Iron Deficiency—More Than Just Anemia: A Literature Review

Abstract

Iron deficiency (ID) is a global public health concern, as it can be a prodrome of gastrointestinal (GI) malignancies, exacerbate chronic conditions, and lead to an overall decreased quality of life. Despite being the most prevalent nutritional deficiency, it remains underdiagnosed by many healthcare professionals. Misconceptions regarding the clinical and laboratory manifestations of ID lead to delayed or missed diagnoses, contributing to poor patient outcomes. Though anemia is a commonly known consequence of ID, there are additional consequences that remain underrecognized by the medical community, including vague signs and symptoms, such as fatigue, depression, and abnormalities in white blood cell and platelet counts. A thorough understanding of the pathophysiology connecting ID to white blood cell and platelet dyscrasias is essential for accurate diagnosis and effective treatment. This review aims to highlight existing gaps in physicians’ ability to diagnose ID and the underrecognized laboratory presentations of ID without anemia.

1. Introduction

Iron is an essential nutrient for oxygen transport, DNA synthesis, and electron transport. When iron intake is inadequate to restore physiological or pathological losses, total body iron stores become depleted, resulting in iron deficiency (ID). Because iron is widely consumed in the synthesis of hemoglobin (Hb), ID may result in iron deficiency anemia (IDA); however, the two disease entities are not synonymous with one another, as ID precedes the onset of anemia.1 In addition to anemia, ID has other significant health ramifications, including decreased cognitive and physical performance and decreased quality of life.2,3 More strikingly, ID was found to cause 1.3 % of global disability-adjusted life years (DALY) while high cholesterol was the cause of 2.0 % of DALY, for comparison.4 A prompt and comprehensive evaluation and management of ID is crucial, as delays in the evaluation of ID can lead to delayed diagnosis of gastrointestinal (GI) malignancies or increased economic burden due to chronic fatigue, depression, or burnout secondary to ID. However, the full range of laboratory manifestations of ID are not well known by healthcare professionals. While anemia is widely recognized to be a consequence of ID, other laboratory abnormalities—including abnormalities in white blood cell and platelet counts—are commonly overlooked. This review aims to highlight the underrecognized presentations of ID by healthcare providers and emphasize the need for targeted educational interventions at various stages of medical education to address this knowledge gap.

1.1. Impact of iron deficiency on health outcomes

ID without anemia has significant medical consequences and requires medical intervention.5 The World Health Organization (WHO) identifies “mild anemia” (Hb between 11 and 11.9 g/dL for women and between 11 and 12.9 g/dL for men) a misnomer, stating ID is well advanced by the time anemia is detected.5 Patients with ID may experience vague symptoms such as fatigue, depression, burnout, sleep disturbances, hair loss, or reduced exercise tolerance.6–9 These debilitating symptoms of ID result in economic consequences with the accumulation of sick leave.6 ID is also a common comorbidity in patients with GI pathologies and may hinder physical and cognitive function, decrease quality of life, and increase the risk for thromboembolic events.10,11 There is also increasing evidence that when ID has progressed to IDA, it is highly associated with the diagnosis of GI cancers.12 Furthermore, in congestive heart failure, ID is an independent risk factor of mortality and hospitalization and is associated with decreased exercise capacity. Notably, iron therapy improved cardiac function and exercise tolerance in these patients.13,14

1.2. Gaps in clinician knowledge on diagnosing ID

Although ID is one of the world’s most common disorders, it often remains undiagnosed for extended periods of time. A retrospective chart review of roughly 1000 referrals to a classical hematology clinic within an academic medical center in Southern California, U.S. demonstrated the diagnosis of ID to be a challenge for first-contact physicians. 15 Additionally, in a survey of 325 U.S. primary care physicians’ (PCPs) self-reported approach to the testing and evaluation of patients for IDA, researchers found that clinicians misinterpreted iron studies, over utilized screening laboratory tests, and under used bidirectional endoscopy for the evaluation of IDA.16 The same study noted the interpretation of iron studies by PCPs was the least accurate in the setting of borderline ferritin levels and low transferrin, with 26.5 % of PCPs incorrectly reporting that this did not denote IDA.16 Likewise, a retrospective analysis of electronic medical records from 13,084 patients with ID within a statewide health system in Minnesota found 58.1 % of patients had no documented resolution of ID within 3 years, which was attributed to providers failing to recognize and diagnose ID.17

Results from several other international studies have found the diagnosis of ID to be similarly challenging.18–20 For example, in a retrospective chart review of 1010 Swiss women with a diagnosis of ID, 35 % received an initial misdiagnosis other than ID to explain their symptoms.6

In patients presenting with unexplained IDA, it is imperative to rule out GI malignancies, and current guidelines from the American Gastroenterological Association recommend bidirectional endoscopy for all patients with unexplained IDA regardless of menopausal status.21 However, despite these guidelines, bidirectional endoscopy remains underutilized in the evaluation of IDA.22 For patients with recurrent or refractory IDA and negative bidirectional endoscopy results, capsule endoscopy should be considered.23

2. Epidemiology

According to the WHO, ID is the most pervasive nutritional deficiency globally.24 A meta-analysis of non-pregnant women of reproductive age and preschool aged children from 23 countries found the proportion of anemia associated with ID to be 37 % and 25 %, respectively.25 Since IDA is a later manifestation of ID, the global prevalence of ID is estimated to be twice as prevalent as IDA.2 In the 2021 Global Burden of Disease Study, the global prevalence of anemia was found to be 24.3 % (1.92 billion people), with ID contributing to 66.2 % of all anemia cases and affecting 825 million women and 444 million men globally.26

3. Causes of iron deficiency

ID may be due to reduced iron absorption, increased demand (as seen in pregnancy and child development), or blood loss (whether physiologic, such as menstruation, or pathologic, such as GI bleeding). Reduced iron absorption can be the result of decreased iron intake (malnutrition or iron-deficient diets) or seen in the setting of duodenal bypass, bariatric surgery, or conditions resulting in malabsorption, including celiac disease.

Iron is consumed both in its ferric and ferrous forms; however, only ferrous iron is absorbed across the enterocytes of the duodenum. Sufficient gastric acid is required to convert ferric to ferrous iron. Antacids which suppress gastric acid production have been linked to iron malabsorption.27–29 Mouse studies have also shown proton-pump inhibitors increase hepcidin expression and hepcidin-inhibition of ferroportin, further impacting iron metabolism.30 Gastric surgical procedures both decrease the relative surface area for iron absorption and increase gastric pH, thus hindering the conversion of ferric to ferrous iron and diminishing enterocyte uptake of ferrous iron.31 The prevalence of ID varies widely after both the gold standard Roux-en-Y procedure and restrictive sleeve gastrectomy, ranging from 18–53% and 1–54 %, respectively.32 Additionally, inadequate absorption may be caused by the dietary consumption of iron-absorption inhibitors, including calcium, phytates in cereal-based products, and tannins in teas and coffee.33

4. Iron metabolism

Hepcidin, an acute phase reactant produced mainly by the liver, is the master regulator of body iron storage.34 Hepcidin binds to ferroportin, an iron export protein, to obstruct iron efflux by inducing its degradation. Ferroportin is expressed on macrophages, hepatocytes, and duodenal enterocytes; therefore, it mediates both iron absorption and export to plasma.1 During times of ID, hepcidin expression is suppressed by multiple factors that downregulate its transcription, including the BMP-SMAD signaling pathway.35 Hepcidin suppression upregulates iron absorption and recycling to increase circulating iron concentrations.

However, the efflux of iron from the storage pool to be used for erythropoiesis is impeded by infection or inflammation due to increased hepcidin expression in response to inflammatory cytokines. The subsequent hepcidin-induced degradation of ferroportin results in decreased intestinal absorption and increased retention of iron within reticuloendothelial cells, leading to an increase in ferritin.36 This ultimately results in the clinical manifestations of ID in patients with inflammatory conditions, such as heart failure, chronic kidney disease, inflammatory bowel disease, and aging.37

5. Diagnosis of iron deficiency

The diagnosis of ID requires obtaining a detailed history and laboratory iron studies. Low serum ferritin is characteristic of ID, as it is a measure of iron stores. In clinical practice, ferritin levels <30 ng/mL indicate ID, and ferritin levels with concurrent anemia are usually <10–12 ng/mL1. The optimal ferritin cutoff point for ID has been widely debated, with proposed cutoffs ranging from 12 to 50 ng/mL38. However, a correlational analysis between serum ferritin concentration and red cell parameters in 28,134 individuals found that the inflection points at which red cell parameters began to decrease corresponded with a ferritin concentration of 44–65 ng/mL39. This suggests that the upper end of the ferritin range may align more closely with changes in red cell parameters. Additionally, many women are iron deficient and symptomatic because of their monthly menstruation, and if their ferritin levels fall within the current reference range, they may not receive adequate treatment. Therefore, raising the ferritin cutoff may enhance the screening and treatment of ID in women.40 Supporters of increasing the ferritin cutoff to 50 ng/mL have also cited that GI iron absorption, which is elevated in states of ID, returns to baseline at a serum ferritin level of 50 ng/mL41. However, a current Cochrane review seeking to determine the diagnostic accuracy of ferritin concentrations found insufficient evidence to confidently recommend a ferritin threshold for the diagnosis of ID, demonstrating the need for diagnostic test accuracy studies to establish a precise threshold.42

Aside from ferritin levels, reticulocyte Hb content and the percentage of hypochromic red blood cells reflect iron availability and have been proposed as early biomarkers of ID.43 Reticulocyte Hb content is indicative of recent iron availability for erythropoiesis (3–4 days) while the percentage of hypochromic red blood cells reflects iron availability for the prior 2–3 months.44 Other laboratory markers may also be considered to aid in the diagnosis of ID when ferritin studies are inconclusive, but clinicians should be wary of the limitations of each laboratory test.40,44–46 For example, MCV, which may be decreased in ID, can be also decreased in various conditions, including thalassemia and x-linked sideroblastic anemia. In contrast, the coexistence of ID with other conditions that increase MCV, such as liver disease, alcohol use, or other nutritional deficiencies (e.g. zinc, B12, copper), may falsely normalize MCV.40,44–46 While low transferrin saturation, <20 %, can be useful, soluble transferrin receptor (sTFR) and the sTFR to log(ferritin) ratio may be more reliable in patients with inflammation. However, these are of little diagnostic relevance in clinical practice, as they are often unavailable.1,44

The diagnosis of ID in the context of inflammation requires a ferritin level <100 ng/mL, but a ferritin level >100 ng/mL in inflammatory conditions does not rule out ID.45 Therefore, the sole use of serum ferritin to diagnose ID has also been called into question.1,42,44 In these cases, red cell indices, such as decreased red blood cell counts, low mean corpuscular hemoglobin (MCH), low mean corpuscular volume (MCV), and high red cell distribution width (RDW) may be indicative of ID.1 Also, special attention should be paid to older adults, as ferritin levels can increase with aging due to the low-grade chronic inflammation that arises with aging.46,47

6. Stages of iron deficiency

ID occurs in three stages. Initially, to maintain serum iron concentration, Hb, and hematocrit in the normal range, iron stores are reduced. During this stage, body iron stores are utilized for erythropoiesis. Then, serum iron and transferrin saturation decrease to keep Hb and hematocrit in the normal range by lowering MCV and MCH. It is only after iron stores, serum iron, and transferrin saturation are exhausted that Hb eventually decreases, resulting in the final stage—IDA.48

7. Other iron deficiency-induced hematological abnormalities

Although anemia is the most widely recognized consequence of ID, other hematological abnormalities, including thrombocytosis, neutrophilia, thrombosis, thrombocytopenia, leukopenia and pancytopenia may also occur. The prevalence of these abnormalities in the literature varies, likely due to differences in laboratory reference ranges, studied populations, and sample sizes. A detailed understanding of the pathophysiology linking ID to these conditions is instrumental to the proper diagnosis.

• Thrombocytosis

Primary thrombocytosis is due to myeloproliferative disease while secondary, or reactive thrombocytosis, is the consequence of infection, malignancy, chronic inflammation, and ID. A retrospective chart review of a large institutional patient data registry found that the rate of reactive thrombocytosis in patients with IDA was 32.6 %.11 Another study found 10.37 % of patients with IDA had thrombocytosis.49 In a randomized placebo-controlled study on the effects of iron replacement therapy on reactive thrombocytosis in iron deficient patients with inflammatory bowel disease, iron therapy normalized platelet levels, platelet aggregation, and p-selectin expression.50 In patients with chronic kidney disease, iron therapy was found to decrease platelet levels as well.51

The mechanisms underlying ID-induced thrombocytosis remain largely unknown. Current research illustrates that ID directly alters megakaryopoiesis through expansion of megakaryocyte progenitors, increased ploidy and accelerated megakaryocyte differentiation.52 The effects on megakaryopoiesis may be due to increased erythropoietin stimulation of platelet production, as erythropoietin is structurally similar to thrombopoietin, but this theory is not conclusive.53,54 ID also modulates gene expression, increasing expression of hypoxia-inducible factor 1, α subunit (HIF2α) protein and vascular endothelial growth factor (VEGF)-A, which may explain the changes in megakaryopoiesis seen in ID.55

• Neutrophilia

The relationship between ID and neutrophilia has yet to be fully elucidated. Inflammation has been thought to underly the link between IDand increased neutrophil counts. A study of Saudi patients with anemia found increased neutrophil-to-leukocyte ratios in patients with anemia as compared to controls, but causality between anemia and neutrophilia could not be established.56 Similarly, a retrospective chart review investigating the association between ID and complete blood count abnormalities found that ID was the underlying cause of the neutrophilia in 71.4% of patients with neutrophilia.15 ID may also increase neutrophil chemotactic activation and recruitment, leading to neutrophilia; however, data in this area is limited.57 Treatment with iron therapy has been shown to diminish neutrophil function by decreasing the chemotactic and phagocytic activities of neutrophils in hemodialysis patients with ID.57,58 Recently, superparamagnetic iron oxide nanoparticles used to treat IDA, such as Ferumoxytol, have been shown to diminish the chemotactic activation and inflammatory properties of neutrophils. Ferumoxytol is hypothesized to accelerate calcium clearance, resulting in decreased capacity for neutrophil signaling and decreased neutrophil recruitment from circulation.59

• Thrombosis

Platelets play an essential role in hemostasis and coagulation. Reactive thrombocytosis is generally regarded as benign; however, emerging research has documented ID induced peripheral vascular and cerebrovascular thrombotic events.60,61 In fact, animal studies have shown that ID leads to thrombocytosis and increased venous and arterial thrombus size, and these effects can be reversed through the administration of iron therapy.52,55,62 A large retrospective chart review found the rate of thrombosis in patients with IDA and thrombocytosis to be 15.8 % while the rate of thrombosis in IDA patients without thrombocytosis was 7.8 %.11 This increased risk may be linked to the upregulation of the cellular adhesion molecule, p-selectin observed in ID.62

In addition to inducing thrombocytosis, ID may elevate the risk of thrombosis by enhancing coagulation. Previous studies have found low serum iron levels are associated with increased plasma concentration of coagulation factor VIII, and treatment with intravenous iron decreased factor VIII activity in patients with IDA.63,64

Venous thrombosis has also been associated with neutrophilia. Interestingly, persistent neutrophilia, outside of malignancies, infection, or leukocytosis-inducing steroid medications, has been shown to be an independent risk factor in the development of venous thrombosis.65 The relationship between neutrophils and thrombosis is still under investigation, but current research has shown that neutrophils migrate to the sites of inflammation, where they release neutrophil extracellular traps that provide a scaffold for thrombus formation.66,67 Patients with VTEs have also been shown to exhibit persistent neutrophil activation two years after an acute VTE event, suggesting a bidirectional relationship between neutrophil activation and thrombosis.68 As ID may also exacerbate thrombosis, more research is needed to understand the mechanisms by which neutrophil induced thrombosis is modulated by underlying ID.

• Cytopenias

Although more commonly implicated in thrombocytosis, ID may also cause cytopenias, including thrombocytopenia, neutropenia/leukopenia, and pancytopenia.15 In a study of the prevalence of cytopenia in the general population, it was found that ID caused 42.2 % of all cases of cytopenia, including anemia, neutropenia, and/or thrombocytopenia. 69 Numerous studies have demonstrated the reversal of the cytopenia upon administration of iron therapy in patients with ID.70–82

• Thrombocytopenia

There have been several case reports of thrombocytopenia developing in the context of ID with complete reversal upon treatment with iron therapy.15,71,72,74,75,82 The mechanism behind ID-induced thrombocytopenia is largely unknown but may occur through two different pathways. ID may decrease the activity of iron-dependent enzymes in thrombopoiesis and leukopoiesis.70,82 Alternatively, ID may cause the shunting of hematopoietic precursor cells towards the erythroid pathway over the megakaryocyte pathway.75,83 Regardless of the mechanism, ID-induced thrombocytopenia, which can be seen in ID secondary to bleeding, must be differentiated from immune thrombocytopenia. ID-induced thrombocytopenia can be discerned by decreases in Hb, MCV, and ferritin levels and the lack of reticulated platelets. Reticulated platelets indicate intact platelet production, as seen in peripheral autoimmune platelet degradation, while the lack of reticulated platelets points to impaired platelet production due to a central thrombocytopenia.83,84

• Neutropenia/Leukopenia

ID has also been documented to cause leukopenia, and treatment with iron therapy reversed the cytopenia.15,73,76–80 A study of leukopenia in patients with IDA found 17.6 % of patients had leukopenia.73 Another study found the incidence of leukopenia and neutropenia in female patients with IDA to be 5.1 % and 4 %, respectively, and the leukocyte and neutrophil counts increased following iron therapy.76 In a study of the etiology of patients admitted due to isolated leukopenia, it was determined that IDA was among the most common causes of isolated leukopenia in nonneutropenic patients (21.8 % of cases) and neutropenic patients (10.2 % of cases).85

This association may be explained by evidence showing that ID disrupts early stages of hematopoiesis, disproportionately affecting erythro-myeloid progenitors more than erythroid progenitors.86 Supporting this, a mouse model of plasma iron and neutrophil production found low plasma iron was associated with decreased circulating frequencies of neutrophils, and neutrophils produced during iron restriction had impaired ability to phagocytose E. coli, produce cytokines, and kill S. aureus.87 Further research on the effects of ID on neutrophil counts and function is warranted.

• Pancytopenia

There have been limited case reports for pancytopenia in iron deficient patients.15,70,81

8. Conclusion

In conclusion, early detection of ID without anemia is essential, as ID can signal the onset of GI malignancies, worsen chronic conditions, and reduce quality of life. However, misconceptions about the clinical and laboratory manifestations of ID among healthcare professionals often result in delays in ID diagnosis and treatment, leading to impaired quality of life and economic losses.6,15 To enhance providers’ diagnostic skills of ID, educational interventions should be designed for various levels of medical training. Additionally, given the vague symptom presentation of ID without anemia, universal screening for ID may be indicated but this requires supporting cost-benefit studies.