Iron Metabolism notes

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Learning Homeostasis will make our understanding of IDA, IRIDA, anemia of chronic disease & sideroblastic anemia easier.

Iron is an essential component of various systems in our body thus its deficiency and excess both are likely to cause disease.

Danger of iron:

Iron when free can cause toxicity by producing free radicals like superoxide and H2O2 via fenton reaction thus our body has a system that not only provided needed iron but also keeps iron toxicity in check.

Iron in Human body:

Iron is present in Hb, myoglobin, cytochrome enzyme system in mitochondria and various other enzyme systems

Hemoglobin in circulating red cells and developing erythroblasts – approximately 2.0 to 2.5 g

●Iron-containing proteins (e.g., myoglobin, cytochromes, catalase) – 300 to 400 mg

●Plasma transferrin-bound iron – 3 to 4 mg

●The remainder is storage iron in the form of ferritin or hemosiderin

Iron exist in 2 forms:

Fe2+ ferrous

Fe3+ ferric

Components of Iron Homeostasis

Transferrin –

 

Basically it an iron chelator

Apo-transferrin is a transport protein for iron which binds iron obtained from intestinal transport or from iron storage and supplies to required places such as RBCs for HB synthesis.

It can bind 1 to 2 iron depending on adequacy of iron

It transports iron in ferric form

It is synthesized in liver and liver increases synthesis during ID Thus we can get high transferrin in ID states. Whereas level falls during inflammation.

What is Hypotransferrinemia?

Hypotransferrinemia is a rare AR disorder where its absence can cause ID as intestinal iron cannot be absorbed and there will iron load in storage are as in liver RE

Transferrin receptor

Transferrin binds to the target cell using Tf receptor which can bind 2 Tf molecule. After binding the iron-transferrin complex is endocytosed & at the same time Ferric iron is reduced to ferrous form.

After the TF-Fe complex is taken up apo-transferrin is recycled back to circulation.

During the IDA the Tf receptors liberated from cell surface to circulation and this is the serum Tfr which is a measure of ID state.

Ferritin

Ferritin is an important protein in iron homeostasis

It is a storage protein for iron which binds the excess iron that can be toxic to the cell and when required it liberates iron to the cell iron pool. It has the ferrireductase activity that converts toxic & metabolically active Ferrous form to inert ferric.

1 ferritin molecule can bind up to 4500 iron atoms

Ferritin is an acute phase reactant and its levels are increased in inflammation, infection.

Medical use of serum ferritin

Serum ferritin level is used for diagnosis of ID.

Ferritin measured clinically in plasma is usually apoferritin, a non-iron containing molecule.

The plasma level generally reflects overall iron storage, with 1 ng of ferritin per mL indicating approximately 10 mg of total iron stores. So, if ferritin level is 50ng/dL it indicates 500 mg of iron store

Hemosiderin:

The excess Ferritin is proteolyzed by lysosomal enzymes to Hemosiderin which is stained by Prussian blue dye. It is iron rich but liberates it iron slowly.

Clinical pearl: Hemosiderin iron has low bioavailability and iron chelators given in iron overload state draws hemosiderin iron at the end.

 

Iron regulatory protein 1 and 2

They have special role in iron metabolism. During iron overload state IRPs increase ferritin and reduce Tf receptor and these changes are reversed in IDA.

Hemojuvelin (HJV)

It is a glycosylphosphatidylinositol (GPI)-anchored protein that regulates hepcidin production in hepatocytes. HJV is present in a membrane-associated form and also as a soluble form with opposite effects on hepcidin activation.

Divalent metal transporter 1(DMT1)

The duodenal divalent metal transporter 1 (DMT1) is the major route for the uptake of non-heme iron from the intestinal lumen. It is a transporter protein present along the apical membrane of duodenal epithelial cell.

Duodenal cytochrome b —

Duodenal cytochrome b (DCYTB) is a membrane reductase that facilitates iron absorption as ferrous iron from the lumen. It converts ferric iron to ferrous which is then absorbed through DMT1.

Ferroporitin-

It is major iron exporter that helps in iron transport from mother to fetus from enterocytes to circulation and helps macrophage recirculate iron from old senescent rbcs.

Hepcidin

This molecule is synthesized in liver and it acts on ferroporitin and inhibits its function thus inhibiting iron absorption from enterocytes.

Erythroferrone

It is stimulated by erythropoietin, a circulating hormone essential for the maturation and survival of erythroid progenitor cells to raise the red blood cell count in response to hypoxia or anemia. ERFE downregulates hepcidin to ensure iron supply.

Absorption of Iron

Iron absorption occurs in proximal duodenum. About 8-10 mg of iron is taken in diet and 10-30% are reabsorbed. Intestine is the major site of iron regulation.

Iron in diet exist in 2 forms - heme and non-heme.

Animal proteins are major heme source and it has better bioavailability than non-heme iron which is present in vegetarian diet. Heme iron is directly absorbed into the enterocytes by specific receptors.

Gastric acidity lower duodenal pH and enhances iron absorption.

Similarly, ascorbate and citrate also enhance absorption.

Whereas phytates, tannins, oxalates inhibit iron absorption. These interactions affect inorganic iron rather than heme form.

The non-heme iron in ferric form is insoluble and unstable thus it is converted to Ferrous form by cytochrome b. And the ferrous iron thus formed is taken up by DMT1 into the enterocytes.

Upon entering the enterocytes, the iron can either be transported through basolateral membrane transport system or deposited in enterocytes and sloughed. This depends upon the adequacy of body iron.

At the basolateral lateral membrane, the ferroporitin molecule transports iron to the circulation and then the ferrous iron is converted to ferric form with help of Hephaestin molecule.

How is iron released from macrophage?

Approximately 20 to 25 mg of iron are released daily from the breakdown of senescent red cells in the macrophages. Upon its release from ferroporitin, ferrous iron is oxidized to the ferric form, and loaded onto transferrin. The oxidation process involves ceruloplasmin.

Absence of ceruloplasmin can result in iron deficiency state