Flashcards in Absorption of Iron and GIT disease Deck (38):
What is the role of iron In human biology?
- Oxygen transport and storage
- Electron transport (oxidative phosphorylation generation of ATP involves cytochromes which are iron containing proteins)
- Plethora of enzymes, ribonucleotide reductase (rate limiting step in DNA synthesis) and RNR needs iron
- Cell cycle control, cells will die without iron
Why does iron have to be tightly regulated?
- There is no active excretory mechanism for iron, it enters the duodenum and stays in the body
- Need to tightly regulate, if body is iron rich you need to ensure no further iron is absorbed because if you continue to absorb this will be detrimental obviously
What is the process o Erythropoiesis?
- Circulating pool of iron, which is directed to the bone marrow to make more red cells
- Erythrocytes produces, then after 120 odd days they are destructed and engulfed by macrophades resulting in a plasma iron pool as iron is recycled back out of haem (haem is broken to bilirubin)
- Plasma iron pool contributes to the liver and liver to plasma iron pool
What does the iron we consume in our diet come from?
- Inorganic ion, predominately in the ferric form, Fe3+, this is poorly absorbed because it has to be reduced to ferrous and often tends to be complexed with other things in the diet that render it inert and relatively unabsorbable
- Haem, which is found in meat
- Consume 20mg but only need to absorb 1-2mg
- Mainly absorbed in duodenum
What are the proteins in iron transport?
- Inorganic iron, ferric Fe3+ will have to be reduced to ferrous iron Fe2+, this in part happens in acid by the acid in the stomac and duodenal cytochrome b
- Absorbed by divalent metal transporter 1 =, dmt1
- Once ferrous ion is in the cell it can; be used by that cell for whatever process, can be stored within the cell in ferritin which binds the iron and renders it inert so it does not drive free radicals, can be effluxed out of enterocyte into the blood via Ferroportin which is reoxideised by hephaestin and circulates around the body bound to a protein called transferrin which also renders it inert
What reduces ferric iron to ferrous iron?
- this happens in part by the acid in the stomach and duodenal cytochrome b
What changes ferrous iron to ferric iron?
How is iron stored?
Ferritin, this renders it inert so it does not drive free radicals
- free radicals can drive lipid oxidation etc
What is Ferrorportin?
- the protein that effluxes iron out of cells
What is hephaestin
- allows it to be bound to transferring
How to other cells get iron into them?
capture transferring via a transferrin receptor
cells express a transferrin receptor
How is iron transported in the blood?
How is haem transported/absorbed?
HCP1 to absorb haem
haemooxygenase 1 will then break it down into bilivirdin and free iron
How do we make haem?
What happens if there are issues with enymes involved in making haem?
can lead to porphyria which is where you have a build up of precuroses such as glycine and succinyl coa
Where is Iron stored?
liver, spleen and bone marrow
How do these stores communicate to the small intestine to tell it to stop absorbing?
- hepcidin has bacterialcidal activity
- hepcidin inhibits iron metabolism
- induced in inflammation and infection
How does hepcidin acts as an inhibitor of iron absorbtion
- Binds to ferroportin (which is the efflux protein)
- Feerroportin is an iron efflux protein, when hepcidin binds to it you lose ferrorportin expression so it cannot absorb/efflux iron
- Binds and internalises ferrorportin
What happens under high iron levels?
- You are going to want to stop other iron from being absorbed
- You will switch hepcidin on which will bind to ferror portin so no more transport through enterocyte
- High iron is sensed by proteins within the hepatocytes; TFR2, HFE and HJV
- Lots of iron, sensed by hepatocytes and proteins, so they produce hepcidin which binds to ferorportin and block iron absorbtion
What if there are too little iron levels?
What if there are too little iron levels?
- Such as anaemia or hypoxia
- You will want to stimulate more iron absorption
- You suppress hepcidin levels so it cannot stop iron efflux, and as much iron is absorbed as possible
What happens in instances of inflam/infection
- Hepcidin is induced
- When you have an infection you switch hepcidin on by stimulated IL-6
- IL-6 stimulates hepcidin translation
- Hepcidin will stop iron absorption and bind to ferrorportin on macrophages so the macrophage will become iron loaded and cant efflux the iron into the iron pool, this is because bacteria need iron, so hepcidin makes the human body limit iron and prevents bacteria from getting to iron
- Bacteria produce ciddorifors which compete for this iron
What does IL-6 do?
it stimulates hepcidin translation
What is a ciddorifor?
This is how bacteria compete for the iron
What happens if you limit the iron pool?
- You limit erythropoiesis and so develop anaemia
- In infection you may develop anaemia because the iron, as a result of hepcidin binding to the macrophage ferrorportin preventing iron efflux and locking iron in, so you have less iron in the lay iron pool for erythropoiesis by the bone marrow
- This type of anaemia is an anaemia of chronic disease, ACD
What happens in incidence of inflammation?
- Ferrous iron is toxic, so will make the inflammatory insure worse
- We induce hepcidin as a mechanism to insure the iron is not making it any worse
Why do patients with rheumatoid arthritis commonly have anaemia?
- RA is an autoimmune inflammatory disorder, inflammatory issues induce hepdicin
- Hepcidin binds to ferrorportin and switches it on resulting in less absorption of iron and locking iron away
- This results in less iron in the lay iron pool which means that it cannot be used to create more blood
- This is anaemia of chronic disease
- This is because iron is toxic and can induce free radicals and make everything worse
What happens with obese individuals and iron status?
- They have a poor functioning iron status
- Presenting with an anaemia of chronic disease
- When they lose weight iron status improves and hepcidin levels go down
What is the difference between ACD and Iron deficiency anaemia?
- You can use serum ferritin, there is circulating ferritin which is a measure of iron levels (ferritin is induced by iron) low ferritin implies iron deficient
- But ferritin is a protein so can be high not because of iron
- Low ferritin is likely to be IDA, high is likely to be ACD
What is Ferritin?
a store of iron
What happens when you cant make hepcidin?
- this is called hereditary haemochromatosis
- iron overload
What is haemochromatosis?
- Hereditary disease with improper dietary iron metabolism causing the accumulation od iron in a number of body tissues
- Iron accumulation can cause organ damage
- Treat with phlebotomy you- take away their blood, they are good donors
- Mutations in HFE rendered an individual with less hepcidin
- Mutations In TfR2 and HJV also causes it
- Subclassified depending on the type of mutation
Mutations in what genes causes herediary haematochrosis?
- Mutations in hepcidin itself
- Ferrorportin is mutated and so may be insensitive to hepcidin signalling so it is no longer turned off when hepcidin hollas at it
Why is HFE important?
- HFE is expressed when you have high iron levels
- HFE switches iron on
- A mutation in HFE means it can no longer sense a high iron so you do not switch hepcidin on!
How is iron toxic?
- It drives free radicals through fenton reactions
- Develop fibrosis, cirrhosis in the liver etc
- High risk of cancer
- Arrhythmias, diabetes
What are the common causes of IDA?
- Premenopausal women as we are losing lots of blood
- Vegan diet, iron restrictive diet and losing a reasonable amount every month
- Blood loss from GIT, such as a carcinoma or cancer or tumour or ulceration with bleeding like chronns is likely to present with an iron deficiency anaemia
What are NSAID users more likely to develop?
- they inhibit the COX pathway
Treatment strategy for IDA?
- Ascorbate, 200mg a day which is an iron formulation