Iron metabolism

Iron in the body exists in the following forms:

• Incorporated into Hb (80%)• Myoglobin, Enzymes,Cytochromes (15%)• Stored iron in the form of ferritin/hemosiderin.• Plasma transferrin-bound iron.

( divalent metal transporter 1)

Iron exists in 2 forms:• Inorganic/non-heme iron (90%) Fe3+ (less soluble)• Organic/heme iron (10%) Fe2+ (more soluble)

• To be soluble, Ferric (Fe3+) needs to be reduced to Ferrous (Fe2+).

• The enzyme that does this is called Duodenal cytochrome b (Dcytb)

• This enzyme is Vitamin C dependent.

• From the gut lumen, iron needs to be moved into the enterocyte before getting to the bloodstream.

• Therefore, it needs a transporter to do this.

• Inorganic iron uses DMT1 • Organic iron uses HCP1

• Once in the enterocyte, iron is moved to the bloodstream.

• Fe2+ is transported out by ferroportin1(FPN)

• Once it leaves the enterocyte, the Fe2+

changes back to Fe3+ by Hephaestin.

• Once in the bloodstream, Fe3+ couples with Transferrin (Tf) forming a Tf-Fe complex.

• Tf-Fe complex meets up with transferrin receptor 1 (TfR1) in most cells.

• Proton ATPase drops the pH in the endosome to release Fe3+ from Tf.

• This reduction is achieved by Steap3.

• Macrophages engulfs old RBCs and releases heme.

• Heme contains protoporphyrin and Fe.

• Heme oxygenase separates them and Fe is then stored as ferritin.

Transferrin

• Major transporter for iron trafficking through the plasma.

• Increased in iron deficiency.

• Rare disease: Hypotransferrinemia.• Characterized by low transferrin level, severe

iron deficiency anemia and iron overloading.

Serum soluble transferrin receptorHigh transferrin receptor= high Erythroid mass.

Causes for low transferrin receptor: erythroid hypoplasia.• Aplastic anemia• CRF

Causes for raised transferrin receptor: erythroid hyperplasia.

• Chronic hemolysis• Thalassemia• Iron deficiency (absence of erythroid hyperplasia)

• Not elevated in anemia of chronic disease.

Transferrin saturationReduced: when iron supply is reduced.• Iron deficiency anemia• Anemia of chronic disease• Ferroportin mutation

Increased: when iron supply is in excess.• Hemochromatosis• Aplastic anemia• Sideroblastic anemia• Ineffective erythropoiesis.• Liver disease with reduced transferrin synthesis.

Ferritin• Cellular storage protein for iron.

• Plasma level reflects overall iron stores.

• Also an acute phase reactant.

• Orchestrates cellular defense against oxidative stress and inflammation.

• When body gets inflammation, the normal response is to save the iron (keep it in storage) so that it will be less available to the microbes.

• Raised ferritin = Inflammation.

• Low ferritin = iron deficiency anemia (99%)

• Raised ferritin but no infection/inflammation= Iron overload.

• Extremely high ferritin = hemophagocytic lymphohistiocytosis.

Hepcidin• Hepatic Bactericidal Protein.• Negative regulator of iron metabolism.

Actions:• It inhibits intestinal transport.• Blocks Fe transport across placenta.• Induces Fe sequestration in macrophages.

• If low iron stores = hepcidin expression reduced.

• If high iron stores = hepcidin expression increased.

• Molecular target of Hepcidin is Ferroportin.

Here’s how it works…

• When iron is low,• Hepcidin expression is reduced.• Leads to increased ferroportin expression.• Therefore, more transport of Fe from cells to

blood bound by Tf.

Hepcidin decreased in:• Hypoxia • Anemia• Iron deficiency.

Hepcidin increased in: Inflammation leading to:• low transferrin Sat (low iron saturation)• increased ferritin (storage of iron)• anemia.

Inappropriately decreased in chronic hemolytic anemia and thalassemias.

Ferroportin

• Major exporter of iron.• Transports iron from mother to fetus• Transferring absorbed iron from enterocytes

into the circulation.• Allow macrophages to recycle iron from

damaged red cells back into the circulation.

• When hepcidin level increase,• Hepdicin binds to ferroportin.• Induces internalisation and lysosomal

degradation.• Therefore, reduces amount of iron released

into circulation from duodenal cells and macrophages.