Iron (1) - Physiology

NEJM January 26, 2011 - two articles on iron pathophysiology, one on iron overload the other on minihepcidins. It motivated me to review iron physiology.

Iron physiology:

How much iron do we have? ~4 grams


Absorption in duodenum 1-2mg/day, transport by transferrin, utilization by BM and muscle, storage as ferritin in liver and reticuloendothelial cells (ferritin can be oxidized to hemosiderin), loss mainly by sloughed mucosal cells.

Iron store regulation is achieved by regulating iron absorption, there are no physiological means of iron excretion!

Iron absorption:


Bioavailability: heme > Fe 2+ > Fe 3+ 

Why heme is better absorbed? Different mechanism.


What form of iron is absorbed?

Iron is rapidly oxidized in physiologic pH, low pH slows this process.

Most dietary iron is turned into it's ferric form (Fe 3+), which is insoluble. Ferric iron is reduced by an enteral brush border enzyme to ferrous (Fe 2+) so the DMT-1 can transport it into the cell. Low gastric pH and vitamin C facilitate this process by slowing iron oxidation.

Where? Duodenal enterocytes

How? DMT-1 which stands for divalent metal transporter-1, so a lot of divalent metal get in this way and can compete with iron. Examples? Lead, copper,
cobalt, zinc, strontium, cadmium

What next? Iron stays in the cell as ferritin or gets out transfered by ferroportin

What helps ferroportin?

Hephaestin, a copper-dependent enzyme, oxidizes iron back into ferric form to help iron efflux from the cell; it is found mainly in the intestinal villi;


Two key proteins in iron physiology:


1. Ferroportin - transporter, which transports iron out of cells;

2. Hepcidin - liver peptide, binds to ferroportin stimulating its internalization and lysosome degradation

How do we lose iron? Sloughing of enterocytes. How does iron know to get into enterocytes to be lost?

High hepcidin -> low ferroportin -> iron stays in entrocytes -> epithelium sloughed -> iron loss

So iron never gets out of the enterocytes in the first place!

Iron transport


Why iron cannot be free? It's dangerous! Free radical production by the Fenton's reaction.

Fe²⁺ + H₂O₂ ----> Fe³⁺ + .OH + OH^-

Fe³⁺ + H₂O₂ ----> Fe²⁺ + .OOH + H⁺

It is bound to transferrin.

Utilization

1. BM -> erythroid precursors -> hemoglobin

2. Muscle -> myoglobin

Storage

1. Liver -> hepatocytes and Kupffer cells (reticuloendothelial cells)

2. Reticuloendothelial system 

So where in our bodies is most of the iron contained?

Tricky question... in circulating RBC's (~1800 mg), almost half.