How to manage a patient with iron refractory iron deficiency anemia (IRIDA) who has not responded to traditional oral iron supplementation?

Management of Iron Refractory Iron Deficiency Anemia (IRIDA)

For patients with true iron refractory iron deficiency anemia (IRIDA) who have failed oral iron supplementation, intravenous iron therapy is the definitive treatment, with consideration of oral iron combined with ascorbic acid as an initial alternative before escalating to IV formulations. 1

Diagnostic Confirmation

Before proceeding with treatment, confirm the diagnosis of IRIDA:

• Measure serum hepcidin levels in patients with unexplained microcytic anemia, low transferrin saturation (TSAT), and normal or reduced ferritin who do not respond to oral iron 1
• Calculate the hepcidin:TSAT ratio - a ratio greater than the local upper reference limit is suggestive of IRIDA 1
• Perform TMPRSS6 mutation analysis if elevated hepcidin is confirmed - homozygous or compound heterozygous defects confirm genetic IRIDA 1
• Rule out acquired causes of iron refractoriness including gastrointestinal pathologies, inflammatory conditions, H. pylori infection, celiac disease, and autoimmune gastritis 1, 2, 3

Treatment Algorithm

First-Line Approach

Trial oral iron with ascorbic acid enhancement:

• Administer oral iron (ferrous sulfate 200 mg) with 250-500 mg ascorbic acid to enhance absorption 1
• Continue for 4-6 weeks and assess hemoglobin response (expect ≥1 g/dL increase if effective) 2
• This approach may work in some IRIDA patients despite the underlying pathophysiology 1

Second-Line: Intravenous Iron Therapy

When oral iron fails or is insufficient, switch to IV iron:

Formulation selection priorities 1:

• Choose IV iron formulations that can replace iron deficits with 1-2 infusions rather than multiple infusions
• All IV iron formulations have similar safety profiles; true anaphylaxis is very rare 1
• Most reactions are complement activation-related pseudo-allergy (infusion reactions), not true anaphylaxis 1

Dosing strategy 1, 4:

• Calculate total iron deficit based on hemoglobin deficit and need to rebuild iron stores
• For adults: typical total treatment course is 1000 mg elemental iron 4
• Administer doses every 3-7 days until total calculated dose is reached 1
• Do not exceed maximum single dose per formulation guidelines 1

Monitoring during IV therapy 1:

• Monitor serum ferritin levels closely
• Keep ferritin below 500 mg/L to avoid iron overload toxicity, especially in children and adolescents 1
• Repeat IV iron courses when iron deficiency recurs 4

Alternative Consideration

Combination therapy with erythropoietin:

• While evidence is limited, combining IV iron with erythropoietin may prevent toxic iron loading in some IRIDA patients 1
• This approach lacks strong evidence but represents a reasonable option in refractory cases 1

Follow-Up Protocol

Hemoglobin and iron parameter monitoring:

• Check hemoglobin concentration and red cell indices every 3 months for the first year 1
• Recheck after an additional year 1
• Measure ferritin in doubtful cases when hemoglobin or MCV falls 1
• Administer additional IV iron if hemoglobin or MCV cannot be maintained at normal levels 1

Critical Pitfalls to Avoid

Do not continue ineffective oral iron indefinitely - if hemoglobin fails to rise by 2 g/dL after 3-4 weeks of oral therapy, this indicates treatment failure requiring escalation to IV iron 1

Avoid iron overload - in IRIDA patients requiring repeated IV iron courses, ferritin levels above 500 mg/L increase toxicity risk, particularly in younger patients 1

Do not assume all iron refractoriness is genetic IRIDA - acquired causes (inflammatory bowel disease with active inflammation, celiac disease, H. pylori, autoimmune gastritis) are far more common and require different management approaches 1, 2

Recognize that oral iron absorption is blocked by hepcidin for 48 hours - there is no benefit to dosing oral iron more than once daily, as this only increases side effects without improving absorption 1