Iron homeostasis Flashcards
What is ferrous iron?
Fe2+
What is ferric iron?
Fe3+
Why can iron be toxic in excess?
Participates in intracellular ‘Fenton reactions’ (e.g. Fe2+ + H2O2 => Fe3+ + OH· + OH- ) that can generate harmful free-radicals compounds.
What form is most dietary iron in?
Fe3+
What form is dietary iron converted to in the gut?
Fe2+
What promotes absorption of non-haem iron in the gut?
Absorption of non-haem iron in the gut is promoted by vitamin C.
What is the total dietary uptake of iron per day?
1-2mg
What cells are the site of iron absorption?
Duodenal enterocytes
What converts Fe3+ to Fe2+ in the gut?
DCYTB enzyme (duodenal cytochrome B)
Why is dietary iron converted in the gut?
So it can be absorbed
How does iron move across the apical membrane?
via the DMT1 transporter
What happens to iron once it enters enterocytes?
Iron may be stored as ferritin in enterocytes (and subsequently lost via cell shedding), or absorbed via the ferroportin transporter.
Why is regulation of iron absorption so important?
The body has no pathway for iron excretion, so absorption is the key regulatory step in controlling total body iron.
What happens to Fe2+ after it is moved out of the enterocyte?
After Fe II moves out via ferroportin, converts it back to Fe III.
After iron moves out of the enterocyte via ferroportin what converts it back to Fe3+?
Hephaestin
What transporter moves iron out of enterocytes?
Ferroportin
What does iron travel in the blood bound to?
Transferrin
How many Fe3+ can transferrin carry?
Two
What form is iron carried on transferrin?
3+
How does serum transferrin change in response to iron deficiency?
Rises
Are free serum iron levels good indicators of iron status?
Free serum iron levels are variable, and alone rarely a good index of iron status.
What is transferrin saturation usually?
~20-30%
What is transferrin saturation used as ?
Index of iron availability.
What do target cells of transferrin express?
Transferrin receptors TfR1, which bind and internalize the Fe(III)-transferrin complex
What are target cells of transferrin?
Erythroid cells and bone marrow
What transferrin receptor do liver cells express, what may its role be?
TfR2, which may be important in sensing iron availability.
Describe process after transferrin receptor binding?
Receptor complex is endocytosed in clathrin-coated pit.
Endosome is acidified to release iron
Iron stored as ferritin or combined into iron containing molecule
When may levels of ferritin rise?
Acute phase protein - may rise with inflammation or infection
What can ferritin be a good indicator of?
Body iron stores
How else can iron be stored in cells (not ferritin)?
Smaller amounts of iron can be stored in cells as insoluble haemosiderin.
What is the principle hormone that regulates iron?
Hepcidin
What organ releases hepcidin?
The liver
When is hepcidin released?
In response to elevated iron levels.
What does hepcidin do?
Hepcidin inactivates ferroportin
Iron therefore becomes unavailable and trapped inside cells (i.e. macrophages).
What is the effect of erythropoiesis on hepcidin?
Erythropoiesis suppresses hepcidin production, independent of iron levels.
What is the issue of erythropoiesis suppressing hepcidin?
Causes problems in patients with excessive but ineffective erythrocytosis (e.g. thalassaemia), in whom profound hepcidin suppression can produce tissue iron overload.
What is the effect of hypoxia on hepcidin?
Hypoxia reduces hepcidin production, partly by stimulating erythropoiesis and causing iron deficiency, but (perhaps) also directly through the hypoxia-inducible factor (HIF) family of transcription factors.
What is the effect of inflammation on hepcidin? What is the benefit?
Several inflammatory cytokines, particularly interleukin-6, stimulate hepcidin production by the liver.
This may reflect an evolutionary desire to deprive invading microbes of iron, and probably explains the ‘anaemia of chronic disease’ commonly seen in inflammatory conditions (e.g. rheumatoid arthritis).
What is the role of iron regulatory proteins (IRPs)?
Coordinate cellular iron uptake and storage by controlling expression of important proteins, according to iron levels.
What effects does IRP have when iron is low?
When cellular iron levels are low, (IRP bind RNA) ferritin mRNA translation is inhibited and transferrin receptor mRNA is stabilised, to encourage iron uptake.
What effects does IRP have when iron is high?
When cellular iron rises, IRPs are inactivated, leading to increased ferritin expression, reduced transferrin receptor expression, and a protective shift towards iron storage and reduced iron uptake.
What anaemia is characteristic of iron deficiency anaemia?
Hypochromic microcytic anaemia (lack colour and size).
Causes of iron deficiency
Inadequate dietary intake
Malabsorption (e.g. coeliac disease)
Excessive use of iron (e.g. pregnancy, growth)
Hookworm infection (common worldwide)
Blood loss: Blood donation Menstrual loss in young women, haemorrhage
Causes of iron overload
Primary genetic disease (haemochromatosis)
Alcoholic cirrhosis
Excessive oral intake of iron
Repeated blood transfusions
Excessive (ineffective) erythropoiesis (altitude)
Hereditary haemochromatosis
Relatively common group of genetic diseases characterised by excessive dietary iron absorption or cellular iron retention. Most are due to inadequate hepcidin expression.
Presenting features due to iron deposition in parenchymal tissues…
Liver (cirrhosis), Pituitary (hypogonadism), Pancreas (diabetes), Joints (arthropathy), Heart (cardiomyopathy), Skin (hyperpigmentation)
The normal amount of iron contained in an adult human body is within the range
4-5g (4000-5000mg)
The largest amount of iron in the body is within
Red blood cells (In Hb)
Fe2+ leaves macrophages via
Ferroportin
What is DMT-1 coupled to?
H+
