Iron metabolism + microcytic anaemias Flashcards
what is microcytic anaemia
reduced rate of haemoglobin synthesis so erythrocytes smaller and paler (hypochromic) than normal
causes of microcytic anaemia (TAILS)
- thalassaemia reduced globin chain synthesis
- anaemia of chronic disease hepcidin results in functional iron deficiency so reduced haem synthesis
- iron deficiency reduced haem synthesis
- lead poisoning acquired defect that inhibits enzymes of haem synthesis
- sideroblastic anaemia inherited defect in haem synthesis
function of iron
oxygen carriers
- haemoglobin
- myoglobin
co-factor in many enzymes
- cytochromes in ETC
- catalase protecting against oxidative stress
- Krebs cycle enzymes
why is free iron toxic to cells
- catalyst in formation of free radicals from ROS
- complex regulatory systems to ensure safe absorption, transportation and utilisation of iron
- body has no mechanism for excreting iron
ferrous vs ferric iron
- ferrous iron Fe2+ is reduced form of iron
- ferric iron Fe3+ is oxidised form of iron
- haem iron (Fe2+) is more readily absorbed than non-haem iron (mixture of Fe2+ and Fe3+)
- ferric iron must be reduced to ferrous iron before being absorbed from diet
how much iron is needed in diet
10-15 mg/day
1-2mg lost from body each day from skin and GI mucosa
dietary sources of haem iron (Fe2+)
- liver
- kidney
- beef
- chicken
- duck
- pork chop
- salmon/tuna
dietary sources of non-haem iron (Fe2+ and Fe3+)
- fortified cereals
- raisins
- beans
- figs
- barley
- oats
- rice
- potatoes
where does iron absorption occur
- duodenum
- upper jejunum
factors affecting absorption of non-Haem iron from food
negative influence
- tannins(tea) and phytates(chapattis, pulses) bind non-haem iron, inhibiting absorption
- antacids(Gaviscon) inhibit reduction of ferric to ferrous iron
- fibre
positive influence
- vitamin C prevents formation of insoluble iron compounds and helps reduce ferric to ferrous iron
- citrate prevents formation of insoluble iron compounds
iron absorption and transport
- DMT1 on apical surface of enterocytes facilitates uptake of non-haem ferrous iron (Fe2+) from intestinal lumen
- ferric iron (Fe3+) in intestinal lumen is reduced to ferrous iron by reductase (DcytB) before uptake by DMT1
- haem iron readily absorbed by enterocytes via folate transporter
- inside enterocyte haem degraded by haem oxygenase to release ferrous iron to join cytoplasmic pool of Fe2+
- iron in the enterocytes can be stored as ferritin or transferred into bloodstream via ferroportin
- in blood hephaestin converts Fe2+ to Fe3+
- transferrin binds to ferric iron in blood to transport around body
- mostly transported to bone marrow for erythropoesis or taken up by macrophages in RES as storage pool
regulation of iron absorption
- depends on dietary factors, body iron stores and erythropoiesis
- dietary iron levels sensed by enterocytes
control mechanisms
- regulation of transporters e.g ferroportin
- regulation of receptors e.g transferrin receptor
- hepcidin and cytokines
- crosstalk between epithelial cells and other cells
how does hepcidin regulate iron absorption
- hepcidin directly binds to ferroportin resulting in its internalisation and degradation, preventing iron from leaving cell (enterocytes and macrophages)
- down regulates iron uptake by inhibiting transcription of DMT1 gene
hepcidin synthesis increased in iron overload and decreased by high erythropoietic activity
iron recycling
- only small fraction of total daily iron requirement gained from diet
- most from recycling old or damaged red blood cells engulfed by macrophages in RES
- mainly by splenic macrophages and liver Kupffer cells
- macrophages catabolise haem from RBC
- amino acids reused and iron exported to blood (transferrin) or returned to storage pool as ferritin
where is functional iron
- haemoglobin ~2000mg
- myoglobin ~300mg
- enzymes ~50mg
- transported iron (transferrin) ~3mg
iron storage
ferritin (soluble)
- globular protein-iron complex with hollow core
- pores allow iron to enter and be released
haemosiderin (insoluble)
- aggregates of clumped ferritin particles, denatured protein and lipid
- accumulates in macrophages particularly in liver, spleen and marrow
cellular iron uptake
- Fe3+ bound transferrin binds transferrin receptor and enters cytosol by receptor-mediated endocytosis
- Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+
- Fe2+ transported to cytosol via DMT1
- in cytosol Fe2+ can be exported by ferroportin, stored as ferritin or taken up by mitochondria for use in cytochrome enzymes
cellular iron uptake
- Fe3+ bound transferrin binds transferrin receptor and enters cytosol by receptor-mediated endocytosis
- Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+
- Fe2+ transported to cytosol via DMT1
- in cytosol Fe2+ can be exported by ferroportin, stored as ferritin or taken up by mitochondria for use in cytochrome enzymes
mechanism of anaemia of chronic disease
- inflammatory condition causes cytokines released by immune cells
- causes causes inhibition of erythropoietin production by kidney and increased production of hepcidin by liver
- hepcidin causes inhibition of ferroportin so decreased iron release from RES and absorption in gut
- plasma iron is reduced (functional iron deficiency) so inhibition of erythropoiesis in bone marrow
how is iron lost
- desquamation of epithelia
- menstrual bleeding
- sweat
- pregnancy
iron deficiency
- most common nutritional disorder worldwide
- accounts for half of anaemia cases
- clinician must always seek to find underlying cause of deficiency
- could be due to insufficient intake/poor absorption, physiological reasons (pregnancy) or pathological reasons (bleeding)
causes of iron deficiency
- insufficient iron in diet vegan/vegetarian, financial constraints, anorexia
- decreased absorption of iron vegan/vegetarian, gastrectomy, coeliac disease
- bleeding menstruation, GI due to chronic NSAID usage, renal, nose, lungs
- increased requirement pregnancy, growth spurts, lactation
- anaemia of chronic disease functional iron deficiency
groups at risk of iron deficiency anaemia
- infants during transition from milk to solid food
- children
- menstruating women
- geriatric age group
signs and symptoms of iron deficiency anaemia
physiological effects
- tiredness
- pallor
- reduced exercise tolerance
- cardiac - angina, palpitations, heart failure
- increased repsiratory rate
- headache, dizziness, light-headedness
pica - unsual craving for non-nutritive substances e.g dirt, ice
cold hands and feet
epithelial changes
- angular cheilitis (mouth)
- glossy tongue with atrophy of lingual papillae
- Plummer-Vinson syndrome (oesophagus)
- koilonychia (nails)
FBC results in iron deficiency anaemia
- low MCV (mean corpuscular volume)
- low MCHC (mean corpsucular Hb conc)
- elevated platelet count (>450,000/µL
- normal or elevated WBC count
- low serum ferritin, serum iron and %transferrin saturation
- raised TIBC (total iron binding capacity)
- low reticulocyte haemoglobin content (CHr)
peripheral blood film results in iron deficiency anaemia
- microcytic and hypochromic RBC
- anisopoikilocytosis
- pencil cells and target cells
testing for iron deficiency
plasma ferritin as an indirect marker of total iron status
- reduced ferritin definitively indicates iron deficiency
- normal or increased ferritin doesn’t exclude iron deficiency as levels can increase in cancer, infection, inflammation, liver disease
CHr - reticulocyte haemoglobin content recommended by NICE
- functional iron deficiency
- CHr remains low during inflammatory responses
- CHr low in thalassaemia
treatment of iron deficiency
- first line: oral iron supplements (ferrous sulphate) but poor compliance and GI side effects, 2-3 months to replete iron stores
- dietary advice
- intramuscular iron injections
- intravenous iron
- blood transfusion if severe anaemia with cardiac compromise
response to iron deficiency treatment
20g/L rise in haemoglobin per 3 weeks of treatment should be expected with oral iron treatment if there’s no ongoing blood loss
iron excess
- excess iron can exceed binding capacity of transferrin
- excess iron deposited in organs as haemosiderin
- iron promotes free radical formation and organ damage
transfusion associated haemosiderosis
- repeated blood transfusions give gradual accumulation of iron
- 400ml blood = 200mg iron
- problem for transfusion dependent anaemias such as thalassaemia and sickle cell
- iron chelating agents (desferrioxamine) can delay inevitable effects of iron overload
- accumulation of haemosiderin in liver heart and endocrine organs causes:
liver cirrhosis, diabetes mellitus, hypogonadism, cardiomyopathy, arthropathy, slate grey colour of skin
what is hereditary haemochromatosis
- autosomal recessive disease caused by mutation in HFE gene on Chr6
- HFE protein interacts with transferrin receptor, reducing its affinity for iron-bound transferrin and also promotes hepcidin expression through activation of signalling pathways in liver
- mutated HFE results in increased iron uptake and absorption so too much iron enters cells and accumulates in organs since there’s no way to excrete excess iron, causing damage
treatment for hereditary haemochromatosis
venesection (therapeutic phlebotomy)
what do patients with hereditary haemochromatosis present with
- liver cirrhosis
- diabetes mellitus
- hypogonadism
- cardiomyopathy
- arthropathy
- increased skin pigmentation
- adrenal insufficiency
- heart failure
- arthritis
