8. Iron metabolism Flashcards
What is microcytic anaemia caused by?
- Reduced haem synthesis
- Reduced globin chain synthesis
What anaemias are due to reduced haem synthesis(which results in microcytic anaemias)?
- iron deficiency - not enough iron for haem synthesis
- lead poisoning - lead inhibits enzymes in haem synthesis
- anaemia of chronic disease - hepcidin results in functional iron deficiency
- sideroblastic anaemia - inherited defect in haem synthesis
What anaemias are due to reduced globin chain synthesis(which results in microcytic anaemias)?
- alpha thalassaemia- deletion/ loss of function of one or more of the four alpha globin genes
- beta thalassaemia- mutation in beta globin genes leading to reduction or absence of the beta globin
What happens to RBCs in microcytic anaemias?
- smaller than normal (microcytic)
- often paler than normal (hypochromic)
How is the rate of haemoglobin synthesis in microcytic anaemia?
Reduced rate of haemoglobin synthesis
What are the five main types of microcytic anaemias?
T : thalassaemia A : anaemia of chronic disease I : iron deficiency L : lead poisoning S : sideroblastic anaemia
What is iron required for?
• Oxygen carriers: - Haemoglobin in red cells - Myoglobin in myocytes • Co-factor in many enzymes: - Cytochromes (oxidative phosphorylation) - Krebs cycle enzymes - Cytochrome P450 enzymes (detoxification) - Catalase
Why are complex regulatory systems used to ensure the safe absorption, transportation and utilisation of iron?
Free iron potentially very toxic to cells - generates free radicals —> oxidative damage
Body has no mechanism for excreting iron
Which oxidation states can iron exist in?
- ferrous iron - reduced form Fe2+
- ferric iron - oxidised form Fe3+
What does dietary iron consist of?
- haem iron - Fe 2+
- non-haem - mixture of Fe 2+ and Fe 3+
Ferric iron must be reduced to ferrous iron before it can be absorbed from the diet
Under what conditions is ferrous iron converted to ferric iron?
- Oxidation
* Alkaline
Under what conditions is ferric iron converted to ferrous iron?
- Reduction
* Acidic
How much iron do you need daily?
10-15 mg
Where is iron absorbed?
duodenum and upper jejunum
What are good sources of haem iron?
Liver, kidney, beef, chicken, duck, pork, salmon, tuna
What are good sources of non-haem iron?
Fortified cereals, raisins, beans, figs, barley, oats, rice, potatoes
How is iron absorbed?
- haem iron can pass through the membrane into the cytoplasm of the enterocyte where it is degraded by the enzyme haem oxygenate to release Fe2+
- for non-haem iron, duodenal cytochrome B reductase on apical surface of enterocytes converts ferric Fe3+—> ferrous Fe2+ - vit C donates this electron
- ferrous enters enterocytes via DMT1 - every molecule in, sends a proton out into the chyme
- Fe2+ released from both haem and non-haem iron can either be stored as ferritin (Fe3+)
- or leaves basolateral surface into the blood via ferroportin
- Hephaestin facilitates conversion back to Fe3+ needed to bind to transferrin to be transported in blood
What factors have a negative influence of absorption of non-Haem iron from food?
- tannins in tea: bind non-haem iron in intestine which reduces absorption
- phytates (e.g. chapattis, pulses): binds to non-haem
- fibre: binds to non-haem
- antacids e.g. graviscon: reduces acidity needed to reduce ferric —> ferrous
What factors have a positive influence on non-haem absorption ?
Vitamin C and citrate:
- prevents formation of insoluble iron compounds
- helps reduce ferric to ferrous iron: provides acidity and also an electron donor
What are examples of functional (available) iron?
iron associated with proteins/ enzymes and transported around the body
- Hb
- myoglobin
- enzymes e.g. cytochromes
- transported iron (in serum mainly in transferrin)
How much iron does the body contain? How much is stored?
3350 mg with 1000 mg stored
Name and describe two intracellular protein-iron complexes that are used to store iron?
Ferritin:
- soluble, globular protein complex with hollow core
- pores to allow iron in and out
- cytosolic , small amounts secreted into serum for use as a n iron carrier so a ferritin blood test is a useful diagnostic
Haemosiderin:
- only found within cells
- aggregates of clumped ferritin particles, denatured ferritin and denatured protein and lipid
- Unlike ferritin, the iron within deposits of haemosiderin is very poorly available
- accumulates in macrophages, especially in the liver, spleen and BM
How do cells take up iron?
- Fe3+ iron bound transferrin binds to transferrin receptor and enters the cytosol via receptor- mediated endocytosis
- ferric iron within an endosome is released by acidic micro environment and reduced to ferrous iron
- ferrous iron can now directly enter the cytosol. Transported via DMT1
- once in the cytosol, can be stored in ferritin, exported out and recycled by ferroportin (FPN1) or taken up by the mitochondria for use in cytochrome enzymes
How is iron recycled?
- more than 80% of iron requirement is met by recycling damaged/ senescent RBCs - only small amount from diet
- old RBCc engulfed by macrophages(phagocytosis) - mainly splenic macrophages/ kupffer cells of liver
- haem that is released from RBCs is catabolised by macrophages
- amino acids are reused and iron is exported to blood (transferrin) to storage as ferritin in macrophage
How is iron absorption regulated?
- depends on dietary factors, body iron stores and erythropoiesis
- dietary levels sensed by enterocytes
- control mechanisms include:
- regulation of transporters e.g. ferroportin
- regulation of receptors e.g. transferrin receptor and HFE protein (interacts with transferrin receptor)
- hepcidin and cytokines
- crosstalk between epithelial cells and other cells like macrophages
What does hepcidin do?
- inhibits dietary iron absorption from SI and release of iron from macrophages
- increased in iron overload
- decreased by high RBC activity
- induces internalisation and degradation of ferroportin (pushes it inside enterocyte) so less iron can be absorbed into the blood and less can be recycled from RBCs in macrophages
What happens in anaemia of chronic disease?
- inflammatory condition (e.g. rheumatoid arthritis, chronic infection, malignancy) means cytokines such as IL6 are released by immune cells
- these increase production of hepcidin by liver: inhibition of ferroportin means decreased iron release from reticuloendothelial system and decreased iron absorption in gut so plasma iron is reduced
- cytokines also inhibit EPO production in kidneys
- all these factors inhibit erythropoiesis in BM
- cytokines also directly inhibit erythropoiesis in BM
- These 3 factors all lead towards inhibition of eryhtropoiesis in BM
How are iron levels controlled? (Homeostasis)
- amount of iron absorbed in diet = amount lost by desquamation of epithelia, menstrual bleeding, sweat and pregnancy
- RBCs constantly being destroyed by macrophages releasing iron into plasma iron pool(Fe3+ bound to transferrin) which is used up to produce eryhtrocytes in the same amounts in bone marrow
- iron can be stored in the liver
How is iron excretion regulated?
No mechanism to do so!
What causes iron deficiency?
- insufficient iron in diet - e.g. Vegan & vegetarian diets
- malabsorption of diet - e.g vegan and vegetarian diets, Gastrectomy, coeliac disease
- bleeding e.g. menstruation, gastric bleeding due to chornic NSAID usage
- increased requirement- e.g in pregnancy/ rapid growth
- anaemia of chronic disease - e.g. inflammatory bowel disease
Is iron deficiency a diagnosis?
No, iron deficiency is a sign not a diagnosis
Which groups are at risk of iron deficiency?
- infants
- children
- women of child bearing age
- geriatric age group
What are signs and symptoms of iron deficiency?
• Physiological effects of anaemia - tiredness - pallor - reduced exercise tolerance due to reduced oxygen carrying capacity - angina, palpitations, heart failure - increase resp rate - headache, dizziness, light-headedness • pica - unusual cravings (dirt, ice) • cold hands and feet • Epithelial changes - angular cheilitis - glossitis of tongue with atrophy of lingual papillae - koilonychia - spoon nails
risk of neurocognitive defects in developing children
What do FBC results of iron deficiency show?
- low MCV
- low MCHC
- elevated platelet count
- normal/ elevated WBC count
- low serum ferritin, serum iron and %transferrin saturation
- raised TIBC - total iron binding capacity
- low reticulocyte Hb (CHr)
What does a peripheral blood smear of iron deficient patient show?
- microcytic, hypochromic RBCs in chronic cases
- anisopoikilocytosis - different sizes and shapes
- sometimes pencil and target cells
What two ways can you test for iron deficiency?
plasma ferritin:
- indirect marker of total iron status - Ferritin is predominantly a cytosolic protein but small amounts are
secreted into blood where it functions as an iron carrier - reduction definitely indicates iron deficiency
- BUT.. Normal or increased ferritin does not exclude iron deficiency (ferritin levels can also increase considerably in cancer, infection, inflammation, liver disease, alcoholism can mask)
CHr (reticulocyte Hb content):
- better as it remains low during inflammatory responses
- however it is also low in patients with thalassaemia so cant be used in this scenario
How is iron deficiency treated?
- dietary advice
- oral supplements (ferrous sulphate) - GI side effects
- intramuscular iron injections
- intravenous iron
- blood transfusion in severe cases, where imminent cardiac compromise is likely
What should be the response to iron deficiency treatment?
- improvement in symptoms
- 20g/L rise in Hb in 3 weeks
Why is excess iron dangerous?
- excess iron can exceed binding capacity of transferrin
- Excess iron deposited in organs as haemosiderin
- iron promotes free radical formation and organ damage through the Fenton reaction
- hydroxyl and hydroperoxyl radicals cause damage to cells by removing electrons = lipid peroxidation, damage to proteins and DNA
What is transfusion associated haemosiderosis?
- repeated blood transfusion = accumulation of iron in liver, heart and endocrine organs
- 400ml blood contains 200mg iron
- this can be a problem in transfusion dependent anaemias such as thalassaemia and sickle cell anaemia
- iron chelating agents such as desferrioxamine can delay but not stop iron overload
What are symptoms of transfusion associated haemosiderosis?
- liver cirrhosis
- diabetes mellitus
- hypogonadism
- cardiomyopathy
- arthropathy
- slate grey skin colour
What is hereditary haemochromatosis?
- autosomal recessive
- mutation in HFE gene on chromosome 6
- HFE protein normally interacts with transferrin receptor to reduce its affinity for iron bound transferrin
- mutated HFE cant bind to transferrin so this negative influence on iron uptake is lost
- HFE also has a negative influence on hepcidin production so a negative influence on iron uptake is lost once more
- too much iron enters cells - accumulates causing damage
Where does iron build up in haemochromatosis?
Liver, pancreas, heart, pit gland, joints, skin
What are symptoms of hereditary haemochromatosis?
- liver cirrhosis —> can lead to cancer
- type 1 diabetes mellitus —> detruction of beta islet cells in pancreas
- hypogonadism
- cardiomyopathy —> if absorbed in heart
- arthropathy - joints
- increased skin pigmentation - bronze
- tissue fibrosis
How is hereditary haemochromatosis treated?
Venesection - periodically draw blood
What is haemosiderosis?
The process of depositing iron in tissues
Why does it take a while for women to be diagnosed with haemochromatosis?
Menstrual bleeding - usually diagnosed after menopause
What is total iron binding capacity?
Blood test taken to see how much more iron the blood can carry
If less capacity, means transferrin is saturated
What do blood tests show for haemochromatosis?
Transferrin is saturated
Total iron binding capacity decreases
More ferritin produced
What are microcytic anaemias?
Microcytic anaemias are those anaemias that result in erythrocytes being smaller than normal (i.e. microcytic) due to a reduced rate of haemoglobin synthesis. Cells are often also hypochromic (paler than normal) due to the reduced haemoglobin content.
