Core concept5 exam ›
- Ferroportin is the only cellular iron exporter - basolateral enterocyte, macrophage, hepatocyte, placenta
- Hepcidin (hepatocyte-derived) binds ferroportin -> internalisation and degradation
- -> iron trapped inside the cell
- -> dec dietary absorption and dec macrophage recycling -> dec transferrin saturation
- One sentence to hold on to: hepcidin up = iron locked away; hepcidin down = iron floods out
| Hepcidin increased by | Hepcidin decreased by |
|---|---|
| Inflammation - IL-6 -> STAT3 (it is an acute phase protein) | Iron deficiency |
| Iron loading - BMP6 / hemojuvelin / SMAD, sensed via HFE and TFR2 | Hypoxia (HIF) |
| Erythropoietic drive - erythroferrone from erythroblasts | |
| Testosterone, EPO |
- The name encodes both facts: hepatic origin, antimicrobial (cidal) activity - withholding iron from pathogens is its evolutionary job
Key detail
Absorption sequence - duodenum
- Dietary Fe3+ -> duodenal cytochrome b reductase -> Fe2+
- -> DMT1 apical uptake -> stored as ferritin or exported via ferroportin
- -> hephaestin / ceruloplasmin oxidise back to Fe3+ -> loaded onto transferrin
- Haem iron uses a separate, more efficient route
- ~1-2 mg absorbed per day balances ~1-2 mg lost - there is no regulated excretory pathway
The genetic diseases are all hepcidin diseases
- HFE haemochromatosis - HFE mutation -> the liver cannot sense iron -> inappropriately LOW hepcidin -> unrestrained ferroportin -> loading
- C282Y homozygote commonest; H63D low penetrance
- Juvenile haemochromatosis - HJV (hemojuvelin) or HAMP (hepcidin itself) -> most severe, cardiac and endocrine failure in the 2nd-3rd decade
- Ferroportin disease (SLC40A1) - autosomal dominant
- Loss of function: macrophage loading, high ferritin with normal/low TSAT, poorly tolerant of venesection
- Thalassaemia / ineffective erythropoiesis - erythroblast erythroferrone suppresses hepcidin -> iron loading even before transfusion
Clinical relevance
| Ferritin | TSAT | Transferrin / TIBC | |
|---|---|---|---|
| Iron deficiency | low | low | high |
| Anaemia of inflammation | normal or high | low | low |
| Combined | <100 despite inflammation | low | low-normal |
| Haemochromatosis | high | >45-50% | low-normal |
- Ferritin is an acute phase reactant - a normal ferritin does not exclude iron deficiency when CRP is up
- Use TSAT, soluble transferrin receptor, or the disease-specific cutoffs (ferritin <100, or <300 with TSAT <20%, in heart failure and CKD)
- A single oral iron dose raises hepcidin for ~24 h -> alternate-day single dosing gives higher fractional absorption than tds dosing
- IV iron bypasses the enterocyte and hepcidin entirely - the rational choice when hepcidin is high: CKD, IBD, heart failure, post-operative
- PPIs reduce non-haem iron absorption - acid is needed to reduce Fe3+ to Fe2+
- Hepcidin explains why oral iron fails in inflammation, and why haemochromatosis is treated by venesection (which raises erythropoietic drive) rather than by diet
- Therapeutic hepcidin mimetics are in late-phase development for polycythaemia vera; antagonists for anaemia of inflammation and beta-thalassaemia
Correlations
- Iron deficiency anaemia; anaemia of chronic disease
- Hereditary haemochromatosis; iron overload and chelation
- Thalassaemia; myelodysplasia and ineffective erythropoiesis
- Anaemia of CKD - EPO plus iron, and HIF-prolyl hydroxylase inhibitors (which lower hepcidin)
- Heart failure - IV iron for iron deficiency with or without anaemia
Study aid only. These notes are written with the help of AI. Not for guiding clinical decisions.