8. Iron Metabolism Flashcards
What are the 5 microcytic anaemias?
Reduced globin chain synthesis: - Thalassaemia Reduced haem synthesis: - Anaemia of chronic disease - Iron deficiency - Lead poisoning - Sideroblastic anaemia
What is iron required for?
Oxygen carriers - haemoglobin in red blood cells, myoglobin in myocytes
Co-factor in many enzymes - cytochromes, Krebs cycle enzymes, cytochrome P450 enzymes, catalase
Can iron be excreted?
No, the body has no mechanism for excreting iron
What is the difference between ferrous and ferric iron?
Ferrous iron (Fe2+) is the reduced form Ferric iron (Fe3+) is the oxidised form
What does dietary iron consist of?
Haem iron (Fe2+) and non-haem (mixture of Fe2+ and Fe3+) Ferric iron must be reduced to ferrous iron before it can be absorbed from diet
How much iron is needed in the diet?
10-15mg/day
Where does absorption of iron occur?
Duodenum and upper jejunum
List good sources of haem iron
Liver Kidney Beef steak Chicken Duck
List good sources of non-haem iron
Fortified cereals Raisins Beans Figs Barley
How is haem absorbed into the body?
Haem moves across enterocyte apical surface
Then converted to Fe2+ by haem oxidase
Can either then be converted to Fe3+-ferritin and stored or move into the blood via a ferroportin
It is then converted to Fe3+ by Hephaestin
Fe3+ is the bound to transferrin and transported around the body
How is Fe3+ absorbed into the body?
Fe3+ is converted to Fe2+ using reductase and vitamin C (electron donor)
Fe2+ then moves into the enterocyte through DMT1 (divalent metal transporter)
Fe2+ can then either be stored as Fe3+-ferritin or transported into the blood via ferroportin
Fe2+ is then converted to Fe3+ by hephaestin and bound to transferrin to be transported around the body
What is the role of hepcidin?
Produced in liver and inhibits ferroportin
What can have a negative influence on absorption of non-haem iron from food?
Tannins (in tea)
Phytates (e.g. chapattis, pulses)
Fibre
Antacids (e.g. gaviscon)
What can have a positive influence on absorption of non-haem iron from food?
Vitamin C and citrate
- prevents formation of insoluble compounds
- vit C also helps reduce ferric to ferrous iron
What are the two forms of stored iron?
Ferritin - globular protein complex with hollow core, pores allow iron to enter and be released
Haemosiderin - aggregates of clumped ferritin particles, denatured protein and lipid, accumulated in macrophages, particularly in liver, spleen and marrow
How is iron taken up in cells?
- Fe3+ bound transferrin binds transferrin receptor and enters the cytosol by receptor-mediated endocytosis
- Fe3+ within endosome released by acidic micro environment and reduced to Fe2+
- Fe2+ transited to cytosol via DMT1
- Once in cytosol, Fe2+ can be stored in ferritin, exported by ferroportin, or take up by mitochondria or use in cytochrome enzymes
What is iron recycling?
Most iron requirement met form recycling damaged or senescent red blood cells
Old RBCs engulfed by macrophages (phagocytosis)
Mainly by splenic macrophages and Kupffer cells of liver macrophages catabolise haem releases from RBC
Amino acids reused and iron exported to blood or returned to storage pool as ferritin in macrophage
What are dietary iron levels sensed by?
Enterocytes
What are the control mechanisms for regulation of iron absorption?
Regulation of transporters (ferroportin)
Regulation of receptors (transferrin receptors and HFE protein)
Hepcidin and cytokines
Crosstalk between epithelial cells and outer cells like macrophages
What is hepcidin?
Key negative regulator of iron absorption
Induces internalisation and degradation of ferroportin
Hepcidin synthesis is increased in iron overload
Decreased by high erythropoietic activity
What is anaemia of chronic disease?
Functional iron deficiency
An inflammatory condition leads to cytokines released by immune cells
Therefore increased prodcution of hepcidin by liver, inhibiting ferroportin, decreasing iron release from reticuloendothelial system and decreased iron absorption in gut - reduce plasma iron
Also inhibits erythropoietin production by kidneys
All leads to inhibition of erythropoiesis in bone marrow
How much iron is in erythrocytes?
2500mg
How much iron is in the plasma iron pool?
2-3mg
How much iron is in the iron stores (mainly liver)?
1000mg
What are the causes of iron deficiency?
Insufficient iron in diet Malabsorption of iron Bleeding Increased requirement Anaemia of chronic disease
What are the groups at risk of iron deficiency?
Infants
Children
Women of child bearing age
Geriatric age group
What are the signs and symptoms of iron deficiency?
Physiological effects of anaemia
- tiredness
- pallo
- reduced exercise tolerance
Pica (unusual cravings for no-nutritive substances)
Cold hands and feet
Epithelial changes (angular cheilitis, glossy tongue, koilonychia)
What are the FBC results in iron deficiency anaemia?
Low mean corpuscular volume (MCV)
Low mean corpuscular haemoglobin concentration (MCHC)
Elevated platelet count
Normal or elevated WBC count
Low serum ferritin, serum iron, raised TIBC
Low reticulocyte haemoglobin content
What are the peripheral blood smear results in iron deficiency anaemia?
RBCs are microcytic ad hypochromic
Anisopoikilocytosis - change in size and shape
Sometime pencil cells and target cells
How to test for iron deficiency
Plasma ferritin
Reduced plasma ferritin, however normal or increased ferritin does not exclude iron deficiency
What is the treatment of iron deficiency anaemia?
Dietary advice Oral iron supplements Intramuscular iron injections Intravenous iron Blood transfusion
Why is iron excess dangerous?
Excess iron can exceed binding capacity of transferrin
Excess iron deposited in organs as haemosiderin
Iron promotes free radical formation and organ damage
What can cause excess iron?
Transfusion associated haemosiderosis
Hereditary haemochromotosis
What is transfusion associated haemosiderosis?
Repeated blood transfusions give gradual accumulation of iron
Problem with transfusion dependent anaemias such as thalassaemia and sickle cell anaemia
Iron chelating agents such as desferrioxamine can delay but not stop inevitable effects of iron overload
What can transfusion associated haemosiderosis cause?
Liver cirrhosis Diabetes Hypogonadism Cardiomyopathy Arthropathy Slate grey colour of skin
What is hereditary haemochromotosis?
Autosomal recessive disease caused by mutation in HFE gene
HFE protein normally interacts with transferrin receptor reducing its affinity for iron-bound transferrin
Mutated HFE can’t bind to transferrin so negative influence on iron uptake lost
HFE ha negative influence on hepcidin production
Too much iron enters cells
What is the treatment for hereditary haemochromotosis?
Venesection
What can hereditary haemochromotosis cause?
Liver cirrhosis Diabetes Hypogonadism Arthropathy Cardiomyopathy Increased skin pigmentation
