IRIDA

Introduction and Pathophysiology

Iron-refractory iron-deficiency anemia (IRIDA) is an extremely rare autosomal recessive disorder characterized by a primary defect in iron absorption and recycling.
It accounts for less than 1% of all cases of iron-deficiency anemia (IDA) encountered in clinical practice.
The disorder is caused by biallelic pathogenic mutations in the TMPRSS6 gene, which encodes the protein transmembrane protease, serine 6 (also known as matriptase-2).
Under normal physiologic conditions, matriptase-2 functions to inhibit the specific signaling pathway that activates hepcidin, the master iron regulatory hormone produced by the liver.
Mutations in TMPRSS6 lead to a loss of this inhibitory function, resulting in congenital hepcidin dysregulation and inappropriately high serum hepcidin levels.
The elevated hepcidin binds to ferroportin, leading to its degradation, which fundamentally blocks the absorption of dietary iron from the intestine and traps processed iron within reticuloendothelial macrophages.

Patients present with an iron-deficiency anemia that is classically refractory to standard oral iron supplementation.
The complete blood count and peripheral smear demonstrate a striking microcytosis.
Iron studies reveal an extremely low transferrin saturation.
Unlike classic IDA where ferritin is severely depleted, serum ferritin levels in IRIDA are characteristically normal or borderline-low.
Direct measurement of serum hepcidin reveals significantly elevated levels, which is paradoxical in the setting of iron deficiency.

The diagnosis is suspected in patients with a microcytic anemia who fail to demonstrate an adequate reticulocyte or hemoglobin response to a monitored trial of oral iron.
Confirmation of the diagnosis requires molecular genetic testing to identify pathogenic variants (via sequencing) in the TMPRSS6 gene.

Before diagnosing IRIDA, physicians must exclude the most common causes of oral iron refractoriness, which include poor patient adherence, inadequate dosing, use of ineffective enteric-coated preparations, persistent occult blood loss, or gastrointestinal malabsorption syndromes (e.g., celiac disease or Helicobacter pylori infection).
Anemia of Chronic Disease (ACD): ACD shares the feature of elevated hepcidin (driven by inflammatory cytokines such as IL-6); however, ACD is an acquired condition where patients generally retain normal to high iron stores, distinguishing it from the congenital hepcidin dysregulation of IRIDA.
Medical Mimics: Rare conditions that mimic IRIDA include gastrointestinal vascular malformations, autoimmune gastritis, Castleman disease (where massive IL-6 overproduction drives hepcidin elevation), and germline KCNQ1 variants that impair gastric acid secretion.

Parenteral (intravenous) iron supplementation is required to treat the condition, as it bypasses the hepcidin-mediated block in intestinal iron absorption.
Even with intravenous iron, the hematologic response is typically slow and often incomplete because hepcidin continues to prevent the efficient export of processed iron from macrophages into the circulating plasma.
Parenteral iron therapy raises body iron stores and increases serum ferritin in a dose-dependent manner; this requires careful monitoring as it poses a risk for iron overload, which in IRIDA would be expected to exhibit a reticuloendothelial rather than parenchymal pattern of iron loading.
The optimal formulation and dosing schedule of parenteral iron for IRIDA are not strictly established due to the rarity of the condition.
Oral iron therapy generally does not play a significant role, though isolated hematologic responses have been noted when oral ferrous sulfate is co-administered with ascorbic acid.
Therapy with recombinant erythropoietin-stimulating agents has not been found to produce any significant clinical benefit in these patients.