Subtitle: Iron metabolism for pathology exams: absorption in the duodenum (Dcytb, DMT1, ferroportin, hephaestin), transport on transferrin, storage as ferritin and haemosiderin, macrophage recycling, hepcidin regulation, iron studies in deficiency, inflammation and overload, a video, a question and 8 MCQs.
Author: PathologyMCQ Editorial Board
Category: Haematology
Last Updated: October 2026
Read Time: 6 minutes
At-a-Glance
- Absorption: duodenum; Dcytb reduces Fe3+ to Fe2+, DMT1 brings it in, ferroportin exports it, hephaestin oxidises it for transferrin.
- Transport: transferrin carries Fe3+; cells take it up by transferrin receptor 1.
- Storage: ferritin (soluble) and haemosiderin (Perls positive).
- Recycling: macrophages recover 20–25 mg/day from old red cells; only 1–2 mg/day is absorbed.
- Hepcidin degrades ferroportin: high in inflammation and iron overload, low in iron deficiency and active erythropoiesis.
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Why Iron Matters
Iron carries oxygen in haemoglobin and myoglobin and sits at the centre of cytochromes, ribonucleotide reductase and many other enzymes. The body has no regulated route for iron excretion, so balance is controlled entirely at the point of absorption and release, which is why a single hormone, hepcidin, matters so much.
Absorption
- Site: duodenum and upper jejunum. Daily absorption is only 1–2 mg, matching losses from shed cells, sweat and menstruation.
- Haem iron (meat) is absorbed intact, about 15–35% efficient; non-haem iron (plants, fortified food) about 2–20%, helped by vitamin C and gastric acid and hindered by phytates, tannins and calcium.
- Dcytb (duodenal cytochrome b) reduces Fe3+ to Fe2+ at the brush border.
- DMT1 (divalent metal transporter 1) carries Fe2+ into the enterocyte.
- Inside the cell iron is either stored as ferritin and lost when the enterocyte sheds, or exported.
- Ferroportin on the basolateral membrane is the only known iron exporter; hephaestin oxidises Fe2+ to Fe3+ so it can bind transferrin.
Transport and Uptake
- Transferrin binds two Fe3+ atoms and delivers iron to the marrow, liver and other tissues; normal saturation is 20–45%.
- Cells take up transferrin-bound iron by transferrin receptor 1 (TfR1) and endocytosis; iron is released in the acidic endosome and reduced by STEAP3 before DMT1 moves it into the cytoplasm.
- Ceruloplasmin in plasma performs the same oxidation as hephaestin for iron leaving macrophages and hepatocytes.
- Cellular iron balance is tuned by iron regulatory proteins (IRP1, IRP2) binding iron-responsive elements on ferritin and TfR1 mRNA.
Storage and Recycling
- Ferritin: a 24-subunit shell storing up to 4500 iron atoms, mainly in liver, spleen and marrow; serum ferritin reflects stores but rises in inflammation and liver disease.
- Haemosiderin: insoluble, partly degraded ferritin aggregates, visible as golden-brown granules and blue with Perls Prussian blue.
- Recycling: splenic and hepatic macrophages phagocytose senescent red cells, haem oxygenase splits haem into iron, carbon monoxide and biliverdin (then bilirubin), and ferroportin returns the iron to transferrin. This supplies 20–25 mg/day, ten times the dietary intake.
Hepcidin: The Master Regulator
Hepcidin is a 25-amino-acid peptide made by hepatocytes. It binds ferroportin and triggers its internalisation and degradation, so iron is trapped in enterocytes, macrophages and hepatocytes and plasma iron falls.
| Signal | Pathway | Effect on hepcidin | Clinical setting |
|---|---|---|---|
| High iron stores / high transferrin saturation | BMP6 – HJV – SMAD; HFE and TfR2 sensing | Increases | Protects against overload |
| Inflammation | IL-6 – STAT3 | Increases | Anaemia of chronic disease: iron trapped in macrophages, low serum iron |
| Iron deficiency, hypoxia | Less BMP/SMAD signalling; matriptase-2 (TMPRSS6) cleaves HJV | Decreases | More absorption |
| Expanded erythropoiesis | Erythroferrone from erythroblasts | Decreases | Thalassaemia: iron loading even without transfusion |
| Mutations in HFE, HJV, HAMP, TFR2 | Loss of hepcidin production | Decreases | Hereditary haemochromatosis |
| Ferroportin mutations | Resistance to hepcidin | No effect on level | Ferroportin disease |
Iron Studies
| Condition | Serum iron | TIBC / transferrin | Transferrin saturation | Ferritin | Soluble TfR | Hepcidin |
|---|---|---|---|---|---|---|
| Iron deficiency anaemia | Low | High | Low (<15%) | Low | High | Low |
| Anaemia of chronic disease | Low | Low or normal | Low or normal | Normal or high | Normal | High |
| Hereditary haemochromatosis | High | Normal or low | High (>45%) | High | Normal | Low |
| Transfusional overload | High | Normal | High | Very high | Variable | High |
| Sideroblastic anaemia | High | Normal | High | High | Normal | Variable |
Video
Question
Which statement about hepcidin is false? A. Hepcidin inhibits ferroportin · B. Hepcidin levels rise in iron deficiency anaemia · C. Hepcidin rises in acute and chronic inflammation · D. Hepcidin blocks the export of iron across the basolateral membrane of the enterocyte
Show answer
B is false. Hepcidin falls in iron deficiency so that more iron can be absorbed. It rises with iron overload and with inflammation (IL-6), and it acts by binding ferroportin and causing its internalisation and degradation, which blocks iron export from enterocytes and macrophages.
Test Yourself: 8 MCQs
Iron metabolism: 8 MCQs
Absorption, transport, storage, hepcidin and the iron studies, with instant explanations.
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Exam Pearls
- Dcytb reduces, DMT1 imports, ferroportin exports, hephaestin/ceruloplasmin oxidise, transferrin carries.
- Hepcidin up: inflammation, overload. Hepcidin down: deficiency, erythropoiesis (erythroferrone), haemochromatosis.
- Ferritin low = iron deficiency; ferritin high does not exclude it when inflammation is present (use soluble TfR).
- Transferrin saturation above 45% is the screening trigger for haemochromatosis.
- Macrophage recycling, not diet, supplies most daily iron.
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References
- Ganz T, Nemeth E. Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012;1823:1434–43.
- Camaschella C. Iron deficiency. Blood. 2019;133:30–9.
- Bain BJ, Bates I, Laffan MA, eds. Dacie and Lewis Practical Haematology. 12th ed. Elsevier; 2017.
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