IRIDA

Definition & Genetics

Extremely rare, autosomal recessive disorder of iron absorption and trafficking.
Accounts for <1% of iron-deficiency anemia (IDA) cases.
Caused by pathogenic variants in the TMPRSS6 gene.
Usually identified in childhood.

Pathophysiology

TMPRSS6 gene encodes transmembrane protease, serine 6 (also known as matriptase-2).
Matriptase-2 normally inhibits signaling pathways that activate hepcidin (the primary iron regulatory hormone).
Loss-of-function TMPRSS6 mutation leads to uninhibited, constitutively high hepcidin levels.
Excess hepcidin binds to ferroportin (cellular iron exporter) on enterocytes and macrophages.
Promotes internalization and lysosomal degradation of ferroportin.
Results in dual defect: impaired intestinal iron absorption and defective iron release from reticuloendothelial macrophages into plasma.

Laboratory Investigations

Diagnosis suspected in microcytic anemia refractory to adequate oral iron trial.
Final confirmation requires genetic sequencing of the TMPRSS6 gene.

Parameter	Finding in IRIDA
Red Cell Indices	Striking microcytosis; hypochromic anemia.
Transferrin Saturation	Extremely low.
Serum Ferritin	Normal or borderline-low.
Serum Hepcidin	Inappropriately high (diagnostic hallmark).

Differential Diagnosis

Before considering IRIDA, common causes of oral iron resistance must be excluded (poor adherence, ongoing gastrointestinal bleeding, underlying celiac disease).

Differential Diagnosis	Distinguishing Features
Anemia of Chronic Disease (ACD)	Acquired hepcidin elevation via inflammatory stimuli (e.g., IL-6). Retains normal/high iron stores. Ferritin usually elevated.
Castleman Disease	IL-6 overproduction causes acquired hepcidin elevation.
Autoimmune Gastritis	Impaired iron absorption due to achlorhydria. Anti-parietal cell antibodies present.
KCNQ1 Germline Variants	Defective gastric acid secretion impairing iron absorption.
Atransferrinemia / Aceruloplasminemia	Other rare inherited defects of iron recycling. Distinct genetic testing (TF or CP genes). Aceruloplasminemia features elevated ferritin and liver iron.

Management

Oral Iron Therapy

Lacks significant therapeutic role.
Fails to correct anemia due to hepcidin-mediated intestinal block.
Isolated case reports suggest partial hematologic response utilizing ascorbic acid combined with oral ferrous sulfate.

Parenteral (Intravenous) Iron Therapy

Required therapeutic modality to bypass intestinal absorption block.
Response Characteristics: Hematologic response typically slow and incomplete.
Mechanism of Incomplete Response: High hepcidin levels persistently trap infused iron within reticuloendothelial macrophages, limiting export to circulating transferrin for erythropoiesis.
Dosing: Optimal formulation and dosing not universally established due to disease rarity.

Treatment Complications & Monitoring

Parenteral iron administration increases serum ferritin levels in a dose-dependent manner.
Raises clinical concern for iron overload.
Iron loading pattern typically reticuloendothelial rather than parenchymal (differentiating it from primary hemochromatosis).

Ineffective Therapies

Recombinant erythropoietin (EPO) administration produces no significant clinical benefit.**