iron stuff

Question 1

Fe + ? -> haem

Answer 1

porphyrin ring + Fe -> haem

Fe + protoporophyrin leave mitochondrion to cytoplasm + form haem

Question 2

when is iron absorbed

Answer 2

mainly duodenum
- uptake into cells of duodenal mucosa
- influenced by dietary factors

Question 3

what enhances / inhibits iron absorption?

Answer 3

enhanced by -
- ascorbic acid (vit c) - reduces iron to Fe2+ form
- alcohol

inhibited by -
- higher gastric pHs
- tannins - teas
- cereals, bran, nuts, seeds (phytates)
- calcium - dairy produce

Question 4

causes of elevated iron

Answer 4

beta thalassaemia major
sideroblastic anaemia
oral contraceptive pills
multiple transfusions
hereditary haemochromatosis

Question 5

mechanism of iron absorption

Answer 5

duodenal cytochrome B - found on luminal surface, reduces ferric iron (Fe3+) to ferrous form (Fe2+)

DMT (divalent metal transporter) - transports ferrous iron into duodenal enterocyte

ferroportin - facilitates iron export from enterocyte, passed on to transferrin for transport elsewhere

Question 6

how is iron absorption regulated

Answer 6

hepcidin
- major negative regulator of iron uptake
- produced in liver in response to increased iron load + inflammation
- binds to ferroportin + causes degradation
- iron therefore “trapped” in duodenal cells + macrohphages

hepcidin levels decrease when iron deficient

Question 7

transferrin

Answer 7

protein with 2 binding sites
transports iron from donor tissues (macrophages, intestinal cells + hepatocytes) to tissues expressing transferrin receptors

erythroid marrow especially rich in transferrin receptors

Question 8

how is iron supply measured

Answer 8

transferrin saturation measures iron supply

Question 9

ferritin

Answer 9

spherical intracellular protein, stores up to 4000 ferric ions

tiny amount of serum ferritin reflects intracellular ferritin synthesis -> indirect measure of storage iron

*also acts as acute phase protein - goes up with infection, malignancy

Question 10

pathophysio of anaemia of chronic disease

Answer 10

inflammatory cytokines + increase ferritin stimulates hepcidin release which is inhibitory to iron absorption (decreases activity of ferroportin)

-> results in impaired iron supply to marrow erythroblasts + eventually hypochromic red cells

Question 11

sideroblastic anaemia

Answer 11

uncommon, microcytic anaemia refractory to intensive iron therapy
- assoc with an atypically high serum ferritin + iron

excess iron build up in mitochondria (blue granules around neucleus) due to failure to incorporate iron into haem

can be hereditary or acquired - MDS, lead poisoning, alcohol excess

Question 12

causes of iron overload

Answer 12

primary
- long term excess iron absorption with parachymal rather than macrophage iron loading
- hereditary haemochromatosis

secondary
- transfusional
- iron loading anaemias

Question 13

hereditary haemochromatosis

Answer 13

gradual iron accumulation + deposits in many organ with risk of end organ damage

due to mutations in HFE gene on both copies of chromosome 6 - autosomal recessive
- decreases synthesis of hepcidin -> increases iron absorption

Question 14

hereditary haemochromatosis presentation

Answer 14

bronze skin
weakness/fatigue
joint pain
impotence
cirrhosis
diabetes
cardiomyopathy

presentation usually middle age or later iron overload >5g
may be asymptomatic until irreversible organ damage has occured

Question 15

hereditary haemochromatosis investigations

Answer 15

transferrin saturation raised
serum ferritin raised
deranged LFTs

mutations of HFE gene (incomplete penetrance)
- autosomal recessive
- many carry the gene

Question 16

Hereditary haemochromatosis phenotype diagnosis

Answer 16

transferrin saturation >50% - sustained on repeat fasting sample
increased iron stores - serum ferritin >300ug/l in men or >200 ug/l in premenopausal women

liver biopsy - rarely needed, fibroscan for liver cirrhosis

Question 17

management of haemochromatosis

Answer 17

venesection
- aim to exhaust iron stores initially
- there after keep ferritin below 50ug/l + tranferrin <50%

2nd line = desferrioxamine

Question 18

family screening for haemochromatosis

Answer 18

1st degree relative of cases - especially siblings (risk 1 in 4)

children - wait till they are adults able to give informed consent

Question 19

iron loading anaemias

Answer 19

disorders
- massive ineffective erythropoiesis - thalassaemia, sideroblastic anaemia
- refractory hypoplastic anaemias - red cell aplasia, myelodysplasia

sources
- repeated red cell transfusions
- excessive iron absorption related to overactive erythropoiesis

Question 20

treatment of secondary iron overload

Answer 20

venesection not an option in already anaemic patients
iron chelating agents
- desferrioxamine - subcut or IV
- newer oral agents - deferiprone, deferasirox

Question 21

assessment of iron status

Answer 21

function iron -> haemoglobin

iron supply -> transferrin saturation

storage iron -> serum ferritin (beware of acute phase reaction)

Question 22

iron overload with red cell transfusions

Answer 22

Iron overload is inevitable with regular red cell transfusions, but risk of excess intestinal iron absorption may be hidden until tissue damage becomes symptomatic

Question 23

MCV vs MCH

Answer 23

MCV = cell size
MCH = cell Hb content

Question 24

what to do if haemolytic anaemia suspected

Answer 24

look for evidence of red cell breakdown products + reticulocytosis
then consider cause - blood film + history review

Question 25

causes of macrocytic anaemia

Answer 25

nuclear maturation defects - failure of cell division
- nutritional - B12/folate (megaloblastic)
- myelodysplasia
- drugs

apparent
- agglutination
- (reticulocytosis)

Question 26

causes of macrocytosis without significant anaemia

Answer 26

hypothyroidism
alcohol
liver disease

Question 27

renal anaemia =

Answer 27

anaemia of chronic disease - due to failure of erythropoietin production

Question 28

why can anaemia of chronic disease sometimes be microcytic?

Answer 28

if the predominant mechanism through hepcidin stimulation in that individual
- reduced relase of iron from macrophages due to block of ferroportin
- low available iron even though iron stores adequate
- failure of haemoglobin synthesis so microcytosis
- explains low transferrin saturation despite normal/raised ferritin