Iron in Health and Disease Flashcards
What are the different forms of iron?
Ferric (Fe3+)
Ferrous (Fe 2+)
Where is iron present in the body?
Haemaglobin
Myoglobin
Cytochromes
Why can iron be dangerous?
Chemical reactivity; oxidative stress and free radical production
Adaptive requirements for safe transport, storage and absorption required
We have no mechanism to excrete iron
What is the fenton reaction?
Formation of free radicals from iron
Ferrous + Water = Ferric + free radical + hydroxyl group
Where is haem synthesised?
Cytoplasm of cell
Some of it occurs in the mitochondrion
How much iron is absorbed a day?
1mg/ day
How much iron is present in the plasma?
4mg
How much iron is found in the erythroid marrow?
150mg
How much iron is found in the haemaglobin of red cells?
2500 mg
How much iron is found in the macrophages?
500mg
How much iron is found in parenchymal tissues (liver)?
500mg
How much iron is lost a day?
1mg / day
Where does iron absorption occur?
Duodenum
What will enhance iron absorption?
Haem vs non-haem iron (dedicated haem iron transporter)
Ascorbic acid (reduces iron to Fe2+ form)
Alcohol
What will inhibit iron absorption?
Tannins e.g. tea
Phytates e.g. cereals, bran, nuts, seeds
Calcium e.g. dairy produce
What is the function of duodenal cytochrome B?
Found on luminal surface of duodenum
Reduces ferric iron (3+) to ferrous form (2+)
What is the function of DMT?
Transports ferrous iron into the duodenal enterocyte
What is the function of ferroportin?
Facilitates iron export from enterocyte
Passed onto transferrin for transport elsewhere
How is iron absorption regulated?
Hepcidin:
Major negative regulator or iron uptake
Produced in liver in response to increased iron load and inflammation
Will bind to ferroportin to result in degradation and therefor iron is “trapped” in the duodenum cells and macrophages
How is iron transported within transferrin?
Fe3+
This occurs via hephaestin present on the duodenal enterocyte
How is functional iron assessed?
Hb conc
How is transport iron/ supply to tissues assessed?
% saturation of transferrin with iron
How is storage iron assessed?
Serum ferritin Tissue biopsy (rarely needed)
How many ion of iron can transferrin carry?
2 binding sites
What is the function of transferrin?
Transports iron from donor tissues (macrophages, interstitial cells and hepatocytes) to tissues expressing transferrin receptors
What is a structure especially rich in transferrin receptors?
Erythroid marrow
What measures iron supply?
Transferrin saturation
Serum iron/ total binding capacity x 100%
Reflects proportion of diferric transferrin
What is a normal transferrin saturation?
20-50%
What is holotransferrin?
Iron bound to transferrin
What is apotransferrin?
Unbound transferrin
What will happen to transferrin saturation in iron overload?
Increased (and vice versa)
How many ferric ions can ferritin store?
4000
What can cause high levels of ferritin outwith iron stores?
Acts as an acute phase protein so increased in infection, malignancy etc
What are disorders of iron metabolism?
Iron deficiency
Iron malutilisation - anaemia of chronic disease
Iron overload
What are the consequences of a negative iron balance?
Exhaustion of iron stores
Iron deficiency erythropoiesis; falling red cell MCV
Microcytic anaemia
Epithelial changes; dry skin, koilonychia, angular stomatitis
What does hypochromic microcytic anaemia suggest?
Deficiency haemaglobin synthesis
What can cause a haem deficiency?
Lack of iron for erythropoiesis - iron deficiency, anaemia of chronic disease
Congenital sideroblastic anaemia
What can cause a globin deficiency?
Thalassaemia
What can cause an iron deficiency?
Insufficient intake to meet physiological needs
Bleeding
Malabsorption; coeliac
What can cause chronic blood loss?
Menorrhagia
GI; tumours, ulcers, NSAIDs, parasitic infection
Haematuria
What can cause occult blood loss?
GI blood loss of 8-10 ml a day (4-5mg of iron) without any symptoms or signs
Max dietary iron absorption is 4-5mg a day
How pathologically, will chronic disease lead to iron deficiency anaemia?
AOCD; inflammatory macrophage iron block
Increased transcription of ferritin mRNA by inflam cytokines so ferritin synthesis increased
Increased plasma hepcidin blocks ferroportin mediated release of iron
This results in an impaired iron supply to marrow erythroblasts and eventually hypochromic red cells
Why does inflammatory macrophage iron block occur?
Protective mechanism to reduce supply of iron to pathogens
What are the primary and secondary causes of iron overload?
Primary; hereditary haemochromatosis
Secondary: transfusional, iron loading anaemia
What is primary iron overload?
Long term excess iron absorption with parenchymal rather than macrophage iron loading
Describe hereditary haemochromatosis
Commonest form due to mutations in HFE gene
Decreases synthesis of hepcidin
Increased iron absorption
Results in gradual iron accumulation with risk of end-organ damage
What are the clinical features of hereditary haemochromatosis?
Weakness/ fatigue Joint pains Impotence Arthritis Cirrhosis Diabetes Cardiomyopathy
What is defined as iron overload?
> 5g
How is haemochromatosis diagnosed molecularly?
Mutations of HFE gene
Mutations of other iron regulatory proteins e.g. transferrin receptor, hepcidin, ferroportin
What is the phenotype of haemochromatosis?
Transferrin saturation >50%
Serum ferritin >300 microgram/l in men or >200 microgram/l in pre-menopausal women
Liver biopsy; rarely needed as fibroscan available now to assess cirrhosis
How is haemochromatosis treated?
Weekly venesection; 450-500ml (200-250 mg iron)
Initial aim to exhaust iron stores (ferritin <20 microgram/l)
Maintenance <50 microgram/l
What causes the most deaths in haemochromatosis?
Hepatic failure
Hepatoma
Is family screening indicated in haemochromatosis?
First degree relatives esp siblings
Children; wait until adults for informed consent
HFE genotype and iron status
Why are family studies so important in haemochromatosis?
May be asymptomatic until irreversible organ damage has occured
What can cause iron loading anaemia?
Repeated red cell transfusions
Excessive iron absorption related to over active erythropoiesis
Thalassaemia
Sideroblastic anaemia
Refractory hypoplastic anaemia; red cell aplasia, myelodysplasia
How much iron does each unit of blood contain?
250 mg
Beta thal maj - transfusion every 2-3 weeks
How is secondary iron overload treated?
Venesection not an option in already anaemic patients
Iron chelating agents; desferrioxamine, deferiprone, deferaasirox
What is sideroblastic anaemia?
Failure to incorporate iron into haem
Can be hereditary or acquired (MDS, lead poisoning, alcohol excess)
