Iron deficiency in children with a focus on inflammatory conditions

1. Iron adaptation at a systemic level

The mechanism of systemic iron adaptation is regulated by hepcidin-based homeostatic control [1]. Hepcidin is a small peptide hormone primarily synthesized in the liver. This protein binds to the iron exporter FPN and blocks iron efflux into the plasma. FPN is highly expressed in enterocytes and macrophages, and hepcidin induces the degradation of iron-containing FPN, blocking the iron efflux pathway [1].

When ID occurs, hepcidin is suppressed by iron supply optimization via iron absorption enhancement and recycling. Several mechanisms downregulate hepcidin transcription in hepatocytes (Fig. 1A). First, the bone morphogenetic protein (BMP)-SMAD signaling pathway is repressed by low levels of BMP6. Transmembrane serine protease 6 disrupts hepcidin synthesis by cleaving hemojuvelin, a coreceptor of BMP [9]. In addition, the ALK3 signal is reduced because transferrin receptor 2 is not stabilized on the cell surface, which in turn reduces hepcidin transcription. Histone deacetylase 3 participates in hepcidin suppression by erasing the markers of hepcidin activation [10]. Additionally, increased erythroferrone blocks hepcidin transcription via an unknown mechanism [3]. The reduction in hepcidin levels by these mechanisms increases FPN activity and consequently increases the amount of iron entering the plasma [11].

Fig. 1.

Hepcidin, produced in the liver, plays a key role in iron regulation. Hepcidin blocks the export of iron from the cell to the plasma by degrading ferroportin (FPN) in enterocytes, macrophages, and hepatocytes. (A) Adaptation to iron deficiency: Several mechanisms interfere with hepcidin production. The bone morphogenetic protein (BMP)-SMAD signaling cascade and ALK3 (activin receptor-like kinase 3) signaling are repressed. Increased erythroferrone blocks the hepcidin pathway via an unknown mechanism. In addition, iron deficiencyinduced hypoxia-inducible factor-2α (HIF-2α) increases divalent metal transporter 1 expression to increase the transfer of dietary iron and the production of erythropoietin (EPO) to stimulate erythropoiesis. (B) In the inflammatory state, several cytokines (interleukin [IL]-6, IL- 1β, lipopolysaccharide) increase hepcidin production. In addition, cytokines such as tumor necrosis factor (TNF)-α and interferon (IFN)-γ stimulate the production of ferritin in macrophages, allowing iron to remain in the cells and eventually reducing plasma iron levels. LSEC, liver sinusoidal endothelial cells; NEO1, neogenin; BMPR, bone morphogenic protein receptor; TMPRSS6; transmembrane serine protease 6; HFE, hephaestin; HOX1, heme oxygenase 1; HCP, hepcidin; HAMP, hepcidin gene; STAT3, signal transducer and activator of transcription-3; TfR1, transferrin receptor 1; LPS, lipopolysaccharide.

Additionally, erythropoietin (EPO) production stimulates erythropoiesis in erythroblasts. In enterocytes, ID-induced hypoxia-inducible factor-2α (HIF-2α) upregulates the expression of divalent metal transporter 1 (DMT1) to increase dietary iron uptake [3].

2. Iron adaptation at a cellular level

Intracellular iron homeostasis is regulated by iron regulatory proteins (IRPs) that bind to the iron-responsive element (IRE) [11]. IRE resides in the untranslated region (UTR) of messenger RNA (mRNA) and synthesizes the proteins involved in iron metabolism. When iron is insufficient in cells, an IRP binds to the IRE present in the 5′-UTR and interferes with mRNA transcription, reducing the synthesis of ferritin, FPN, and HIF-2α while binding to the IRE present in the 3′-UTR increases the synthesis of transferrin receptor 1 (TfR1) and DMT1 [11]. In addition, inhibition of the mammalian target of rapamycin activates tristetraproline, which reduces both TfR1 and FPN expression and conserves the iron required for tissue metabolism [4].

In ID, cells can recover the iron stored in ferritin by degradation (ferritinophagy) via nuclear receptor coactivator 4 [3]. Ferritin plays an important role in intracellular iron storage.

3. Iron adaptation in inflammatory condition

Several inflammatory cytokines are released by cells in the immune system that respond to microbial molecules, autoantigens, or tumor antigens, which alters whole-body iron metabolism [12]. First, proinflammatory cytokines affect hepcidin production and release. Interleukin (IL)-6, IL-1β, and lipopolysaccharide are potent inducers of hepcidin; however, they reduce the expression of the iron transport protein transferrin [12]. Among them, IL-6 is considered the most important factor that stimulates hepcidin production through STAT3 [13]. Consequently, FPN is degraded, iron is retained in macrophages, and the efflux of absorbed iron from the duodenum is blocked. In addition, several cytokines (IL-1β, IL-6, IL-10, and interferon-gamma [IFN- γ]) promote iron uptake into macrophages via transferrin receptor–mediated endocytosis [14]. Because this can increase radical-mediated damage, they stimulate ferritin production to ensure safe and efficient iron storage. In addition, these cytokines reduce FPN expression by inhibiting its transcription [15]. Another cytokine, tumor necrosis factor-α (TNF-α), decreases duodenal iron absorption through a hepcidin-independent mechanism that has not yet been precisely elucidated [12]. These events induce iron restriction at the cellular level by the storage of iron as ferritin and prevention of its outflow into the plasma, thereby causing ID (Fig. 1B).

1. Neurodevelopmental deficits

Iron plays an important role in brain and cognitive development [2]. Brain development accelerates in the 3rd trimester of pregnancy, for which sufficient iron is required. ID during this period can result in neurological and cognitive deficits, delayed motor development, deficits in auditory memory and learning, and emotional disorders [38]. Although it remains unclear precisely which areas of the brain are affected by ID, several studies have suggested that ID impairs energy metabolism and affects hippocampal neuron development [38]. Other neurodevelopmental processes known to be disrupted by ID include myelination, dendriogenesis, synaptosis, and neurotransmission [39].

In children, ID leads to delayed cognitive, motor, attention, and memory deficits; visual and auditory deficits; decreased school performance; and/or behavioral disorders, some with persistent long-term effects. In adolescents, ID can lead to decreased psychomotor skills and concentration, thereby affecting school performance. The relationship between attention-deficit/hyperactivity disorder (ADHD) and ID has been suggested in several studies [40]. First, the ferritin levels of children with ADHD were reportedly lower than those of children without ADHD, and ADHD symptoms improved with iron supplementation [40]. Second, it been hypothesized that ID may cause dysregulation of central dopaminergic neurotransmission, a pathological cause of ADHD [41].

In addition, breath-holding spells increase in ID, and the frequency of which decreases with iron therapy [42]. RLS is a relatively common neurological disorder associated with ID. An association between iron metabolism and dopaminergic neurotransmission disorders in the striatum, the presumed cause of RLS, has been suggested in animal models [43]. In addition, 2 genes (MEIS1 and BTBD9) were identified in a genomic analysis related to RLS that appears to affect both the expression of periodic limb movements during sleep and iron homeostasis [44]. For this reason, the International Restless Legs Syndrome Study Group reported iron supplementation when ferritin levels are <50 μg/L [45].

2. Dysregulation of immune and respiratory systems

Iron is essential for the immunosurveillance systems as well as tissue proliferation, such as the intestinal epithelium, which serves as a physical barrier to infection [46]. In addition, iron status directly impacts innate immunity and indirectly impacts adaptive immunity [47,48]. Therefore, iron homeostasis is important for the normal development of the immune system and immune cell differentiation.

Macrophages are the primary cells for iron transmission, distribution, and mobilization; therefore, ID status directly impacts innate immunity [47,49]. ID reduces the distribution capacity of macrophages, leading to a transition toward a proinflammatory phenotype and low-level inflammation with decreased production of macrophage inhibitory factors [47,49]. ID also causes a shift in monocytes and decreases monocyte phagocyte activity in patients with IDA [48]. The development, proliferation, activation, and function of neutrophils and natural killer cells are also reportedly affected by ID [48]. For example, myeloperoxidase activity is reduced, and intracellular bactericidal activity may be impaired in patients with ID [49-51].

Second, ID interferes with adaptive immunity to a relatively low degree. ID reduces the counts of T lymphocytes, affects their differentiation, and reduces CD4+ and CD8+ T-cell numbers in the circulation, or it alters the proliferation of T helper (Th)-1 and Th-2 subsets. T-cell activation is controlled by TFR1 (CD71)-mediated iron uptake via an IL-2-dependent pathway. Therefore, TFR1 mutations can lead to defects in iron endocytosis and T-cell dysfunction, which can result in combined immunodeficiency diseases [48,52]. The lack of iron contributes to downregulation of the antibody response. Recent studies reported that serum iron levels affect antibody formation following vaccination [53]. In addition, although controversial, another study demonstrated that the concentrations of immunoglobulin G subgroups are reduced in patients with ID [54].

Other studies suggested that these immunological impairments are due to the dysregulation of IL and other cytokines (e.g., IL-6, IL-2, TNF-α, IFN-γ, and IL-10) in patients with ID [49-51]. In particular, serum IL-6 level was significantly lower in patients with ID, and T-cell dysfunction may be the result of low cytokine activity [55]. In addition, impaired IL-2 production by lymphocytes was observed in children with ID [56].

ID is associated with several immune diseases and affects host susceptibility to infection.In particular,ID is a risk factor for the development of recurrent respiratory tract infections and has been associated with several lung diseases, such as chronic obstructive pulmonary disease, lung cancer, cystic fibrosis, idiopathic pulmonary fibrosis, and asthma [57]. Several studies have shown that lower respiratory tract infections occur more frequently in the presence of ID, a risk that is significantly reduced by iron supplementation [57,58]. Furthermore, the observed risk could be due to the low oxygen-carrying capacity in the pulmonary vasculature and parenchyma that leads to a low level of protection against invading pathogens [58]. Other studies reported an association between low serum iron levels and abnormal lung function with increased high and small airway resistance [59]. Moreover, several studies reported that urinary tract infections, intensive care unit–acquired infections, postoperative infections, and otitis media are more common in patients with ID [46].

3. Impact on CID

Multifactorial ID causes are common comorbidities in patients with CID. ID is a comorbidity that exacerbates the underlying disease and increases mortality rates.

One study identified ID in 56% of pediatric patients with heart failure, and ID was associated with an increased risk of ventricular assist device implantation, heart transplantation, and death.In addition,this study suggested that ID resulted in a significantly shorter time of onset for these composite adverse events [60]. Another pediatric cohort study reported that low serum iron levels were associated with inpatient hospitalization, inotropic medication use, or worse heart failure severity, while low ferritin levels were associated with increased mortality rates [61]. These studies suggest that ID may be an actionable biomarker and a potential new therapeutic target in the field of pediatric heart failure. In addition, the use of anemia alone as the threshold for treating ID may be insufficient, thereby prolonging compromised tissue function and delaying treatment initiation [60,61]. Other studies argued that ID is a poor prognostic factor for heart failure, even in the absence of anemia [62]. Therefore, routine and repeated screening for ID at the time of diagnosis and every 3–6 months thereafter should be performed in pediatric patients with heart failure [60].

ID is a major complication in pediatric patients with CKD. The prevalence ofID in patients with CKD is as high as 85% and increases as CKD progresses [6]. In a Korean cohort study of children with CKD, the disease history, systolic blood pressure, and presence of comorbidities were significantly higher in patients with versus without ID [63]. In this cohort study, ferritin levels increased with increasing CKD stage, whereas transferrin levels did not change. This suggests that ferritin levels can be increased by both inflammation and ID in pediatric patients with CKD [63]. Unlike heart failure, many CKD-related guidelines focus more on anemia than on ID [28,29]. However, ID plays an essential role in anemia in patients with CKD. This is due to both a lack of iron storage (absolute ID) and relative (functional) ID: The chronic inflammatory state in CKD reduces erythropoiesis in the bone marrow, reduces EPO production in the kidney, and increases hepcidin production in the liver, thereby inhibiting iron absorption from the gut and its release from iron-storing cells [64,65]. Increased levels of proinflammatory cytokines such as IL-6 and TNF-α affect this mechanism [64].

The prevalence of ID is reportedly as high as 80%–90% in patients with IBD [18]. The mechanism involves chronic blood loss in the gastrointestinal tract, impaired iron absorption in the intestine, and chronic proinflammatory cytokines that block iron transport and increase hepcidin production [6]. Although ID can be more easily corrected before anemia occurs, IBD treatment also focuses on evidence of anemia [66]. Additionally, patients with IBD are generally not treated appropriately for ID during disease activation, and the ID status usually does not recover even if remission is achieved. However, even in patients with IBD, iron replacement therapy for ID without anemia improves the quality of life [67].

1. ID without complex condition

There is evidence that all patients diagnosed with ID, especially those who are symptomatic, should be adequately treated with iron, even in the absence of anemia [17]. Clinically, iron intake in patients with non-anemic ID reduces fatigue self-scores [68]. Iron also improves maximal exercise performance and aerobic capacity [69]. Another review showed that iron supplementation reduced RLS/periodic limb movement disorders [70]. Iron supplementation improved cognitive performance in children aged 5–12 years and improve verbal learning and memory in adolescent girls aged 13–18 years [71,72].

Most guidelines recommend oral iron therapy as first-line treatment, even in children, owing to its effectiveness, ease of administration, and low cost. Ferrous sulfate, fumarate, gluconate, ascorbate, lactate, succinate, and glycine sulfate are typically used as oral iron supplements. One or 2 doses of iron at a total daily dose of 3–6 mg/kg are adequate; the maximum dose is 150–200 mg of elemental iron [9]. Ideally, oral iron should be administered for at least 3 months to completely replenish iron stores, defined as reaching a serum ferritin level ≥50 ng/mL. However, common side effects such as epigastric discomfort, nausea, diarrhea, and constipation, which are not severe, are reported in 30%–70% of cases of iron supplementation [9]. For these reasons, drug compliance is poor or treatment fails, and iron supplementation can be administered intravenously. The indications for parenteral iron therapy are shown in Table 4.

Table 4.

Indication and contraindication for parenteral iron therapy in children [2,9]

2. ID with complex condition(s)

Parenteral iron is recommended as the primary treatment for many cases ofID with complex medical conditions. Oral iron therapy is ineffective in chronic diseases because it increases hepcidin synthesis owing to inflammation and blocks the absorption of oral iron by enterocytes [6].

For patients with heart failure, effort is required to reduce the readmission rate, which is directly related to mortality. Several studies have demonstrated that reducing the incidence of ID can reduce hospitalization and treatment costs for patients with heart failure [73]. In addition, the most common comorbidity in heart failure is ID, which is relatively easy to diagnose, and its treatment is simple and effective [73]. Therefore, the early identification and treatment of ID have been suggested in many heart failure guidelines [26,74]. The 2021 European Society of Cardiology guidelines recommended that intravenous iron therapy be considered in patients with chronic heart failure (left ventricular ejection fraction ≤45%) and ID (defined as ferritin<100 μg/L or ferritin 100–300 μg/L with TSAT<20%) [26]. The American College of Cardiology and American Heart Association guidelines also recommend intravenous iron therapy for adult iron-deficient patients with heart failure [27]. In pediatric patients with heart failure, the role of intravenous iron therapy was emphasized in a recent study that revealed the poor efficacy of oral iron replacement therapy [74].

Almost all patients with CKD suffer from absolute and functional ID via various mechanisms; consequently, parenteral iron produces higher results and requires a greater reduction of the required doses of EPO agents than oral iron in patients with CKD [64,65]. TSAT and ferritin levels suggest that the start or end of treatment varies among guidelines (Table 2). In CKD, absolute ID is defined as a TSAT <20% and ferritin <100 mg/L in patients not on hemodialysis (NDCKD) or <200 mg/L in hemodialysis (HDCKD) patients. Functional ID was defined as a TSAT <20% and a ferritin >100 mg/L in patients with NDCKD or >200 mg/L in patients with HDCKD [75]. The Proactive IV Iron Therapy in Hemodialysis Patients study was a randomized controlled trial of more than 2,000 patients in which the administration of high-dose (400 mg)intravenous iron to dialysis-dependent CKD patients with ID (serum ferritin <700 μg/L and TSAT ≤40%) reduced all-cause death, nonfatal myocardial infarction, nonfatal stroke, and heart failure hospitalization rates [76]. The clinical benefits of iron supplementation in CKD patients are presented in Table 5. However, although many studies have shown the safety of intravenous iron, there are limitations regarding whether it is safer than oral iron supplementation, especially in patients without dialysis [65].

Table 5.

Clinical benefits of supplement of iron in patient with CKD

Although the correction of iron status in IBD patients is known to significantly improve quality of life, >50% of ID patients, even those with anemia, do not receive adequate iron treatment [67]. A systematic review found that, in patients with IBD, parenteral iron improved the hemoglobin concentration more than oral iron with no serious adverse events [77]. Since oral ferrous supplements are oxidized in the gut, they form activated hydroxyl radicals and affect the mucosa, exacerbating gastrointestinal symptoms such as nausea and pain in patients with IBD [78]. A recent study conducted in Switzerland also reported that intravenous iron featured less withdrawal due to adverse events than oral iron, demonstrating a good effect; among the administered irons, ferric carboxymaltose was the most cost-effective [79]. A similar finding was reported in children with IBD; both ID and IDA resolved after intravenous iron infusion without serious side effects, and no C-reactive protein elevation was observed [78].

In the 2018 European Society for Medical Oncology guidelines, absolute ID was defined as a serum ferritin level <100 μg/L, while functional ID was defined as a serum ferritin level ≥100 μg/L and TSAT level <20% in patients with cancer [34]. According to the above definition, in the recently reported CARENFER study, 86%–90% of cancer patients were diagnosed with ID [80]. In addition, this guideline recommends ID treatment as soon as possible when the ferritin level is <100 μg/L and the TSAT level is <20% regardless of anemia status [34]. In the National Comprehensive Cancer Network guidelines, oral or intravenous iron administration for absolute ID is always recommended, and functional ID is considered in cases of treatment failure. For functional ID, intravenous iron administration should be considered [33].

As for adults, the International Restless Leg Syndrome Study Group task force recommends that intravenous iron be considered for RLS or periodic limb movement disorder in children [45]. In a pediatric patient analysis report, intravenous iron supplementation improved the clinical severity and laboratory parameters of RLS and periodic limb movement, and the treatment was well-tolerated [81]. The target of iron therapy in pediatric sleep disorders is a serum ferritin level ≥50 μg/L [45].