How I treat iron-refractory iron deficiency anaemia-An expert opinion-based treatment guidance for children and adults

Abstract

Iron-refractory iron deficiency anaemia (IRIDA) is a rare hereditary microcytic anaemia characterized by partial or complete resistance to oral iron supplementation, caused by elevated plasma hepcidin levels resulting from pathogenic variants in the TMPRSS6 gene. Although intravenous iron supplementation is often effective, patient responses can vary significantly due to various factors, and potential side effects of this treatment remain unclear. Additionally, evidence-based international guidelines for diagnosing and managing IRIDA are lacking. This review aims to provide patient-tailored treatment strategies, informed by case studies and expert opinion, to address the specific therapeutic needs of both children and adults with IRIDA.

Keywords: hepcidin; iron distribution disorder; iron therapy; iron‐refractory iron deficiency anaemia.

FIGURE 1

Schematic overview of effects of oral and IV iron therapy in IRIDA. (A) Macrophages release 20–25 mg of iron daily, mainly from the recycling of senescent erythrocytes. Enterocytes absorb 1–2 mg of dietary iron. Iron enters the circulation via the membrane‐bound exporter ferroportin, binds to transferrin and is delivered to iron‐requiring cells, including erythroid precursor cells. Each transferrin molecule can carry up two iron ions; for example, at a TSAT of 50%, each transferrin molecule typically carries one iron ion. (B) In IRIDA, inappropriately elevated hepcidin levels inhibit dietary iron uptake and iron release from macrophages by interacting with ferroportin, reducing circulating iron levels. (C) Oral iron supplements (containing usually 30 mg elemental iron per 100 mg of the compound) are generally ineffective in IRIDA. Hepcidin‐mediated inhibition traps iron in duodenal enterocytes, preventing its release into circulation and macrophages, and thus not significantly improving circulating iron levels. However, positive outcomes have been observed in younger children, although the studies are heterogeneous in terms of treatment regimens. (D) IV iron bypasses this barrier by delivering a significantly higher amount of elemental iron directly to macrophages, where it is unpacked from its carbohydrate shell. Ferroportin mRNA expression in macrophages is upregulated via the IRP/IRE system, overcoming hepcidin inhibition and enabling iron release into circulation while releasing macrophage iron loading. The extent of this release depends on the ferritin set point of a specific patient—the ferritin level at which iron is mobilized from reticuloendothelial stores—which tends to decrease with age and increase with the severity of TMPRSS6 defects.

FIGURE 2

Course of haemoglobin, ferritin and TSAT levels in three female IRIDA patients. The left panels display Hb levels (with CRP for case 3); the right panels show ferritin and TSAT levels. Case 1: Hb and iron metrics over 6 years. This patient initially received IV iron therapy at irregular intervals due to being lost to follow up. At age 26 (6 years post‐diagnosis, time point t = 0), regular IV iron therapy was initiated. Over the subsequent years, she received a cumulative dose of 2500 mg of FCM via five 500 mg infusions, causing a sharp rise in ferritin (>900 μg/L) and TSAT (up to 25%). Despite persistently high ferritin (>700 μg/L), Hb only briefly peaked and remained within the lower normal range. Case 2: Hb and iron metrics over 4 years, including two pregnancies (shown by horizontal bars). At diagnosis (t = 0), this 32‐year‐old patient began monthly IV iron therapy. After a cumulative dose of 1700 mg FCM, the patient became pregnant (unaware at last administration). Particularly during the first pregnancy, TSAT remained stable and the Hb decrease was less pronounced than during non‐pregnancy periods. Case 3: Hb, CRP and iron metrics over 20 years. IV iron (totalling 5800 mg FS at 200 mg/dose) was administered every 2 months, maintaining ferritin >500 μg/L for nearly a decade, with Hb within the reference range. Diagnosis of IRIDA was made at t = 5 when she was 41 years old. Ferritin and TSAT varied widely, likely due to chronic inflammation (CRP ~25 mg/L). In the final years (following t = 15), heavy menstrual bleeding led to a Hb decline, requiring additional IV iron therapy (totalling 1700 mg FCM). Red arrows: IV iron administration; Grey‐shaded area: Hb reference interval. CRP, C‐reactive protein; FCM, ferric carboxymaltose; FS, iron saccharate; Hb, haemoglobin; TSAT, transferrin saturation.

FIGURE 3

Flowchart of expert opinion‐based treatment guidance for IRIDA patients. This figure outlines treatment strategies for IRIDA in children and adults, based on expert opinion. Children: For mild to moderate anaemia without previous oral iron therapy, start once‐daily oral elemental iron (3 mg/kg/day, compared to the 1 mg/kg/day usually used for iron deficiency anaemia), titrating up to a maximum of 10 mg/kg/day based on evidence from case series suggesting better responses with higher doses. Minimize concurrent intake with specific foods (e.g. dairy products and fibres) and medications (e.g. calcium supplements, antacids, proton pump inhibitors) to prevent insoluble complexes that reduce iron availability. Continue oral therapy for at least 3 months before considering IV iron therapy, as prolonged oral therapy may still be effective (Table S1). In iron deficiency anaemia, a 2‐g/dL Hb increase is expected within 4 weeks. If oral iron therapy proves ineffective (including previous attempts) or severe anaemia is present, initiate IV iron therapy at 15–20 mg/kg per dose, up to a maximum of 500 mg per dose. Monitoring recommendations are consistent with adult guidelines. Adults: In adults, IRIDA often presents with a mild(er) phenotype, causing diagnostic delays with subsequent prolonged oral iron therapy before the final diagnosis of IRIDA is established. Therefore, IV iron therapy is recommended as first‐line treatment. Avoid targeting Hb normalization to prevent excessively high ferritin levels. Regularly monitor phosphate levels (at least after two administrations) during FCM therapy due to the risk of hypophosphataemia. Assessing the total iron deficit is not applicable for IRIDA patients, as it is an iron distribution disorder. *Reference intervals and definitions are age‐dependent; severe anaemia is defined according to the WHO guidelines. **Dosages are not applicable for neonates. ***Despite a recent trial found no benefit from adding ascorbic acid to oral iron therapy for iron deficiency anaemia, it may still be considered to improve iron absorption in IRIDA. ****Alternate‐day dosing can reduce hepcidin‐mediated inhibition of iron uptake, which reduces iron absorption for approximately 24 h after iron intake. FCM, ferric carboxymaltose; Hb, haemoglobin; IV, intravenous; QoL, quality of life; TSAT, transferrin saturation.