Iron in Health and Disease

Question 1

why is iron essential?

Answer 1

oxygen transport
electron transport (mitochondrial production of ATP)

Question 2

where is iron present in the cell?

Answer 2

Hb
myoglobin
enzymes (e.g cytochromes)

Question 3

2 forms of iron in the cell?

Answer 3

ferric (Fe3+)

ferrous (Fe2+)

Question 4

why is iron dangerous?

Answer 4

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

Question 5

structure of Hb?

Answer 5

haem group in each globin chain
Fe2+ sits in the porphyrin ring
majority of body iron found in haem

Question 6

how is haem synthesised?

Answer 6

porphyrin ring + Fe2+ = haem
happens in cytosol of cell
(products made in mitochondria but combine in cytosol)

Question 7

describe iron exchange

Answer 7

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

Question 8

how much iron is stored in each area of the body?

Answer 8

4mg in plasma
150mg in erythroid marrow
2500mg in RBC Hb
500mg in macrophage stores

Question 9

how much iron is absorbed and lost per day?

Answer 9

1mg lost and absorbed

Question 10

where does iron absorption occur and how?

Answer 10

mainly in duodenum
uptaken into cells of duodenal mucosa
influenced by dietary factors

Question 11

what enhances iron absorption?

Answer 11

haem vs non-haem iron (there is a dedicated haem iron transporter)
ascorbic acid (reduces Fe3+ to Fe2+)
alcohol

Question 12

what inhibits iron absorption?

Answer 12

tannins (e.g in tea)
phytates (e.g cereals, brain, nuts and seeds)
calcium (e.g dairy produce)

Question 13

3 mechanisms of iron absorption?

Answer 13

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)

Question 14

major signalling protein in regulation of iron absorption?

Answer 14

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

Question 15

3 ways of looking at iron status?

Answer 15

functional iron (basically Hb concentration)
transport iron/iron supply to tissues (% saturation of transferrin with iron)
storage iron (serum ferritin, tissue biopsy)

Question 16

describe transferrin

Answer 16

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)

Question 17

which cells are particularly rich in transferrin receptors?

Answer 17

erythroid marrow

- developing RBCs need lots of iron

Question 18

how is transferrin saturation be measured?

Answer 18

serum iron/total iron binding capacity(to transferrin) X100 %
reflects the proportion of diferric transferrin (high affinity for cellular transferrin receptors)

Question 19

normal transferrin saturation?

Answer 19

20-50%
increased in iron overload
decreased in iron deficiency

Question 20

what is ferritin?

Answer 20

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

Question 21

how can serum ferritin levels be used?

Answer 21

tiny amount of serum ferritin reflects intracellular ferritin synthesis (indirect measure of storage iron)

Question 22

how are ferritin levels affected in disease?

Answer 22

low in iron deficiency
high in inflammation (sepsis, malignancy, liver injury etc)
very high in iron overload

Question 23

possible disorders of iron metabolism?

Answer 23

iron deficiency
iron malutilisation (anaemia of chronic disease)
iron overload

Question 24

consequences of negative iron balance?

Answer 24

exhaustion of iron stores
iron deficient erythropoiesis (falling RBC MCV)
microcytic anaemia
epithelial changes (skin, koilonychia, angular stomatitis)

Question 25

what are hypochromic microcytic anaemias and what can cause them?

Answer 25

deficient Hb synthesis
can be due to:
- haem deficiency (lack of iron for erythropoiesis)
- globin deficiency (thalassaemias)

Question 26

how can iron deficiency be confirmed?

Answer 26

combination of anaemia (decreased Hb iron) and redcued storage iron (low serum ferritin)

Question 27

what can cause iron deficiency?

Answer 27

insufficient intake
loosing too much (bleeding)
not absorbing enough (malabsorption - coeliac disease etc)

Question 28

causes of chronic blood loss?

Answer 28

menorrhagia
GI
- tumours
- ulcers
- NSAIDs
- parasitic infections
haematuria

Question 29

what is occult blood loss?

Answer 29

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

Question 30

anaemia of chronic disease is due to what?

Answer 30

iron malutilisation

Question 31

describe the process of iron block in anaemia of chronic disease?

Answer 31

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)

Question 32

what can cause iron overload?

Answer 32

primary = hereditary haemochromatosis
secondary = transfusional, iron loading anaemias

Question 33

describe primary iron overload?

Answer 33

long-term excess iron absorption with parenchymal rather than macrophage iron loading

Question 34

what is hereditary haemochromatosis?

Answer 34

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

Question 35

clinical features of hereditary haemochromatosis?

Answer 35

weakness/fatigue
joint pains
impotence
arthritis
cirrhosis
diabetes
cardiomyopathy
iron overload >5g

Question 36

molecular diagnosis of hereditary haemochromatosis?

Answer 36

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

Question 37

phenotype diagnosis of hereditary haemochromatosis?

Answer 37

transferrin saturation >50%
serum ferritin >300ug/L in men or >200ug/L in pre-menopausal women
liver biopsy can be done if needed

Question 38

how is hereditary haemochromatosis managed?

Answer 38

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

Question 39

causes of death in hereditary haemochromatosis?

Answer 39

diabetes
infections
cardiac/hepatic failure
bleeding varices
hepatoma

Question 40

family screening in hereditary haemochromatosis?

Answer 40

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)

Question 41

secondary causes of iron overload?

Answer 41

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

Question 42

how much iron in each blood transfusion and when is this used?

Answer 42

250mg
needed every 2-3 weeks for life in thalassaemia
variable need in myelodysplasia

Question 43

result of iron overloading?

Answer 43

total iron loading >5mg or liver iron >15mg/g dry weight

leads to damage to heart, liver and endocrine glands

Question 44

how is secondary iron overload managed?

Answer 44

cant venesect as patients are already anaemic
use iron chelating drugs instead
- desferrioxamine (s/c or IV)
- deferiprone/deferasirox (oral)

Question 45

how is each compartment of iron status assessed?

Answer 45

function iron = Hb
iron supply = transferrin saturation
storage iron = serum ferritin

Question 46

how is haemochromatosis diagnosed?

Answer 46

genetic testing + high transferrin saturation and ferritin

Question 47

how are iron loading anaemias managed?

Answer 47

iron chelating drugs