Iron Metabolism in Humans

Physiology and Requirements

Full-term newborn total body iron: ~0.5 g.
Adult total body iron: 5 g.
Required daily absorption: ~0.8 mg daily during first 15 years; ~1 mg daily to maintain positive balance.
Required daily dietary intake: 8–10 mg (dietary iron absorption efficiency <10%).

Primary absorption site: Proximal duodenum.
Gastric acidity essential for converting insoluble environmental iron salts into absorbable forms.
Agents reducing gastric acidity (e.g., H2 blockers) impair non-heme iron absorption.
Heme Iron: Derived from animal sources. Most readily absorbed. Independent of gastric pH.
Non-Heme Iron: Derived from plant sources. Absorption limited by low solubility and natural chelators (e.g., phytates).
Milk Sources: Breast milk iron bioavailability significantly exceeds cow's milk. Breastfed infants absorb 20-80% of iron; cow's milk fed infants absorb ~10%.

Iron serves essential roles in multiple metabolic processes, oxygen transport, and electron transport.

Compound	Function in Iron Metabolism
Transferrin	Principal iron transport protein.
Ferritin	Primary intracellular iron storage.
Hemosiderin	Secondary iron storage.
Hemoglobin	Oxygen delivery (circulating RBCs).
Myoglobin	Oxygen storage for muscle contraction.
Cytochromes	ATP production, electron transport.

Hepcidin: Key regulatory protein controlling intestinal iron absorption and systemic tissue distribution.
Synthesized primarily by hepatocytes; also expressed in monocytes/macrophages.
Mechanism of Action: Binds to iron exporter ferroportin (expressed in GI tract and reticuloendothelial system).
Induces internalization and lysosomal degradation of ferroportin.
Downregulates iron export to circulating transferrin from enterocytes and macrophages.

Inflammatory cytokines (e.g., IL-6) and endotoxin stimulate excessive hepatic hepcidin synthesis.
Hepcidin degrades ferroportin, preventing iron release into plasma.
Iron accumulates/sequesters in reticuloendothelial macrophages.
Results in functional iron deficiency, iron-restricted erythropoiesis, and impaired heme synthesis despite normal/high total body iron stores.
Characteristic laboratory profile: Low serum iron, normal/low transferrin, elevated serum ferritin (acute phase reactant).

Defect Category	Specific Disorder	Genetic/Molecular Mechanism
Absorption	Iron-Refractory Iron-Deficiency Anemia (IRIDA)	TMPRSS6 mutation; elevated hepcidin degrades ferroportin, blocking intestinal absorption.
Transport	Atransferrinemia	TF gene mutation; absent serum transferrin leading to severe liver iron overload.
Recycling	Aceruloplasminemia	CP gene mutation; absent ceruloplasmin. Iron fails to transport from macrophages to plasma, accumulating in brain/viscera.
Utilization	Sideroblastic Anemias	Defective heme synthesis (ALAS2 mutations common). Iron retention within mitochondria of marrow RBC precursors forming ringed sideroblasts.