Nonanemic Iron Deficiency: The Elusive Metrics of Iron in the Human Body

Abstract

Gold is for the mistress—silver for the maid— Copper for the craftsman cunning at his trade. ‘Good!’ said the Baron, sitting in his hall, But Iron—Cold Iron—is master of them all. —Rudyard Kipling, “Cold Iron” See Article, page 47 The iron in hemoglobin being responsible for the red color of blood has captured the human imagination for centuries, as reflected in Goethe’s legendary tale of Faust, where the devil tempts Dr Faust to seal his fate with a signature in his own blood. “Blut ist ein ganz besonderer Saft,” he declares, blood is indeed a very special fluid. And within this extraordinary liquid, iron emerges as its most remarkable constituent. Hemoglobin possesses an elegant architecture, constructed from the 4 fundamental elements of life: carbon, hydrogen, oxygen, and nitrogen. Nestled at its core are the essential components for oxygen transport, 4 iron atoms. Preoperative anemia has been identified as an independent risk factor for worse postoperative outcomes and an independent predictor for perioperative red blood cell (RBC) transfusion. Nonanemic iron deficiency (NAID) is seen in up to half of patients presenting for major elective surgery, and puts them at risk of anemia, RBC transfusion, and negative effects on other organs such as the heart. Although most body iron is contained in and central to hemoglobin structure and function, it is also crucial for many other metabolic pathways. In this edition of the journal, Peri et al1 looked at the effects of NAID on postoperative outcomes. No major associations with NAID and the specific outcomes measured could be confirmed, except for increased RBC transfusion, a treatment which, apart from being one of the most overused medical procedures, is often erroneously thought to be a good source of immediately available iron, which it is not, as only about 60 mg of the 200 mg iron per RBC unit is transiently available at the time of transfusion.2 This raises the question of whether screening for NAID in patients undergoing cardiac surgery constitutes value-based care. The answer to many questions in medicine, including this one, essentially boils down to “It depends,” contingent on the definition of value-based care and the perspective from which the problem is approached. If we focus narrowly on the specific outcomes of this meta-analysis, while overlooking its acknowledged limitations, the value of screening might be questioned. However, adopting a broader perspective can lead to different conclusions, especially considering that >40% of patients presenting for cardiac surgery in this study were iron deficient. The significant prevalence of NAID demands attention both individually and from a public health standpoint. This is emphasized by the fact that iron deficiency (ID) affects 40% to 50% of chronic and approximately 80% of acute heart failure patients, conditions prevalent in cardiac surgery.3 ID is known to adversely affect patients with heart disease, particularly heart failure, and treatment with intravenous iron has yielded a range of clinical benefits (see Table).4–11 However, many of these effects have not been thoroughly explored in cardiac surgery and were not included in the meta-analysis’s foundational studies. This gap underscores the potential for valuable research into NAID in cardiac surgery patients, with or without heart failure. Notably, the current study did reveal an association between NAID and an increased need for allogeneic RBC transfusions, which may be significant in terms of avoiding transfusion hazards and reducing costs, especially in resource-limited settings. In support of this point, a recent randomized controlled trial showed that a single dose of 1000 mg of intravenous iron (ferricarboxymaltose) 24 to 72 hours before cardiac surgery, in patients without anemia, significantly reduced the need for postoperative RBC transfusion.12 That said, one should recognize the very wide variation in practice with regard to RBC transfusion rate in intensive care units (ICUs) globally, which also appeared to be the case in the studies forming the basis of this meta-analysis.13 This raises the question to what extent the variation in units transfused across these different studies might have had a confounding effect. In addition, the point estimates for increased mortality, postoperative complications, and length of hospital and ICU stay support the need for further, larger, prospective studies that incorporate uniform definitions, detail on the presence or absence of form, amount and duration of iron treatments, an expanded range of end points, and longer follow-up. The authors’ statement “Our findings generate sufficient equipoise to justify further research in this area” thus well encapsulates the findings of the study. We certainly agree that further research is justified. The question remains, however, whether it will ever be possible or practical to determine all the benefits of screening for and treating ID in a population such as this. Probably not, as the required patient numbers may be too large, the costs too high and the end points too diverse. Table. - The Impact of Iron Deficiency on Cardiac Health The impact of iron deficiency (NAID and IDA) on cardiac health Causes of ID related to heart failure: loss of appetite and poor intake, poor iron absorption due to congestion or inflammation, increased loss in patients on antiplatelet agents or anticoagulants and chronic kidney disease. Pathophysiological effects: impaired erythropoiesis, anemia, mitochondrial dysfunction, and impaired ATP generation, impaired nonmitochondrial energetic pathways, decreased cardiomyocyte contractility and increased cardiomyocyte apoptosis, decreased myoglobin content and oxygen storage, decreased peak muscle strength, impaired defense to reactive oxygen species, abnormal DNA replication and repair, cell cycle abnormalities, abnormal immune responses, neural and hormonal abnormalities, increased cardiac remodeling, reduced exercise capacity, increased insulin resistance, decreased peak oxygen consumption, and abnormal ventilatory response to exercise, impaired LV systolic function and contractility, impaired LV diastolic function/relaxation. Clinical and other consequences in heart failure: poorer quality of life, weakness, fatigue, reduced exercise capacity, increased hospitalization, renal dysfunction, impaired blood pressure control, increased all-cause and cardiovascular mortality, increased health care costs. NAID had a greater impact on mortality and hospitalization in heart failure and exercise capacity than anemia alone, with the combination (ie, IDA) being the worst. Diagnostic criteria commonly used: ID in heart failure: SF <100 ng/mL or SF 100–300 + TSAT <20% ID in otherwise healthy patients: SF <30 ng/mL or SF 30–100 + TSAT <20% ID in cardiac surgery patients without heart failure: unknown; usually extrapolated from definitions used in heart failure Effects of treatment with intravenous iron on heart failure patients: improved global health assessment, improved NYHA class, improved exercise capacity, improved 6-min walking test, improved sleep, improved hypercapnic ventilatory response, improved right ventricular function, lower rates of recurrent CV hospitalizations and all-cause and CV mortality, reduced recurrent HF hospitalizations and CV mortality. Abbreviations: ATP, adenosine triphosphate; CV, cardiovascular; HF, heart failure; ID, iron deficiency; IDA, iron deficiency anemia; LV, left ventricular; NAID, nonanemic iron deficiency; NYHA, New York Heart Association; SF, serum ferritin; TSAT, transferrin saturation. Consideration must also be given to the diagnostic challenges of ID, where inconsistent reference ranges have led to varied definitions of absolute and functional ID across different conditions. How to define ID in cardiac surgery—particularly without heart failure—is unclear, and the relevance of heart failure ID criteria to nonheart failure cardiac surgery patients is uncertain and requires further study. Ferritin’s effectiveness as a diagnostic laboratory test for ID is compromised by inflammation, as it can increase regardless of iron stores. Concurrently, high hepcidin levels may induce functional ID by hindering iron absorption and sequestering iron in macrophages, contributing to anemia of inflammation. Differentiating true ID from functional ID due to iron sequestration involves assessing transferrin saturation (TSAT), serum iron, and total iron-binding capacity (TIBC) or serum transferrin. High TIBC with low serum iron indicates true deficiency, while low TIBC and TSAT suggest iron sequestration. This diagnosis is more complex in patients with concurrent anemia of inflammation and ID, often seen in heart failure and other cardiovascular conditions with infective or inflammatory responses. The challenge lies in setting the optimal serum ferritin cutoff: too low reduces sensitivity, while too high reduces specificity, potentially obscuring the true impact of ID on outcomes. This is especially relevant in cardiac surgery patients without heart failure, where a serum ferritin level of 100 to 300 ng/mL might indicate normal iron stores rather than functional iron deficiency (FID) from heart failure. Moreover, it is important to exclude patients with serum ferritin <300 ng/mL and TSAT >20%, as they typically do not show ID on bone marrow staining. Including them in studies might weaken the observed benefits of screening or treatment, as seen in the HEART-FID (Ferric Carboxymaltose in Heart Failure With Iron Deficiency) trial.14 An individual patient meta-analysis followed by an interventional trial may be useful to advance our understanding of these issues. Further studies utilizing more recent markers of ID, such as soluble transferrin receptor levels, reticulocyte hemoglobin content, and hepcidin may prove useful in refining diagnostic accuracy.9 Finally, we should remind ourselves that ID, whether anemia is present or not, is not a final diagnosis and an attempt should always be made to establish the cause, especially in men and postmenopausal women as serious underlying conditions (eg, gastrointestinal or gynecological conditions) are common. Cardiac surgery thus provides us with a population where the yield of diagnosing ID and treatable causes may be high. When students asked the celebrated William Osler about the role of the physician of the day, he is quoted as saying “diagnosis, diagnosis and diagnosis.”15 Diagnostic accuracy should be the starting point for any research into correlating a diagnosis with clinical outcomes and remains a sine qua non for valid epidemiological research. From a clinical practice perspective, optimizing patients preoperatively and taking care of a patient’s need for surgery cannot be removed from finding the cause and treatment of the ID. From a health care system’s point of view, quality management and hemovigilance programs should account not only for the complications of blood transfusion but also for whether the root cause of the anemia and/or ID was established. It emphasizes the fact that clinicians are all part of a larger whole, not limited to a narrow, speciality-defined job description, but as a team, joining forces to the benefit of patients. In the spirit of Kipling’s words, we, as medical professionals, should recognize the role of iron in our field. Iron, in all its complexity, demands our attention and in the intricate tapestry of health care, it is our understanding of “Cold Iron” that will ensure we remain masters of our trade, wielding this elemental force to the best of our ability and to the health of those we serve. DISCLOSURES Name: VJ Louw, MD, PhD. Contribution: This author helped in the conceptualization, writing of editorial, reviewing and revising for intellectual content, and final editing. Conflicts of Interest: V. J. Louw has received honoraria as speaker, advisory board member, travel, and grant support variously from Pharmacosmos, Vifor Pharma, Acino, Austell, and Aspen Pharma. He is a member and scientific associate, International Foundation for Patient Blood Management. He is also a member of the WHO Strategic Committee for Patient Blood Management, AABB Global Standards Committee, Board Member NATA, Global Transfusion Forum Education Subcommittee, member of the International Collaborative Transfusion Medicine guidelines group, and nonexecutive director, Western Cape Blood Service, Global Transfusion Forum Education subcommittee. Name: Isbister JP, MB. Contribution: This author helped in the conceptualization, coauthoring editorial, reviewing, and revising of intellectual content. Conflicts of Interest: J. P. Isbister is a member and scientific associate, International Foundation for Patient Blood Management. This manuscript was handled by: Shannon L. Farmer, DHSc.

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