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Hepcidin - Regulation and its role in Iron metabolism
- 1. Hepcidin Dr. Reenaz Shaik MD Pathology
- 2. Anemia 1.6 Billion people affected globally with anemia Most common: Iron Deficiency Anemia Key Regulator in Iron Metabolism: Hepcidin Iron deficiency anemia Iron refractory anemia Iron overload Anemia of Chronic Disease Anemia in kidney disease Hepcidin acts as a Moderator in:
- 3. Iron • A typical human adult has about 3-5 grams of total body iron. 60% of iron is found in circulating haemoglobin 10% in myoglobin in muscles 20% is stored in liver cells (hepatocytes and Kupffer cells) as ferritin Rest is divided between enzymes such as cytochromes, peroxidases, catalase and others. • To replenish the daily loss of 1-2 mg of iron from mucosal cell sloughing, sweat and urine excretion, duodenal enterocytes must absorb an equal amount of iron.
- 4. Iron Homeostasis Duodenal enterocytes Absorb iron Erythroid precursors Use Iron Hepatocytes and tissue macrophages Store Iron Splenic macrophages Recycle Iron Iron concentrations in our body are tightly regulated both at cellular level and systemic level. Crucial element in maintenance of Iron homeostasis is effective communication between absorption, storage, usage and recycling of Iron.
- 5. Hepcidin • Hepcidin is a peptide hormone synthesised in hepatocytes. It is composed of 25 amino acids and includes 4 disulfide bonds which binds with ferroportin. • Normal range for plasma hepcidin is in range of 1 to 55 ng/ml. Decreases Iron Absorption Increases Iron Absorption
- 6. Iron Absorption and Hepcidin Iron absorption takes place at the apical surface of duodenal enterocytes. Non-haem iron is released from food as Fe3+ (ferric iron) and reduced to Fe2+ (ferrous iron) by duodenal cytochrome b (DCYTB). Iron is then transported across the brush-border membrane by the divalent metal transporter DMT1. Iron is transported across the serosal membrane by ferroportin-1.
- 7. Potential of Hepcidin as a marker • Hepcidin can help in diagnosis of Iron deficiency anemia even before routine haematological parameters and iron profile diagnose anemia. • Hepcidin helps in differentiating Iron deficiency Anemia and Anemia of Chronic Disease • Few studies have shown that hepcidin antibodies, BMP agonists or antagonists, cytokine receptor antibodies can modify hepcidin expression and reverse iron abnormalities in vivo. • Hepcidin has emerged as the potential marker as it has a known mechanism of action good stability rapid response to iron stores, inflammatory stimuli and bacterial infections
- 8. Regulation of Hepcidin Physiological Induction of Hepcidin: Bone morphogenetic protein (BMP) along with hemochromatosis protein (HFE), transferrin receptor 2 (TFR2), hemojuvelin (HJV), Metallothionein (MT2) and a specific iron- related bone morphogenetic protein, BMP6 activates SMAD signalling pathway. This causes hepcidin transcription. Pathological hepcidin induction: During inflammation or infection, interleukin-6 (IL-6) increase hepcidin production. Activation of JAK- STAT3 pathway by IL6 promotes hepcidin production.
- 10. Regulation of Hepcidin • Physiological hepcidin suppression: When there is an increased demand for iron during anemia and hypoxia, hepcidin is supressed, independent of the amount of iron stores present. This is indirectly mediated by the hormone erythropoietin (EPO) and erythroferrone. • Pathologic hepcidin suppression: Occurs in the iron-loading anemia. Hepcidin transcription is suppressed by exuberant but ineffective erythropoiesis. Hepcidin is also supressed by the cytokines GDF-15 (Growth Differentiating Factor), TWSG1 (Twisted granulation BMP signalling modulator), Hepatocyte growth factor (HGF), Epidermal growth factor (EGF).
- 11. Correlation of Hepcidin with other anemia markers Hepcidin Condition Biochemical markers Haematological markers Low Iron Deficiency Iron, Ferritin, Tfs TIBC Hb , MCV, MCH RDW Low Ineffective erythropoiesis Iron, Ferritin, Tfs Hb N RDW Low Iron Overload Iron, Ferritin, Tfs Hb, MCV, MCH High Anemia of Chronic Disease Iron, Tfs, TIBC Ferritin Hb, MCV, MCH N RDW
- 12. Physiological Process in Different Anaemia's: Type of Anemia Hepcidin level Physiological Process Iron Deficiency Anemia Low Suppression by Erythropoietin Iron Refractory Anemia High Mutation of TMPRSS6 (Suppressor Matriptase) Iron Overload Low Suppression due to increased erythropoietic activities which increases Erythroferrone Ineffective Erythropoiesis Low Suppression by Cytokines GDF15 and TWSG1 Anemia of Chronic Disease High Induction by Interleukin 6 Anemia in Kidney Disease High Decreased hepcidin clearance and lack of erythropoietin Beta Thalassemia (pre-transfusion) Low Suppression by Cytokine GDF15 Beta Thalassemia (post-transfusion) High Due to suppression of erythropoietin Megaloblastic Anemia Low Decreased nucleotide production causes ineffective erythropoiesis. Leukaemia and Lymphoma High Induction by BMP6 and IL6