7.2 - Anaemia II Flashcards
what are microcytic anaemias
- due to deficit in haemoglobin
- erythrocytes smaller than normal
- cells paler than normal (hypochromic)
due to…
reduced haem synthesis
- iron deficiency
- lead poisoning
- anaemia of chronic disease aka anaemia of inflammation
- sideroblastic anaemia
reduced globin chain synthesis
- α thalassaemia
- β thalassaemia
more about each one on other slide
causes of microcytic anaemia
- α thalassaemia where there is a deletion or loss of function of one more more of the 4 α globin genes
- β thalassaemia where there is a mutation in β globin genes, leading to reduction or absence of β protein
- anaemia of chronic disease/inflamation where hepicidin results in functional iron deficiency. Note this can also be normocytic.
- iron deficiency insufficient iron for haem synthesis
- lead poisioning aquired. Lead inhibits enzymes involved with haem synthesis
- sideroblastic anaemia inherited defect in haem synthesis
broad categories: reduced globin chain synthesis (thalassaemia) and reduced haem synthesis (all the others)
can be remembered using TAILS mneumonic
iron
- essential element in all living cells
- required as oxygen carrier (eg haemoglobin in red cells and myoglobin in myocytes)
- required as co-factor in many enzymes (cytochromes in oxidative phosphorylation, kreb’s, detoxification and catalase)
- free iron is very toxic to cells (Fenton reaction - formation of free radicals that can cause oxidative damage)
- complex regulatory to ensure safe absorbtion, transportation and utilisation
- body has no mechanism for excreting iron
- this means can get iron build up
ferrous vs ferric iron
iron can exist in range of oxidation states
ferrous
- Fe 2+
- used in kreb’s, haemoglobin etc
- ie reduced state
- Fe 2+ → Fe 3+ + e- (oxidation, occurs at high pH)
ferric
- Fe 3+
- not liked or used by body
- ie oxidised form
- Fe 3+ + e- → Fe 2+ (reduction, occurs at low pH)
- therefore acid in stomach promotes ferric → ferrous
haem vs non-haem iron
haem
- Fe 2+
- best source
- animal foods eg liver, kidney, beef steak, chicken, duck, pork, salmon, tuna
non haem
- Fe 2+ and 3+
- ferric iron must be reduced to Fe 2+ before it can be absorbed from the diet
- plant based foods eg fortified cereals, beans, oats, rice, raisins, barley
where does absorbtion occur for iron
duodenum and upper jejunum
→ acid in stomach promotes reduction of ferric to ferrous due to low pH
how much iron is required per day in the diet
need 10-15 mg per day in diet… in reality will actually absorb much less than this
how is iron absorbed from the diet
- proteins and enzymes on the brush border of apical surface of enterocytes are in contact with the chyme
- Fe3+ is reduced to Fe2+ using enzyme reductase (on apical surface of enterocyte) and an electron donated by vitamin C
- Fe2+ enters enterocyte via DMT1 (allows only Fe2+ to enter)
- Fe2+ can be stored using ferritin (on sep card)
- can exit enterocyte and enter bloodstream by ferroportin
- hephaestin converts Fe2+ → Fe3+ so that it can bind to transferrin to be transported around the body
note: haem can also enter enterocyte, and be converted to Fe2+ inside cell by haem oxygenase
how is iron stored
- by ferritin
- ferritin serves as a storage molecule for iron in 3+ form only
- has pores
- Fe2+ is oxidised → Fe3+ inside enterocyte
what is chyme
the pulpy acidic fluid which passes from the stomach to the small intestine, consisting of gastric juices and partly digested food
what does transferrin do
once Fe2+ is transported out of enterocyte via ferroportin into the bloodstream, hephaestin oxidises Fe2+ → Fe3+
transferrin binds 2 x Fe3+ to be transported around the body
what is hepicidin and what does it do
- peptide produced by the liver
- inhibits ferroportin by binding to it
- iron is trapped inside the enterocyte rather than be exported out
- hepicidin synthesis is increased in iron overload
- decreased by high erythropoietic activity
- hepicidin induces internalisation and degradation of ferroportin
factors affecting absorption of non-haem iron from food
negative influence
- tannins in tea
- phylatates (eg chapattis, pulses)
- fibre
… these can bind non-haem iron in the intestine, causing iron to be excreted rather than absorbed
- antiacids (raises pH so limits reduction of Fe3+ → Fe2+
positive influence
vitamin C and citrate
- prevent formaiton of insoluble iron compounds
- vit C also helps to reduce ferric to ferrous iron
functional vs stored iron
functional
- haemoglobin
- myoglobin
- enzymes eg cytochromes
- transported iron
stored
FERRITIN
- soluble
- globular protein complex with hollow core
- pores allow iron to enter and be released
HAEMOSIDERIN
- insolulbe
- builds up with age
- aggregates of clumped ferritin particles, denatured protien and lipid
- accumulates in macrophages, particularly in liver, spleen and marrow
cellular iron uptake
- Fe3+ bound transferring binds to transferrin receptor
- enters the cytosol via receptor mediated endocytosis
- Fe3+ within endosome is released by acidic microenvironment
- Fe3+ reduced to Fe2+
- the Fe2+ is transported to the cytosol via DMT1
once in cytosol…
- Fe2+ can be stored in ferritin
- exported by ferroportin (FPN1)
- taken up by mitochondria for use in cytochrome enzymes
iron recycling
- only small fraction of daily iron requirement gained from diet
- most of iron requirement met from recycling damaged or senescent RBCs
- old RBCs engulfed by macrophages (phagocytosis)
- mainly by splenic macrophages and kupffer cells (of liver)
- macrophages catabolise haem released from RBCs
- amino acids reused
- iron exported to blood (transferrin), or returned to storage pool as ferritin in macrophage
regulation of iron absorbtion
- depends on dietary factors, body iron stores and erythropoiesis
- dietary iron levels sensed by enterocytes
control mechanisms…
- regulation of transporters eg ferroportin
- regulation of receptors eg transferrin receptor and HFE protein (interacts with transferrin receptor)
- hepicidin and cytokines
- crosstalk between epithelial cells and other cells like macrophages
anaemia of chronic disease
- aka anaemia of inflammation
- functional iron deficiency ie where iron is in body, but not available for use
- due to inflammatory condition eg rheumatoid arthritis
- inflammatory condition causes increased production of cytokines
- elevated cytokines (eg IL6) released by immune cells causes…
increased production of hepicidin by liver
- inhibition of ferroportin
- causes decreased iron to be released from RES and decreased iron absorbtion in gut
- this means plasma iron is reduced
- leads to inhibtion of erythropoiesis in bone marrow
- anaemia
inhibition of erythropoietin production by kidneys
inhibition of erythropoiesis in bone marrow, leading to anaemia
iron homeostatis
- balance between loss and gain of iron from erythrocytes roughly equal
- due to erythrocyte destruction by macrophages (feeds into plasma iron pool) mainly in spleen
- due to erythropoiesis in bone marrow (takes away from plasma iron pool)
- plasma iron pool consists of Fe3+ bound to transferrin
- dietary iron absorbtion feeds into plasma iron pool
- iron stores (in liver) take away from and feed into plasma iron pool
- loss of iron eg by… menstrual bleeding, sweat, pregnancy and desquamination of epithelia
- note: there is no mechanism to regulate excretion of iron
desquamination is the shedding of the outermost membrane or a layer of tissue
iron deficiency
sign not a diagnosis, need to determine underlying issue
caused by…
* insufficient iron in diet, vegans and vegetarians at risk
* malabsorbtion of iron, vegans and vegetarians at risk
* bleeding eg menstruation, gastric bleeding due to chronic NSAID use
* increased requirement eg pregnancy or rapid growth
* anaemia of chronic disease eg inflammatory bowel disease
who are the most at risk groups of iron deficiency
- infants
- children (due to rapid growth and therefore higher requirements)
- women of child bearing age (due to menstruation)
- pregnant women (constant deficiency of iron in pregnancy)
- geriatric age group
- vegans and vegetarians due to poor diet
signs and symptoms of iron deficiency
physiological affects
- tiredness
- pallor
- reduced exercise tolerance (due to reduced oxygen carrying capacity)
- cardiac - anginal, palpitations
- increased respiratory rate
- headache, dizziness, light-headedness
other
- pica (unusual cravings)
- cold hands and feel
epithelial changes
- angular chelitis (red, swollen patches in corner of lips)
- glossy tongue with atrophy of lingual papillae
- koilonychia (spoon nails)
blood parameters in iron deficiency
- low mean corpuscular volume (MCV)
- low mean corpuscular haemoglobin concentration (MCHC)
- often elevated platelet count (compensatory mechanism, not well understood)
- normal or elevated WBC count
- low serum ferritin, serum iron and % transferrin saturation
- raised TIBC (total iron binding capacity)
- low reticulocyte haemoglobin content (CHr)
blood film features in iron deficiency
- red blood cells are microcytic and hypochromic (in chronic cases)
- anisopoikilocytosis: changes in size and shape of red cells
- sometimes target cells present (looks like bullseye)
testing for iron deficiency
- plasma ferritin used as indirect marker of total iron status (small amounts of ferritin are secreted into blood where it functions as an iron carrier)
- reduced plasma ferritin definitively indicates iron deficiency
- BUT normal or increased ferritin doesn’t exclude iron deficiency ★
★ this is because ferritin levels can also increase considerably in cancer, infection, inflammation, liver disease, alcoholism
treatment of iron deficiency
- dietary advice
- oral iron supplements (these can cause GI side effects so compliance with treatment is poor)
- intramuscular iron injections
- intravenous iron
- blood transfusion (only used if severe and at risk of cardiac compromise)
- should see improvement in symtoms
- 20g/L rise in Hb in 3 weeks shows treatment effective
why is iron excess dangerous (and what conditions are associated with this)
details on other cards
- excess iron can exceed binding capacity of transferrin
- excess iron deposited in organs as haemosiderin
- iron promotes free radical formation and organ damage
- involved in Fenton reaction producing hydroxyl and hydroperoxyl radicals from Fe2+ and Fe3+
- these can cause damage to cells by lipid peroxidation, damage to proteins and damage to DNA
conditions associated:
- transfusion associated haemosiderosis
- hereditary haemochromotosis
transfusion associated haemosiderosis
- sickle cell disease and thalassaemia are relaint on regular blood transfusions, so can lead to this over time
- repeated blood transfusions give gradual accumulation of iron
- iron chelating ages such as desferrioxamine can delay (but not stop) inevitable effects of iron overload
accumulation of iron (haemosiderin) in liver, heart and endocrine organs leads to…
* liver cirrhosis
* diabetes mellitus
* hypogonadism
* cardiomyopathy
* arthropathy
* slate grey colour of skin
hereditary haemochromatosis
- autosomal recessive disease
- caused by mutation in HFE gene
- HFE normally interacts with transferrin receptor (reducing its affinity for iron bound transferrin)
- HFE also promotes hepcidin expression
- mutated HFE therefore results in loss of negative influences on iron uptake and absorbtion
- too much iron enters cells; accumulates and causes damage
- treat with regular venesection
leads to..
- liver cirrhosis
- diabetes mellitus
- hypogonadism
- cardiomyopathy
- arthropathy (joint disease)
- increased skin pigmentation (ie looking tanned)
