S4 Iron Metabolism and Microcytic Anaemias Flashcards
What are microcytic anaemias?
Erythrocytes are smaller than normal
Also paler than normal (hypochromic) due to a reduced rate of Hb synthesis
From what two pathways can microcytic anaemias arise?
- Reduced haem synthesis
2. Reduced globin chain synthesis
What 4 types of anaemia result from reduced haem synthesis?
- iron deficiency
- lead poisoning
- anaemia of chronic disease
- sideroblastic anaemia
What 2 types of anaemia result from reduced globin chain synthesis?
- alpha thalassaemia
* beta thalassaemia
What does TAILS stand for?
Thalassaemia Anaemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anaemia
What is iron required for in the body?
- oxygen carriers - Hb in RBCs and myoglobin in myocytes
- it is a cofactor in many enzymes - cytochromes (oxidative phosphorylation), kerbs cycle enzymes, cytochrome P450 enzymes, catalase
Why don’t you want free iron in your body? How is this overcome?
It is very toxic to cells
By a complex regulatory system to ensure safe absorption, transportation and utilisation
Does the body have a mechanism for excreting iron?
No
What is ferrous iron? What is ferric iron?
Ferrous - Fe2+ (reduced form)
Ferric - Fe3+ (oxidised form)
Which form do you need iron in to be absorbed from the diet?
Ferrous iron (Fe2+) (reduced form)
How much iron do you need per day in the diet?
10-15mg/day
Where is iron absorbed from the diet?
Duodenum and upper part of jejunum
What is the best source of iron?
Haem iron (meat/fish)
How is iron from the diet absorbed?
- Fe3+ in the chyme in the s.intestine is reduced to Fe2+ by reductase (vitamin C is involved), Fe2+ is transported through the cotransporter DMT1 (iron in, H+ out) into enterocytes, haem iron is readily absorbed
- Fe2+ is either stored in ferritin or transported out of enterocytes via ferroportin
- In the blood, Fe2+ is oxidised to Fe3+ by hepaestin
- And is transported around the bloodstream bound to transferrin
What does hepcidin do? Where is it produced?
It inhibits ferroportin function (means less iron is absorbed from the diet/moved into bloodstream) - by inducing internalisation and degradation of ferroportin
Produced in liver
What factors affect absorption of non-haem iron from food (negatively and positively)
- negatively - tannins in tea, phytates, fibre (bind to non-haem iron) and antacids (remove acidic environment for ferrous to ferric reduction)
- positively - vitamin C and citrate (helps reduce ferric to ferrous iron and prevents formation of insoluble iron compounds)
What are the two storage complexes of iron? How much iron is stored?
- ferritin (soluble)
- haemosiderin (insoluble)
1g/1000mg
What is haemosiderin? Where does it accumulate?
Aggregates of clumped ferritin particles, denatured proteins and lipids
Accumulates in macrophages (in liver, spleen and marrow)
What is ferritin?
A globular protein complex with a hollow core with pores allowing iron to enter and be released
How much functional/availed iron is there?
About 2.3g
- Hb - 2g
- myoglobin - 300mg
- enzymes - 50mg
- transported iron - 3mg
How is iron taken up by cells?
- Fe3+ bound to transferrin binds to transferrin receptor and enters cytosol by receptor mediated endocytosis
- Fe3+ in endosome is released from transferrin by the acidic microenvironment and is reduced to Fe2+
- Fe2+ is transported into the cytosol via DMT1
- In the cytosol, Fe2+ can be stored as ferritin, exported by ferroportin or taken up by mitochondria for use in cytochrome enzymes
How much of the iron requirement is met by recycling of damaged/senescent RBCs? How does this happen?
About 80%
Macrophages phagocytose old RBCs (splenic macrophages or Kupffer cells in liver), the macrophage catabolises haem. The amino acids are reused and the iron is transported to blood (transferrin) or stored as ferritin in macrophage
What is iron absorption regulation dependent on? How is it controlled?
Dietary factors, body iron stores and erythropoiesis
- regulation of transporters
- regulation of receptors
- hepcidin and cytokines
- crosstalk between epithelial cells and macrophages
What increases hepcidin synthesis? What decreases it?
Increased by iron overload
Decreased by high erythropoietic activity
What is anaemia of chronic disease?
A functional iron anaemia - iron is present but isn’t available to bone marrow as it is stored in ferritin
It is an autoimmune disease that results in cytokines increasing hepcidin production or inhibiting erythropoietin
How is iron lost?
- pregnancy
- menstrual bleeding
- desquamation of epithelia
- sweat
Where are most of the iron stores?
The liver
What are 5 causes of iron deficiency?
- insufficient iron in diet (vegan/veggie)
- malabsorption of iron (vegan/veggie)
- bleeding (menstruation, gastric bleeding)
- increased requirement (pregnancy, growing)
- anaemia of chronic disease (autoimmune)
What groups are at risk of iron deficiency?
- infants
- children
- women of child bearing age
- geriatric age group
What are some physiological effects of anaemia?
- tiredness
- pallor
- reduced exercise tolerance
- cardiac problems
- increased respiratory rate
- headache, dizziness, light-headedness
What are 3 other signs and symptoms of anaemia?
- pica - craving ice or dirt (rare)
- cold hands and feet
- epithelial changes - angular cheilitis, glossitis, koilonychia
What are the results of a FBC for iron deficiency anaemia?
- low MCV
- low MCHC (low Hb)
- high platelet count
- normal/high WCC
- low serum ferritin, serum iron and %transferrin saturation
- high total iron binding capacity
- low reticulocyte Hb content
What does a blood smear look like for iron deficiency anaemia?
- microcytic and hypochromic RBCs
- anisopoikilocytosis (variation in size and shape of cells)
- pencil cells and target cells
What can be used to test for iron deficiency?
- plasma ferritin - if reduced, iron deficiency is present, if normal/increased, doesn’t exclude iron deficiency
- CHr (reticulocyte Hb content) - test for functional iron deficiency
When else is CHr low other than in iron deficiency?
In thalassaemia
How do you treat iron deficiency (in the order of which you do first)
- dietary advice
- oral iron supplements
- intramuscular iron injections
- IV iron
- blood transfusion (only used if cardiac compromise is likely)
Which is excess iron dangerous? How is excess iron stored?
It promotes free radicals formation an organ damage
Stored as haemosiderin
What is the reaction that means excess iron produced free radicals?
Fenton reaction
Fe2+ + H2O2 —> OH* + OH -
Fe3+ + H2O2 —> OOH* + H+
How do hydroxyl and hydroperoxyl radicals damage cells?
- lipid peroxidation
- damage to proteins
- damage to DNA
What is transfusion associated haemosiderosis? When can it occur?
Repeated blood transfusions can lead to a gradual accumulation of iron (in 400ml = 200mg iron)
When giving transfusions to treat Thalassaemia and sickle cell anaemia
How can you delay the iron overload?
By using iron cheating agents libel desferrioxamine
What can accumulation of iron (haemosiderin) do to the liver, heart and endocrine organs? What does the skin look like?
Liver - liver cirrhosis
Heart - cardiomyopathy
Endocrine organs - hypogonadism, diabetes mellitus
‘Slate grey’
What is hereditary haemochromatosis?
An autosomal recessive disease caused by mutation of the HFE gene
What does normal HFE protein do? What does mutated HFE protein do?
Interacts with the transferrin receptor and reduced its affinity for iron bound transferrin
Can’t bind to transferrin receptors and also inhibits hepcidin production so negative influence on iron uptake is lost
Where does iron accumulate in hereditary haemochromatosis?
In end organs
How do you treat hereditary haemochromatosis?
With venesection (removing blood)
What does the skin look like in someone with hereditary haemochromatosis?
Increased skin pigmentation
What can hereditary haemochromatosis lead to?
- liver cirrhosis
- diabetes mellitus
- hypogonadism
- cardiomyopathy
- arthropathy (disease of joints)
