Overview
Human iron metabolism encompasses the processes by which iron is absorbed, transported, stored, utilized, and regulated in the body. Iron is essential for oxygen transport (as a component of hemoglobin), cellular respiration (as part of cytochromes), DNA synthesis, and numerous enzymatic reactions. Because free iron can catalyze the formation of harmful free radicals, its levels are tightly controlled.
Absorption
- Primary site: duodenum and proximal jejunum of the small intestine.
- Dietary iron exists as heme iron (from animal sources) and non‑heme iron (from plant sources). Heme iron is absorbed via the HCP1 (heme carrier protein 1) transporter, while non‑heme iron (Fe³⁺) is reduced to Fe²⁺ by duodenal cytochrome b (Dcytb) before uptake via divalent metal transporter 1 (DMT1).
- Absorption efficiency is low (≈1–2 % of dietary iron) and is modulated by several factors: vitamin C enhances absorption; phytates, polyphenols, calcium, and certain proteins inhibit it.
Transport
- Once inside enterocytes, iron is either stored as ferritin or exported into the circulation through ferroportin, the only known cellular iron exporter.
- Exported Fe²⁺ is oxidized to Fe³⁺ by hephaestin (in the intestine) or ceruloplasmin (in plasma) and bound to transferrin, the major iron‑binding plasma protein.
- Transferrin delivers iron to cells expressing transferrin receptors (TfR1 and TfR2). Cellular uptake occurs via receptor‑mediated endocytosis, followed by release of Fe³⁺ in endosomes, reduction to Fe²⁺, and transport into the cytosol via DMT1.
Storage
- The liver, spleen, and bone marrow are primary iron storage sites.
- Ferritin stores iron intracellularly in a soluble, non‑toxic form; excess iron can be stored in hemosiderin, a less readily mobilizable aggregate.
- Hepcidin, a peptide hormone produced by hepatocytes, regulates storage and release by inducing internalization and degradation of ferroportin, thereby decreasing iron egress from cells.
Utilization
- Erythropoiesis: The majority of systemic iron (~20–25 mg/day) supports the synthesis of hemoglobin in developing red blood cells.
- Mitochondrial functions: Iron is incorporated into heme and iron‑sulfur (Fe‑S) clusters, essential for the electron transport chain and various metabolic enzymes.
- Other tissues: Myoglobin in muscle, enzymes involved in DNA synthesis (e.g., ribonucleotide reductase), and numerous catalytic proteins require iron.
Regulation
- Hepcidin: Central regulator; its synthesis is up‑regulated by high systemic iron, inflammation (via IL‑6), and iron overload, and down‑regulated by anemia, hypoxia, and increased erythropoietic demand.
- Erythropoietin (EPO): Stimulates erythropoiesis, indirectly increasing iron demand and suppressing hepcidin.
- Iron‑responsive element/iron‑responsive protein (IRE/IRP) system: Post‑transcriptional control of ferritin, transferrin receptor, and other iron‑related proteins based on intracellular iron status.
Disorders
| Condition | Pathophysiology | Clinical Features |
|---|---|---|
| Iron‑deficiency anemia | Inadequate intake, absorption, or chronic loss → depleted iron stores | Fatigue, pallor, microcytic hypochromic anemia |
| Hereditary hemochromatosis | Mutations (e.g., HFE C282Y) reduce hepcidin action → excessive absorption and organ iron overload | Hepatomegaly, diabetes, skin hyperpigmentation, cardiac dysfunction |
| Anemia of chronic disease (inflammation) | Cytokine‑mediated hepcidin elevation → sequestration of iron in macrophages, reduced absorption | Normocytic or mildly microcytic anemia, low serum iron, high ferritin |
| Sideroblastic anemia | Defective heme synthesis or Fe‑S cluster formation leading to mitochondrial iron accumulation | Ringed sideroblasts in marrow, variable anemia severity |
Diagnostic Evaluation
- Serum iron, total iron‑binding capacity (TIBC), transferrin saturation, and ferritin are core laboratory tests.
- Hepcidin assays are emerging but not yet standard.
- Genetic testing for HFE and other iron‑regulation genes confirms hereditary hemochromatosis.
Therapeutic Approaches
- Iron deficiency: Oral ferrous salts (e.g., ferrous sulfate) or intravenous iron compounds when oral therapy is ineffective or contraindicated.
- Iron overload: Therapeutic phlebotomy is first‑line for hereditary hemochromatosis; iron chelators (deferoxamine, deferasirox, deferiprone) are used for secondary overload (e.g., transfusion‑related).
- Anemia of chronic disease: Address underlying inflammation; erythropoiesis‑stimulating agents and judicious iron supplementation may be employed.
Key Points
- Iron homeostasis in humans is a tightly regulated network that balances dietary absorption, recycling from senescent red cells, and controlled storage.
- Hepcidin–ferroportin interaction is the principal hormonal axis governing systemic iron levels.
- Disruption of normal iron metabolism can lead to clinically significant anemia or organ toxicity from iron overload.
