24 - Iron Metabolism Flashcards
Describe a basic case presentation of iron deficiency anemia
- A 26-year old female presents with complaints of shortness of breath, dizziness (means lack of oxygen to support brain needs) and a sore tongue (renewal of tissues).
- Physical examination shows pallor (pale) and tachycardia.
What are typical lab finding for iron deficient anemic patients?
- Low serum iron
- Low hemoglobin
- Small erythrocytes ***
- Low hematocrit
- High total iron binding capacity
What is the treatment for iron deficient anemia?
Patient received oral iron supplements and improved rapidly.
Describe the basic properties of iron
- Very useful for binding oxygen and transferring electrons
- It rusts
- Iron needs to be controlled at all times (no free Fe2+/Fe3+ allowed)
Describe the ability of iron to bind oxygen and transfer electrons
- Electricity flows well through iron because iron does not hold on too tightly to the outer electrons
- This means that iron can accept, pass on and donate electrons
- This is useful for conduction, but it also limits its function (rust)
- The electrons on the outer shell of iron can easily be transferred to oxygen … So, Fe 2+ is converted to Fe 3+
- Iron Fe 3+ is not functional in the biological system because it cannot donate an electron any longer
- Oxygen in the reduced form becomes really reactive (a very unhappy molecule)
- Reduced oxygen really wants to get another hydrogen and become water so it is seeking more electrons
How do we control the affinity of iron to react with oxygen?
Iron needs to be controlled at all times, so it needs to be kept away from oxygen by being complexed with something at all times in order to protect it (complexed with another carrier molecule) so that it can’t react with oxygen
What can happen when iron and copper react with oxygen?
Both of these molecules will donate an electron to oxygen
O2 –> O2-
What happens once O2- is formed?
It will react with 2 hydrogen molecules to form H2O2
This can then react for form two hydroxyl groups (OH-)
The hydroxyl ion is bad because it can modify proteins, amino acids and DNA –> REACTIVE oxygen species
How does the body prevent the production of ROS?
We have an intricate system to protect iron from oxygen at all times
This is why the cell needs to respond RAPIDLY to changing levels of iron –> so the excess iron does not contact oxygen
What are the dietary sources of iron?
About 10-20 mg/day in a normal diet
- Plant iron (mostly Fe3+)
- Animal iron (mostly heme-bound)
What is the difference between plant iron and animal iron?
Plant iron (Fe3+) is harder to absorb, so only about 5% of the consumed plant iron is taken up into the enterocytes
Animal iron (heme-bound) is easier to take up and therefore 25% is absorbed from the diet
Is dietary iron sufficient?
Yes, dietary iron is usually sufficient unless there is a high level of growth or increased blood loss
How do we regulate iron excretion?
Trick question! We don’t!
Iron is a “precious” substance to the body, so more conservation and recycling mechanisms are in play than metabolism or excretion. The only two ways to lose are to have blood loss (i.e. intestinal bleeding) or to have “sloughing off” of enterocytes in the gut that have taken up iron but have not used it
How are iron levels in the serum regulated?
By the amount of iron that is released from enterocytes into the serum
Is iron ever lost in the urine by regulation?
No
- No regulated loss through urine
- Iron should be bound to protein all the time
- Iron homeostasis regulated through uptake only
Describe a situation in which iron could be found in the urine
Blood loss in the urine - intravascular hemolysis
You would find hemoglobin in the urine
Where do you “sloughing off”?
Sloughing off of iron-containing cells in the intestine and kidney
There is turn over of cells in the intestine and kidney
Describe the distribution of iron in the body
- 80% of iron is found in the active form
- 20% of iron is found in the inactive form
List the active forms of iron
- Hemoglobin
- Myoglobin
- Cytochromes
- Transport via transferrin
List the inactive forms of iron
- Dynamic storage via ferritin
- Degenerated, long-term storage via hemosiderin
What are cytochromes?
- They are a large family of enzymes
- They carry out oxidation reactions, it has a heme inside just like Hb, it is bound covalently
- They are synthesized in response to stress (alcohol, infection, etc.)
Describe the inactive forms of iron
- Ferritin is how iron is intended to be stored
- If you do not turn over ferritin stores regularly, there will be an iron overload, and ferritin will then degenerate and form hemosiderin
- Hemosiderin is a long-term storage of iron, but it is very hard to mobilize iron from there
Describe the general path of iron in the body
- Taken up from the diet into enterocytes
- If the iron is not needed, it will eventually be sloughed off
- If the iron is needed, it will then be conjugated into transferrin and enter the plasma or conjugated into ferritin and enter the liver
- If the iron enters the plasma in transferrin, it has become an erythroid precursor
- This will become RBC iron and be conjugated into heme
- There is potential at this point for iron to be lost due to bleeding
- If not, the iron found in heme will be taken up by mononuclear phagocytes
- It is then able to be recycled back into transferrin and become a precursor again
What are the three transporters found on the luminal surface of enterocytes?
- DMT I: Fe 2+ can go straight through
- Cytochrome B: Fe3+ is changed into Fe2+ so it can go in through DMT I
- Heme transporter: Heme can go straight through
What happens once heme or Fe2+ enter the enterocyte?
Both Heme and Fe 2+ coming in from the first two transporters become ferritin granules
What happens once the ferritin granules form?
- If there is no need for iron in the circulation, this could be the end of it and the granules would stay stored and not be released
- Ferritin granules would then be sloughed off when the enterocyte dies
- If needed, ferritin granules can enter the circulation
How does the ferritin granule enter the circulation?
Via the ferroportin 1 transporter
The ferroportin 1 transporter will be signaled based on the iron demand in the body
What needs to happen in order for iron to enter the circulation?
- In order for iron to enter the circulation, the iron needs to be extracted from the ferritin granule
- The extracted iron will be Fe2+ which will need to be transformed into Fe3+
How is iron transformed from Fe2+ to Fe3+?
Via interaction with hephaestin
What can happen once Fe2+ has been transformed into Fe3+ via hephaestin?
It can be conjugated into a transferrin granule which is then able to enter the circulation
What is hepcidin?
Hepcidin is a key regulator that INHIBITS the export of iron from enterocytes
When hepcidin is around, no iron will be excreted into the serum
When will hepcidin be produced?
The liver will produce hepcidin in times of stress (chronic diseases, infection, etc.) causing an iron deficiency
This is why many chronicled ill patients will have iron deficiency
What is the purpose of hepcidin in times of stress?
It is intended to be a short-term mechanism to limit the iron in the blood and limit the amount of iron that microbes can get and starve them of iron and kill them
In chronic diseases, this is not effective and rather harms the patient by creating an anemia
What happens when transferrin (holding Fe3+) binds to a cell surface receptor?
- When a cell needs iron, it upregulates transferrin receptors
- Transferrin binds to transferrin receptors and the receptor-substrate complex internalized by receptor mediated endocytosis and is found within an endosome
What type of cells are always taking up a lot of iron?
RBCs and liver
They both have a high need for iron
What happens to the endosome inside the cell?
Protons enter the endosome
- This leads to a pH drop in the endosome
- The drop in pH leads to dissociation of the transferrin from the iron and from the receptor
- The iron is transformed back into the Fe2+ state
- Fe2+ then leaves the endosome and is free to be used by the cell
What happens once iron gets into the cytoplasm?
Inside the cytoplasm, iron is stored in ferritin
Once iron binds to ferritin, it is water soluble and is easy to mobilize
Where will you find high concentrations of iron bound to ferritin?
- Liver
- Spleen
- Bone marrow
What do ferritin particles slowly denature to?
Ferritin particles slowly denature to hemosiderin granules
Describe hemosiderin granules
- Hemosiderin granules should not be there – they are bad
- They are a sign that too much iron is present – an iron overload
- They are water INsoluble
- The iron in hemosiderin granules are hard to mobilize
- This is a sign of iron overload
What is the role of macrophages?
- The end of life of RBCs usually ends in splenic macrophages
- This means the RBCs are taken out of the circulation, into the spleen and are taken up by macrophages there
- The iron of RBCs is taken up by the macrophage as well
What can hemolytic disorders lead to?
- A hemolytic disorder leads to accumulation of ferritin and hemosiderin in macrophages
- There will be a mass destruction of RBCs in macrophages in some diseases, leading to a lot of iron and hemosiderin granules accumulating in macrophages in the spleen
How is iron regulated again?
- Iron uptake into the body is regulated by the release of iron from enterocytes
- The main regulator is the inhibitor HEPCIDIN ***
- Low hepcidin means high uptake (because it is inhibitory)
- Hepcidin also regulates iron release from macrophages
What is an “upstream” regulator of iron that is often defective?
HFE - Human hemochromatosis protein
When there is a mutation in HFE, it causes LOW hepcidin expression
- Low hepcidin means high uptake of iron from the enterocytes into the body
- Common in Europeans
Describe the regulation of iron that is done by the ferritin protein
- Remember, ferritin is the protein that exists within enterocytes and forms granules with iron to be released into the circulation if needed
- The ferritin protein regulation is done on a post-transcriptional level – this means that all of the steps of ferritin protein are completed and the mRNA is produced
- Once mRNA is produced, the iron regulatory protein (ACONITASE) is attached to the mRNA and PREVENTS the ferritin protein from being translated
- This means that the regulation happens after the transcription (post-transcriptional regulation) and before translation
What happes to ferritin mRNA if it is not needed (i.e. the iron levels are high enough)?
- Whether or not you need iron uptake and ferritin protein, the mRNA is made, but if you don’t need it, iron regulatory protein (aconitase is attached)
What happens to ferritin mRNA if iron uptake is needed?
- If you want the ferritin protein, and you need iron uptake, the iron regulatory protein (aconitase) needs to be removed
- This is why when there is low iron and additional uptake is needed, the body can respond so quickly
- There are already a bunch of ferritin protein transcribed (mRNA is already made), it just needs to have iron regulatory protein removed and it can be translated quickly and because the mRNA is already there and it just needs to be slightly modified to get ready
What determines whether or not you get translation of the ferritin protein?
The iron regulatory protein (aconitase) determines whether or not you get TRANSLATION ***
This is what you need to know ***
What laboratory tests will you get if you’re looking at iron levels in clinic?
- Serum iron concentration
- Total iron binding capacity (TIBC) or transferrin saturation
- Serum ferritin
- Red Cell Protoporphyrin
Describe the serum iron concentration test
- The limit of this test is that it gives you no information about body iron STORES, only the free iron
- Not the best test, doesn’t tell you the storage of iron
Describe the total iron binding capacity (TIBC)
TIBC measures UNOCCUPIED transferrin. The higher the TIBC, the lower the iron stores
If the TIBC is high, there is a lot of UNOCCUPIED transferrin
Describe the transferrin saturation test
Transferrin saturation measures OCCUPIED transferrin. The higher the saturation, the higher the iron stores.
Describe the serum ferritin test
- A fraction of ferritin is present in the serum
- This is the BEST MEASURE for body iron stores ***
- It is not available all the time and is a more expensive test
Describe the red cell protoporphyrin test
- Protoporphyrin is a iron-free precursor of heme
- The lower the iron stores, the higher the protoporphyrin ***
- If there isn’t a lot of iron around, you can’t make heme, so you will have a lot of the heme precursor
What can cause iron deficiency?
- Chronic blood loss
- Chronic disease (leading to hepcidin production –> KNOW THIS)
- Poor dietary intake (limited absorption of plant iron)
- Intestinal parasites (compete for Iron)
- Malabsorptive disease (Celiac)
Describe what three things happen when an iron deficiency develops into anemia
1 - Iron depletion occurs, serum FERRITIN falls
- Remember, ferritin is one of the best ways to detect anemia (iron is not low yet, but ferritin is)
2 - Deficient ERYTHROPOIESIS, meaning that hemoglobin will still be normal, but protoporphyrin levels will be up and transferrin saturation falls
3 - Iron deficiency ANEMIA is technically when hypochromic microcytosis develops (low hemoglobin in the cytoplasm, small RBCs are there)
What are potential causes for iron overload?
- Blood transfusions for treatment of hemolytic disease (iron accumulates in macrophages) - If you are infusing iron directly into the patient (blood transfusions frequently) can commonly cause iron overload
- Slow erythropoiesis (renal failure)
- Hereditary hemochromatosis type 1
Describe HFE 1 (hereditary hemochromatosis type 1)
- Up to 10% of the population are carriers for this mutation
- HFE 1 causes an iron uptake disorder and a development of large iron deposits
- Usually they don’t develop symptoms of an iron overload disorder (liver damage) and is just found randomly
What do you look for in iron overload?
- High transferrin saturation
- Hemosiderin deposits
Is iron overload common?
No, it is difficult to achieve because it is so regulated
