Lecture 7 - Iron Metabolism

What is the structure of hemoglobin?

Present in RBCs and carries oxygen

Tetrameric metalloprotein that contains 4 iron atoms

Oxygen binds to...

Fe2+

One hemoglobin transports...

4 oxygen molecules

What is Fe2+?

Ferrous iron

What does iron deficiency cause?

Fewer RBCs produced and those RBCs contain fewer hemoglobin molecules

Can eventually result in anemia

What is anemia?

A decrease in circulating erythrocyte mass

Body has reduced oxygen carrying capacity

What causes iron deficiency?

Nutritional deficiency

True deficiency: increased loss (chronic hemorrhage)

Functional deficiency: sequestration and decreased absorption secondary to inflammation

In what species are we concerned about nutritional deficiency of iron?

Nursing piglets without supplementation or access to soil

What is the main cause of iron deficiency anemia?

Chronic blood loss from...

Blood sucking parasites (hookworms, Haemonchus contortus, fleas)

Vascular injury/erosion (GI ulcer, bleeding neoplasm, chronic cystitis with hematuria)

What can overload of iron cause?

Acute and chronic toxic effects

What can cause iron overload?

Administration of excess parenteral or dietary supplementation/accidental ingestion

May occur in diseases in which RBCs (particularly those from multiple blood transfusions) are repeatedly destroyed

What % of body iron is found in erythrocyte hemoglobin molecules?

50-70%

What % of iron is found in storage and where?

25-40% in RBCs, liver, spleen, and bone marrow (macrophages)

What form is iron stored in the cell?

Hemosiderin or ferritin

Where is the remainder of iron found?

Other iron containing molecules

Dietary iron absorption is regulated...

In the proximal duodenum

Most iron used in the body comes from...

Iron recycled from Hgb in old RBCs

Process is mediated by macrophages particularly in the spleen

Total body iron stores are regulated...

Through the intestine to avoid iron overload or deficits

Dietary iron can be in what forms?

Ferrous (Fe2+) or ferric (Fe3+)

How does intestinal absorption of iron occur?

Dietary Fe3+ is reduced to Fe2+ by enzyme 1 at the intestinal mucosa

A transporter protein (DMT-1) of enterocyte villi moves Fe2_ into the enterocyte

Fe2+ is moved out of the enterocyte into the plasma by a transport protein (ferroportin)

Fe2+ is converted back to Fe3+ by an enzyme associated with the enterocyte membrane

What is apotransferrin?

A transporter protein produced mainly by the liver

How is transferrin created?

In plasma, apotransferrin binds Fe3+

What is the function of transferrin?

Moves iron to and from body tissues

Almost all iron in plasma (not inside RBCs) is in transferrin

In healthy animals, what proportion of Fe binding sites on transferrin are occupied?

1/3

What tissues have transferrin receptors/binding sites?

Erythrocyte precursor cells in bone marrow

Hepatocytes

Many other tissues

How does iron get into RBC hemoglobin?

Iron carrying transferrin molecule binds to the transferrin receptor on RBC precursor cells in the bone marrow

Entire complex is moved into the cell via an endosome

Fe3+ disassociates from transferrin due to the low pH of the endosome

Fe3+ is reduced to Fe2+

A transporter protein present in the endosome membrane can move Fe2+ into cytosol for use in heme synthesis or RBCs can store the cytoplasmic Fe2+ as Fe3+ in ferritin

Where is iron recycled from erythrocytes?

In the spleen

What is the mononuclear phagocyte system or MPS?

Macrophage phagocytoses an erythrocyte "tagged" for removal

RBC releases hemoglobin inside the phagosome

Hemoglobin is split into heme + globin

Heme releases Fe2+ and is degraded

An enzyme in the macrophage converts Fe2+ back to Fe3+

Iron can be stored in the cell (as ferritin or hemosiderin) or exported

What is ferroportin?

Export protein on enterocytes and macrophages

Allows export of Fe3+

What is ferritin?

Apoferritin + Fe3+

Water soluble, mobile, iron-protein complex

Synthesis increases in inflammation (positive acute phase protein) and when more Fe is present so it can be properly stored

Where is ferritin mainly found?

Developing RBCs, macrophages, hepatocytes, enterocytes

Small amount in plasma

Apoferritin is produced by...

Liver and macrophages

What is hemosiderin?

Long term storage form of iron, major storage form

Poorly soluble, less mobile, more stable

Where is hemosiderin primarily found?

Macrophages of liver (Kupffer cells), spleen, bone marrow

What is hepcidin?

An important systemic iron regulator

Small peptide made by hepatocytes

Negative regulator of iron export/movement

What is the net effect of hepcidin?

To reduce iron availability for metabolic processes in the body by decreasing iron absorption from the intestine and decreasing general iron movement within the body

How does hepcidin regulate iron?

Binds to ferroportin, causing it to be internalized into the cell

Decreases iron export from macrophages and hepatocytes

Intracellular iron increases, which causes decreased iron absorption from intestinal lumen and decreased iron uptake by erythroid precursors

The net effect of the changes caused by hepcidin is...

A decrease in iron uptake by erythroid precursors

This reduces production of hemoglobin for new erythrocytes, which in turn hinders production of erythrocytes for circulation

What 3 things control levels of hepcidin?

Hypoxia

Iron availability

Inflammation (especially chronic)

How does hypoxia control levels of hepcidin?

Decreased oxygen at the hepatocyte level leads to decreased hepcidin production

Leads to increased absorption of intestinal iron with export into plasma, as well as release of iron from tissue macrophages

Goal is that this leads to increased RBC production for increased oxygen to tissues

How does iron availability control levels of hepcidin?

High body iron concentration leads to increased hepcidin production

This decreases iron absorption and availability

Decreased body iron decreases hepcidin production to increase iron absorption/availability

How does inflammation control levels of hepcidin?

Release of inflammatory mediators (IL-6 and others) leads to increased hepcidin synthesis and decreased iron availability

Functional iron deficiency

Contributes to the anemia of chronic/inflammatory disease

Suspected the mechanism developed to limit bacterial replication during infection, since bacteria need iron to survive and proliferate

What are results of decreased hepcidin production?

Increased absorption of intestinal iron

Normal enterocyte iron export into plasma

Normal release of stored iron from tissue macrophages and hepatocytes

What are the results of increased hepcidin production?

Prevention of iron absorption by enterocytes

Decreased iron export from enterocytes and macrophages

When do we want to assess body iron levels?

Persistent/nonregenerative anemia

What are characteristics of assessing body iron?

Difficult to accurately assess total body iron

Must interpret results in light of clinical picture

What tests do we use to assess total body iron?

Serum iron concentration

Serum ferritin concentration

Total iron binding capacity (TIBC)

What is serum ion concentration?

Measures the amount of iron bound to transferrin

Assay separates iron from transferrin (by dropping to acidic pH) and measures the iron concentration

Since test uses serum, only assesses circulating iron

Serum iron concentration increases in...

Inappropriate iron injections or potentially with excess dietary iron

Hemolysis

Serum iron concentration decreases in...

True or absolute iron deficiency

Increased iron locked in storage

What may cause true/absolute iron deficiency?

Chronic external blood loss, including GI bleeding, hematuria

Decreased dietary iron or inability to absorb in GI tract

What may cause increased iron to be locked in storage?

Chronic inflammation resulting in functional iron deficiency, effect of hepcidin (anemia of chronic/inflammatory disease)

How does ferritin get into serum?

Secreted into blood by cells, primarily macrophages

Serum ferritin correlates with...

Tissue iron stores in domestic animals

What is serum ferritin useful for?

Separating a true iron deficiency anemia (low serum ferritin) from anemia of chronic disease (normal to high serum ferritin)

What is required to measure serum ferritin?

Species-specific immunoassay

Increases in serum ferritin are seen in...

Diseases that cause increased storage iron

Diseases that cause increased ferritin production (inflammatory disease, ferritin is a positive acute phase protein)

Decreases in serum ferritin are seen in...

True iron deficiency

However, if the animal also has a concurrent inflammatory disease, it may be normal or even elevated