Despite numerous ongoing and past national programs, iron deficiency anemia (IDA) remains a bane for health professionals, particularly in women of childbearing age and children, contributing 54% of cases in ages < 4 years, and 40% in 10–19 years [1]. It arises due to poor dietary intake, increased physiological demand in children, adolescents, and pregnancy, chronic blood loss, or malabsorption. It can influence intellectual development in children, and maternal-neonatal outcomes and serves as a measure of the general health of society.

Hepcidin is the master regulator for iron metabolism impacting absorption from the gut and utilization for erythropoiesis in bone marrow. Hepcidin level variations-based therapies are likely to be most effective for IDA patients, as higher hepcidin levels after daily iron supplementation may suppress further iron absorption [2]. Patients with chronic inflammatory states have elevated hepcidin levels which reduces the ability to absorb oral iron, suggesting the role of intravenous iron therapy in such cases.

While intravenous iron therapies are making great inroads, oral therapy remains applicable for most patients. Poor adherence to oral treatment (in up to 30% of patients) due to frequent gastrointestinal (GI) side effects leading to sub-optimal outcomes is widely recognized. Different formulations, dosing schedules, and dietary adaptations have been contemplated in literature with variable results. In this regard, several studies published in this issue of the Indian Journal of Hematology and Blood Transfusion suggest some innovative approaches:

Beyler et al. [3] did a prospective, randomized trial involving 87 women aged 18–45 years with IDA. Participants received oral iron supplementation on alternate-day dosing (ADD), daily dosing (DD) or twice-a-day (BID) basis. They found better reticulocyte response in BID and DD groups on Day 7; higher haemoglobin (Hb) on Day 15 in BID group (10.8 ± 1 vs. 9.3 ± 0.7 in ADD and 10 ± 1 g/dl in DD) as well as higher ferritin levels on 3rd month in BID group (37.2 vs. 21.9 in ADD and 25.5 ng/ml in DD), with no major changes in hepcidin levels. GI side effects were less in ADD group. They suggest that BID or DD provide earlier improvement in Hb as well as replenishment of iron stores, albeit at the cost of GI toxicity, and a personalized approach will be better. Here the importance of early follow-up visits for observing tolerance and compliance becomes important. Patients with severe toxicity can be offered ADD schedule.

These findings contrasted with those from Dhanush et al. [4], who in a randomized controlled trial in 68 women with IDA, revealed that ADD significantly improved Hb levels at day 14 and 28 days compared to DD (mean change: +2.2 ± 1.3 vs. +1.3 ± 1.1 g/ dL, p = 0.003), together with a lower incidence of adverse effects. ADD prevents the hepcidin surge that inhibits iron absorption, potentially enhancing iron uptake and reducing gastrointestinal distress. However, on day 14 hepcidin was not different in their study groups and neither was compliance, Hb rise was similar by Day 56.

In a randomized controlled trial, Hamed et al. [5] administered 10 mg elemental iron either as amino acid chelated (AAC) or ammonium citrate (AC) formulation once a day for eight weeks to 160 children aged 5–13 years with IDA. Both formulations produced similar significant improvements in Hb, MCV, serum iron, and ferritin. RDW decreased significantly in the AC group with a non-significant increase in side effects. They found that hepcidin level which shot up after 4 weeks of treatment declined by 8 weeks which in turn facilitates iron absorption. AAC iron has superior absorption and reduced interaction with dietary phytates, fibres, and tannins as well as partial resistance to enteric enzymes [6]. However, AC was more cost-effective, and possibly more helpful in their settings.

Naimisha et al. [7] intervened with the addition of sesame jaggery ball (SJB) to iron therapy (3 mg/kg/day) for eight weeks in children aged 6–11 years in a placebo-controlled randomized trial. They showed a statistically significant increase in Hb levels [1.7 (1.0, 2.4) Vs 1.3 (0.6, 2.0), P-0.013], serum ferritin [10.7 (6.4, 16.7) Vs 6.2 (4.6, 13.3), P-0.015], and body weight [0.8 (0.3, 1.4) Vs 0.1 (-0.4, 0.6),P-0.011] at 8 weeks in the intervention group compared to the control group. Vitamin E in sesame seeds promotes the growth of Propionibacterium freudenreichii, which augments iron absorption [8]. SJB is a locally available, inexpensive traditional food item and serves as a dietary adjunct for IDA patients, being rich in other nutrients.

Besides hepcidin, trace elements like cerium, copper, etc. can cause competitive inhibition of iron metabolism at absorption, and transport in plasma and other sites. Tabatabaie et al. [9] revealed cerium (a lanthanide element) can compete with iron for the same binding sites on apo-transferrin. It can reduce iron binding by 14%, as shown by spectrophotometry, measuring the maximum absorption wavelength of iron-transferrin and cerium-transferrin at 240 nm and 465 nm, and equilibrium dialysis methods. Industrial pollution and environmental exposure to such elements may jeopardize the replenishment of iron stores in vulnerable populations. Their analysis emphasizes an intricate relationship between trace elements and iron metabolism and the need for further research to study the impact on patients with IDA.

Even though, the above studies have their limitations due to potential bias, in the form of limited sample size, local geographical population, and being single-center or their open-label study design without any blinding, they provide valuable information on newer dosing schedules, dietary supplementation, and the role of trace elements in the management of IDA patients. Over the last few years, our practice has evolved to offer intravenous iron to more patients with IDA across all age groups and more severe anemia, with oral iron (DD or ADD) for patients with less severe anemia or unwilling for intravenous therapy. Recently, the Indian College of Hematology (ICH), the academic wing of the Indian Society of Hematology and Blood Transfusion (ISHBT) has brought out a comprehensive guideline on the diagnosis and management of nutritional anemia in India [10].

Treating physicians must consider the trade-offs between efficacy and tolerability when selecting an iron dosing regimen. A more nuanced approach—considering hepcidin dynamics, severity of anemia, formulation type, add-on food items, and patient tolerability, will provide maximum benefits (Fig. 1). Oral preparations are challenged by single or two-dose intravenous iron preparations with equivalent or better results. Moving forward, larger multicentric trials are needed to further validate these findings. There is a felt need to develop affordable and accessible assays for hepcidin for field use to design better anemia management strategies.

Oral iron strategies: considerations and challenges