Physiology (Fe, B12, etc)

Question 1

Describe where iron is stored in the body?

Answer 1

In porphyrin ring of heme

• hemoglobin (blood) -2500 mg
• myoglobin (muscle) -300 mg with enzymes below
• catalase ^{(H2O2 (hydrogen peroxide) + H2R → 2H2O + R)}, peroxidases ^{(ROOR’ + electron donor (2 e-) + 2H+ → ROH + R’OH)}, cytochromes ^{(inner-mitochondrial membrane bound heme-containing proteins “hemeproteins” facilitating electron transport chain -> ATP), etc => Fe participates in H&O reactions and ETC}

Non-heme compounds:

• ferritin and hemosiderin - Fe storage - 1000 mg
• transferring (Fe transporter protein in the blood) - 4 mg

Question 2

What is the total iron storage in males vs females?

Answer 2

Males: about 4 g total

females: about 2-3 g due to smaller iron reserves (ferritin), lower [Hb], smaller vascular volume

Question 3

Give a quick overview of iron absorption and loss?

Answer 3

• absorbed through duodenum
• used by muscles (myoglobin), blood (hemoglobin)…
• stored in liver and reticuloendothelial macrophages ^{(in reticuloendothelial connective tissue = has special reticular fibers made of collagen, in liver, spleen and lymph nodes)}
• also stored in skin, cells lining GI and GU which slough off - > iron loss
• iron loss due to menstruation, fetal growth, breast feeding
• 95% of iron is reabsorbed in the body

Question 4

Whats the difference between Fe3+ and Fe2+?

Answer 4

Fe3+ = ferric

Fe2+ = ferrous

Fe3+ (ferric) is the form consumed, but must be converted to Fe2+ (ferrous) to enter intestinal cells

notice that heme contains Fe2+

^{ferric reductase enzyme (gaining electrons = reduction) on brush border of enterocytes converts Fe3+ to Fe2+}

^{Fe 2+ is then transported into cells by divalent (2+)metal transporter (DMT1)}

this is different when we eat meat and fish - heme from there is absorbed directly into cell, then porphyrin ring split

Question 5

Why does Fe2+ need transport protein in the blood?

Answer 5

• b/c iron can be Fe2+ or Fe3+ its biological necessity is built on ability to accept and donate e- (think catalase, peroxidase, electron transport chain rxns)
• this is great when it’s in a place reactions need to happen, but if it is simply in the blood, with O2 available, it would create free radicals (see image)
• therefore, Fe2+ is protein bound in blood and all tissues to prevent damage

Question 6

Outline molecular absorption of iron?

Answer 6

• consume Fe3+ (ferrous) but not biologically active
• Fe 3+ converted to Fe 2+ by ferric reductase
• Fe 2+ then transported into intestinal cell by DMT (divalent metal transporter)
• once in cell 2 choices: storage = ferritin
  
  • transport into blood as Fe 2+
• if transported further into blood, ferroportin (think iron = ferro and door = porte -> control point) is the transport protein that pumps Fe2+ out of intestinal cells - control point for the amount of iron in the body
  
  • ​can be controlled by hemosiderin

Question 7

How is iron cycled between dead and alive RBCs?

Answer 7

new erythrocyte (RBC) -> broken down by macrophages (usually reticuloendocytes in spleen (majority), liver, etc) ; these macrophages also maintain [Fe2+] -> if needed, Fe2+ liberated, binds to transferrin to prevent acting with O2 -> Fe2+-transferrin delivered to bone marrow - > new RBCs produced

infection, malignancy and inflammation can intefere with Fe2+ release from macrophages -> lower Fe2+ and drop in RBC production, even if enough Fe2+ in body

Question 8

What is the tranport protein that carries Fe in the blood?

Answer 8

Transferrin - each binds 2 Fe3+ (3+)

transferrin is membrane bound protein (on enterocyte membranes), that once binds iron becomes invaginated -> clathrin coated pit with H+ pump -> pH inside drops -> Fe released

Question 9

How is iron stored?

Answer 9

2 forms:

Ferritin - protein coat with a lot of iron atoms inside (+-4500), readily available, present in most cells -> isolates reactive iron from outside, image

Hemosiderin - less surface proteins than ferritin, in granules - higher iron concentration but released more slowly

1/3 stored in liver, 1/3 in bone marrow, rest in spleen and other tissues

Question 10

How is iron regulated?

Answer 10

Hepcidin is central regulator

Hepcidin binds to ferroportin, which controls flow of iron out of intenstinal cells and macrophages (remember that they control iron release after digesting RBCs) - > (and into blood)

Once hepcidin binds to ferroportin, the entire complex is taken into the cell and degrated

High levels of hepcidin -> reduced Fe in the blood (ex. iron overload)

Low levels of hepcidin -> release of Fe into blood (ex. iron deficiency)

Hepcidin is produced by the liver

Factors affecting hepcidin production : iron stores, hypoxia, erythropoietin, inflammation (IL6 directly stimulates hepcidin)