. Far from it, especially as precaution is also warranted when considering the risks associated with the Iron Deficiency Assessment Working Group's recommended interventions. "More research is needed" is a hackneyed aphorism, but its relevance here is essential for justifications of interventions to be based on evidence rather than conjecture. The author has disclosed no conflicts of interest.