What are some of the functions of iron?
Oxygen transport = reversible oxygen binding by Hb
Electron transport
What are some molecules that contain iron?
Haemoglobin, myoglobin and enzymes
What are some of the issues with iron?
Can produce free radicals and cause oxidative stress
No mechanism for its excretion
Where is the majority of body iron found?
In haem = Fe2+sits in porphyrin ring
Where does iron absorption mainly occur?
In the duodenum = uptake into duodenal mucosal cells
What influences iron absorption?
Dietary factors
What are some dietary chemicals that influence iron absorption?
Enhanced by ascorbic acid (reduces iron to Fe2+) and alcohol
Inhibited by tannins, phylates and calcium
What are the different mechanisms of iron absorption?
Duodenal cytochrome B, DMT-1 and ferroportin
How does duodenal cytochrome B absorb iron?
Found in lumenal surface = reduces ferric iron (Fe3+) to ferrous form (Fe2+)
How does DMT-1 absorb iron?
Transports ferrous iron into duodenal enterocytes
How does ferroportin absorb iron?
Facilitates iron export from enterocyte where it is passed on to transferrin for transport elsewhere
What is hepcidin?
Major negative regulator of iron uptake = levels decrease in iron deficiency
Where is hepcidin produced?
Produced in liver in response to increased iron load and inflammation
What is the action of hepcidin?
Binds to ferroportin and causes its degradation = iron trapped in duodenal cells and macrophages
How is iron status assessed?
Functional iron = Hb concentration
Transport iron = % saturation of transferrin
Storage iron = serum ferritin, tissue biopsy (rarely used)
What is transferrin?
Protein with two binding sites for iron = transports iron from donor tissues to those expressing transferrin receptors
What area of the body is especially rich in transferrin receptors?
Erythroid marrow
What does saturation of transferrin measure?
Iron supply = serum iron/total iron binding capacity x 100
What does % saturation of transferrin reflect?
Proportion of diferric transferrin = has high affinity for cellular transferrin receptors
What do the different types of transferrin represent?
Holotransferrin represents bound
Apotransferrin represents unbound
How do transferrin saturation vary in different iron states?
In normal levels, saturation is 20-50%
Elevated saturation in iron overload
What is ferritin?
Spherical intracellular protein = stores up to 4000 ferric ions
What does serum ferritin reflect?
Tiny amount of serum ferritin reflects intracellular ferritin synthesis = indirect measure of storage iron
What is the additional function of ferritin?
Acts as an acute phase protein
What causes ferritin levels to rise?
Iron overload, sepsis, inflammation, malignancy
What are examples of disorders of iron metabolism?
Iron deficiency, iron malutilisation (anaemia of chronic disease), iron overload
What are the consequences of negative iron balance?
Exhaustion of iron stores
Iron deficient erythropoiesis = falling rec cell MCV
Microcytic anaemia
Epithelial changes = skin, koilonychia, angular stomatitis
Is iron deficiency anaemia a diagnosis?
No = symptom not a diagnosis, iron replacement therapy will mask symptoms but won’t treat underlying problem
What causes increased ferritin synthesis in anaemia of chronic disease?
Increased transcription of ferritin in mRNA stimulated by inflammatory cytokines
What effect does anaemia of chronic disease have on iron release?
Increased plasma hepcidin blocks ferroportin-mediated release of iron
What is the end result of anaemia of chronic disease?
Results in impaired iron supply to marrow erythroblasts and eventually hypochromatic red cells
Why does inflammatory macrophage iron block occur in anaemia of chronic disease?
Protective mechanism = reduces iron supply to pathogens
What are some causes of iron overload?
Primary = hereditary haemochromatosis Secondary = transfusional, iron loading anaemias
What occurs in primary iron overload?
Long term excess iron absorption with parenchymal rather than macrophage iron loading
What causes the most common form of hereditary haemochromatosis?
Mutation in HFE gene
What occurs in hereditary haemochromatosis?
Decreases synthesis of hepcidin = increased iron absorption resulting in gradual iron accumulation with risk of end organ damage
When does hereditary haemochromatosis present?
In middle age or older when iron overload >5g = may be asymptomatic until end-organ damage has occurred
What are the features of hereditary haemochromatosis?
Weakness/fatigue, arthritis, cirrhosis, joint pains, impotence, diabetes, cardiomyopathy
What are some features of mutations in HFE causing hereditary haemochromatosis?
Accounts for 95% of cases
H63D mutation most common followed by C282Y
Patients usually C282Y homozygotes
Shows incomplete penetrance
How is hereditary haemochromatosis diagnosed?
Transferrin saturation >50% on repeated fasted test
Serum ferritin >300ug/l in men or >200ug/l in women
Liver biopsy = rarely needed, non-invasive techniques like Fibroscan can assess cirrhosis
How is hereditary haemochromatosis treated?
Weekly venesection = 400-500ml, 200-250mg iron
Initial aim to exhaust iron stores = ferritin <20ug/l
Thereafter keep ferritin <50ug/l
What patients are screened for hereditary haemochromatosis?
All first degree relatives of patients (esp siblings)
Wait until children are adults
How is hereditary haemochromatosis screened for?
HFE genotype and iron status = ferritin and transferrin status
What are the causes of iron loading anaemias?
Repeated red cell transfusions, excessive iron absorption related to overactive erythropoiesis
What are some disorders that cause iron loading anaemias?
Massive ineffective erythropoiesis = thalassaemias, sideroblastic anaemias
Refractory hypoplastic anaemias = red cell aplasia, myelodysplasia
How much iron does each unit of blood given in a transfusion contain?
About 250mg of iron
How often do patients with thalassaemia require transfusion?
Every 2-3 weeks lifelong
What organs can be damaged by iron loading?
Liver, heart and endocrine glands
What is the definition of iron loading?
Iron >5g or liver >15mg/g dry weight
How are iron loading anaemias treated?
Venesection = not option in already anaemic patients
Iron chelating agents = desferrioxamine (SC or IV), oral deferiprone or deferasirax