Iron in Health and Disease Flashcards
why is iron essential?
oxygen transport electron transport (mitochondrial production of ATP)
where is iron present in the cell?
Hb
myoglobin
enzymes (e.g cytochromes)
2 forms of iron in the cell?
ferric (Fe3+)
ferrous (Fe2+)
why is iron dangerous?
chemical reactivity (oxidative stress and free radical production) no mechanism for excretion therefore there must be adaptive requirements for safe transport and storage and regulation of absorption
structure of Hb?
haem group in each globin chain
Fe2+ sits in the porphyrin ring
majority of body iron found in haem
how is haem synthesised?
porphyrin ring + Fe2+ = haem
happens in cytosol of cell
(products made in mitochondria but combine in cytosol)
describe iron exchange
enters plasma via absorption and from stores in parenchymal tissues/liver and macrophages
iron then leaves plasma and enters erythroid marrow > RBC Hb > macrophage stores > plasma and the cycle continues
how much iron is stored in each area of the body?
4mg in plasma
150mg in erythroid marrow
2500mg in RBC Hb
500mg in macrophage stores
how much iron is absorbed and lost per day?
1mg lost and absorbed
where does iron absorption occur and how?
mainly in duodenum
uptaken into cells of duodenal mucosa
influenced by dietary factors
what enhances iron absorption?
haem vs non-haem iron (there is a dedicated haem iron transporter)
ascorbic acid (reduces Fe3+ to Fe2+)
alcohol
what inhibits iron absorption?
tannins (e.g in tea)
phytates (e.g cereals, brain, nuts and seeds)
calcium (e.g dairy produce)
3 mechanisms of iron absorption?
duodenal cytochrome B (found in luminal surface and reduces Fe3+ to Fe2+)
DMT (divalent metal transporter) - (transports ferrous iron into the duodenal enterocyte)
ferroportin (facilitates iron export from the enterocyte, passed on to transferrin for transport elsewhere)
major signalling protein in regulation of iron absorption?
hepcidin
produced in liver in response to increased iron and inflammation
binds to ferroportin and causes degredation, iron is therefore trapped in duodenal cells and macrophages
hepcidin levels decrease when iron deficient
3 ways of looking at iron status?
functional iron (basically Hb concentration) transport iron/iron supply to tissues (% saturation of transferrin with iron) storage iron (serum ferritin, tissue biopsy)
describe transferrin
protein with 2 binding sites for iron atoms
transports iron in Fe3+ state from donor tissues (macrophages, intestinal cells and hepatocytes) to tissues expressing transferrin receptors (tissues which need iron)
which cells are particularly rich in transferrin receptors?
erythroid marrow
- developing RBCs need lots of iron
how is transferrin saturation be measured?
serum iron/total iron binding capacity(to transferrin) X100 %
reflects the proportion of diferric transferrin (high affinity for cellular transferrin receptors)
normal transferrin saturation?
20-50%
increased in iron overload
decreased in iron deficiency
what is ferritin?
spherical intracellular protein which stored up to 4000 ferric ions (Fe3+)
also acts as an acute phase protein so goes up with infection, malignancy etc
how can serum ferritin levels be used?
tiny amount of serum ferritin reflects intracellular ferritin synthesis (indirect measure of storage iron)
how are ferritin levels affected in disease?
low in iron deficiency
high in inflammation (sepsis, malignancy, liver injury etc)
very high in iron overload
possible disorders of iron metabolism?
iron deficiency iron malutilisation (anaemia of chronic disease) iron overload
consequences of negative iron balance?
exhaustion of iron stores
iron deficient erythropoiesis (falling RBC MCV)
microcytic anaemia
epithelial changes (skin, koilonychia, angular stomatitis)
what are hypochromic microcytic anaemias and what can cause them?
deficient Hb synthesis
can be due to:
- haem deficiency (lack of iron for erythropoiesis)
- globin deficiency (thalassaemias)
how can iron deficiency be confirmed?
combination of anaemia (decreased Hb iron) and redcued storage iron (low serum ferritin)
what can cause iron deficiency?
insufficient intake
loosing too much (bleeding)
not absorbing enough (malabsorption - coeliac disease etc)
causes of chronic blood loss?
menorrhagia GI - tumours - ulcers - NSAIDs - parasitic infections haematuria
what is occult blood loss?
GI blood loss of 8-10ml per day without any signs or symptoms of bleeding
can cause loss of 4-5mg iron per day
- only 4-5mg made per day so can cause -ve iron balance
anaemia of chronic disease is due to what?
iron malutilisation
describe the process of iron block in anaemia of chronic disease?
increased transcription of ferritin mRNA stimulated by inflammatory cytokines so ferritin synthesis increased
increased plasma hepcidin blocks ferroportin-mediated release of iron
results in impaired iron supply to marrow erythroblasts and eventually hypochromic red cells
(iron cant bind to transferrin)
what can cause iron overload?
primary = hereditary haemochromatosis secondary = transfusional, iron loading anaemias
describe primary iron overload?
long-term excess iron absorption with parenchymal rather than macrophage iron loading
what is hereditary haemochromatosis?
usually due to mutation in HFE gene
decreases synthesis of hepcidin
causes increased iron absorption and gradual iron accumulation with risk of end-organ damage
clinical features of hereditary haemochromatosis?
weakness/fatigue joint pains impotence arthritis cirrhosis diabetes cardiomyopathy iron overload >5g
molecular diagnosis of hereditary haemochromatosis?
mutations of HFE gene account for 95% of cases
patients are usually homozygous for C282Y mutation or occasionally C282Y/H63D heterozygotes
(both mutations present in a lot of unaffected people)
incomplete penetrance
phenotype diagnosis of hereditary haemochromatosis?
transferrin saturation >50%
serum ferritin >300ug/L in men or >200ug/L in pre-menopausal women
liver biopsy can be done if needed
how is hereditary haemochromatosis managed?
weekly venesection of 450-500ml blood (containing 200-250mg of iron)
do this until iron levels are at lower level of normal, then venesect them 2-3 time per year for the rest of their life
aim to bring initial iron stores <20ug/l ferritin then keep below 50ug/l
causes of death in hereditary haemochromatosis?
diabetes infections cardiac/hepatic failure bleeding varices hepatoma
family screening in hereditary haemochromatosis?
screen first degree relatives of cases (esp siblings)
don’t test children until adulthood and able to give consent
can test HFE genotype and iron status (ferritin and transferrin)
secondary causes of iron overload?
repeated RBC transfusions
excessive iron absorption due to over-active erythropoiesis
disorders such as thalassaemia and sideroblastic anaemias which cause massive ineffective erythropoiesis
disorders such as red cell aplasia and myelodysplasia which cause refractory hypoplastic anaemias
how much iron in each blood transfusion and when is this used?
250mg
needed every 2-3 weeks for life in thalassaemia
variable need in myelodysplasia
result of iron overloading?
total iron loading >5mg or liver iron >15mg/g dry weight
leads to damage to heart, liver and endocrine glands
how is secondary iron overload managed?
cant venesect as patients are already anaemic
use iron chelating drugs instead
- desferrioxamine (s/c or IV)
- deferiprone/deferasirox (oral)
how is each compartment of iron status assessed?
function iron = Hb iron supply = transferrin saturation storage iron = serum ferritin
how is haemochromatosis diagnosed?
genetic testing + high transferrin saturation and ferritin
how are iron loading anaemias managed?
iron chelating drugs
