8. Iron metabolism Flashcards

1
Q

What is microcytic anaemia caused by?

A
  • Reduced haem synthesis

- Reduced globin chain synthesis

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2
Q

What anaemias are due to reduced haem synthesis(which results in microcytic anaemias)?

A
  • iron deficiency - not enough iron for haem synthesis
  • lead poisoning - lead inhibits enzymes in haem synthesis
  • anaemia of chronic disease - hepcidin results in functional iron deficiency
  • sideroblastic anaemia - inherited defect in haem synthesis
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3
Q

What anaemias are due to reduced globin chain synthesis(which results in microcytic anaemias)?

A
  • alpha thalassaemia- deletion/ loss of function of one or more of the four alpha globin genes
  • beta thalassaemia- mutation in beta globin genes leading to reduction or absence of the beta globin
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4
Q

What happens to RBCs in microcytic anaemias?

A
  • smaller than normal (microcytic)

- often paler than normal (hypochromic)

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5
Q

How is the rate of haemoglobin synthesis in microcytic anaemia?

A

Reduced rate of haemoglobin synthesis

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6
Q

What are the five main types of microcytic anaemias?

A
T : thalassaemia 
A : anaemia of chronic disease 
I : iron deficiency 
L : lead poisoning 
S : sideroblastic anaemia
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7
Q

What is iron required for?

A
• Oxygen carriers:
- Haemoglobin in red cells
- Myoglobin in myocytes
• Co-factor in many enzymes:
- Cytochromes (oxidative phosphorylation)
- Krebs cycle enzymes
- Cytochrome P450 enzymes (detoxification)
- Catalase
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8
Q

Why are complex regulatory systems used to ensure the safe absorption, transportation and utilisation of iron?

A

Free iron potentially very toxic to cells - generates free radicals —> oxidative damage

Body has no mechanism for excreting iron

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9
Q

Which oxidation states can iron exist in?

A
  • ferrous iron - reduced form Fe2+

- ferric iron - oxidised form Fe3+

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10
Q

What does dietary iron consist of?

A
  • haem iron - Fe 2+
  • non-haem - mixture of Fe 2+ and Fe 3+

Ferric iron must be reduced to ferrous iron before it can be absorbed from the diet

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11
Q

Under what conditions is ferrous iron converted to ferric iron?

A
  • Oxidation

* Alkaline

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12
Q

Under what conditions is ferric iron converted to ferrous iron?

A
  • Reduction

* Acidic

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13
Q

How much iron do you need daily?

A

10-15 mg

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14
Q

Where is iron absorbed?

A

duodenum and upper jejunum

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15
Q

What are good sources of haem iron?

A

Liver, kidney, beef, chicken, duck, pork, salmon, tuna

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16
Q

What are good sources of non-haem iron?

A

Fortified cereals, raisins, beans, figs, barley, oats, rice, potatoes

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17
Q

How is iron absorbed?

A
  • haem iron can pass through the membrane into the cytoplasm of the enterocyte where it is degraded by the enzyme haem oxygenate to release Fe2+
  • for non-haem iron, duodenal cytochrome B reductase on apical surface of enterocytes converts ferric Fe3+—> ferrous Fe2+ - vit C donates this electron
  • ferrous enters enterocytes via DMT1 - every molecule in, sends a proton out into the chyme
  • Fe2+ released from both haem and non-haem iron can either be stored as ferritin (Fe3+)
  • or leaves basolateral surface into the blood via ferroportin
  • Hephaestin facilitates conversion back to Fe3+ needed to bind to transferrin to be transported in blood
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18
Q

What factors have a negative influence of absorption of non-Haem iron from food?

A
  • tannins in tea: bind non-haem iron in intestine which reduces absorption
  • phytates (e.g. chapattis, pulses): binds to non-haem
  • fibre: binds to non-haem
  • antacids e.g. graviscon: reduces acidity needed to reduce ferric —> ferrous
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19
Q

What factors have a positive influence on non-haem absorption ?

A

Vitamin C and citrate:

  • prevents formation of insoluble iron compounds
  • helps reduce ferric to ferrous iron: provides acidity and also an electron donor
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20
Q

What are examples of functional (available) iron?

A

iron associated with proteins/ enzymes and transported around the body

  • Hb
  • myoglobin
  • enzymes e.g. cytochromes
  • transported iron (in serum mainly in transferrin)
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21
Q

How much iron does the body contain? How much is stored?

A

3350 mg with 1000 mg stored

22
Q

Name and describe two intracellular protein-iron complexes that are used to store iron?

A

Ferritin:

  • soluble, globular protein complex with hollow core
  • pores to allow iron in and out
  • cytosolic , small amounts secreted into serum for use as a n iron carrier so a ferritin blood test is a useful diagnostic

Haemosiderin:

  • only found within cells
  • aggregates of clumped ferritin particles, denatured ferritin and denatured protein and lipid
  • Unlike ferritin, the iron within deposits of haemosiderin is very poorly available
  • accumulates in macrophages, especially in the liver, spleen and BM
23
Q

How do cells take up iron?

A
  • Fe3+ iron bound transferrin binds to transferrin receptor and enters the cytosol via receptor- mediated endocytosis
  • ferric iron within an endosome is released by acidic micro environment and reduced to ferrous iron
  • ferrous iron can now directly enter the cytosol. Transported via DMT1
  • once in the cytosol, can be stored in ferritin, exported out and recycled by ferroportin (FPN1) or taken up by the mitochondria for use in cytochrome enzymes
24
Q

How is iron recycled?

A
  • more than 80% of iron requirement is met by recycling damaged/ senescent RBCs - only small amount from diet
  • old RBCc engulfed by macrophages(phagocytosis) - mainly splenic macrophages/ kupffer cells of liver
  • haem that is released from RBCs is catabolised by macrophages
  • amino acids are reused and iron is exported to blood (transferrin) to storage as ferritin in macrophage
25
Q

How is iron absorption regulated?

A
  • depends on dietary factors, body iron stores and erythropoiesis
  • dietary levels sensed by enterocytes
  • control mechanisms include:
  • regulation of transporters e.g. ferroportin
  • regulation of receptors e.g. transferrin receptor and HFE protein (interacts with transferrin receptor)
  • hepcidin and cytokines
  • crosstalk between epithelial cells and other cells like macrophages
26
Q

What does hepcidin do?

A
  • inhibits dietary iron absorption from SI and release of iron from macrophages
  • increased in iron overload
  • decreased by high RBC activity
  • induces internalisation and degradation of ferroportin (pushes it inside enterocyte) so less iron can be absorbed into the blood and less can be recycled from RBCs in macrophages
27
Q

What happens in anaemia of chronic disease?

A
  • inflammatory condition (e.g. rheumatoid arthritis, chronic infection, malignancy) means cytokines such as IL6 are released by immune cells
  • these increase production of hepcidin by liver: inhibition of ferroportin means decreased iron release from reticuloendothelial system and decreased iron absorption in gut so plasma iron is reduced
  • cytokines also inhibit EPO production in kidneys
  • all these factors inhibit erythropoiesis in BM
  • cytokines also directly inhibit erythropoiesis in BM
  • These 3 factors all lead towards inhibition of eryhtropoiesis in BM
28
Q

How are iron levels controlled? (Homeostasis)

A
  • amount of iron absorbed in diet = amount lost by desquamation of epithelia, menstrual bleeding, sweat and pregnancy
  • RBCs constantly being destroyed by macrophages releasing iron into plasma iron pool(Fe3+ bound to transferrin) which is used up to produce eryhtrocytes in the same amounts in bone marrow
  • iron can be stored in the liver
29
Q

How is iron excretion regulated?

A

No mechanism to do so!

30
Q

What causes iron deficiency?

A
  • insufficient iron in diet - e.g. Vegan & vegetarian diets
  • malabsorption of diet - e.g vegan and vegetarian diets, Gastrectomy, coeliac disease
  • bleeding e.g. menstruation, gastric bleeding due to chornic NSAID usage
  • increased requirement- e.g in pregnancy/ rapid growth
  • anaemia of chronic disease - e.g. inflammatory bowel disease
31
Q

Is iron deficiency a diagnosis?

A

No, iron deficiency is a sign not a diagnosis

32
Q

Which groups are at risk of iron deficiency?

A
  • infants
  • children
  • women of child bearing age
  • geriatric age group
33
Q

What are signs and symptoms of iron deficiency?

A
• Physiological effects of anaemia
- tiredness
- pallor
- reduced exercise tolerance due to reduced oxygen carrying capacity
- angina, palpitations, heart failure
- increase resp rate
- headache, dizziness, light-headedness
•  pica - unusual cravings (dirt, ice)
•  cold hands and feet
• Epithelial changes
- angular cheilitis 
- glossitis of tongue with atrophy of lingual papillae
- koilonychia - spoon nails

risk of neurocognitive defects in developing children

34
Q

What do FBC results of iron deficiency show?

A
  • low MCV
  • low MCHC
  • elevated platelet count
  • normal/ elevated WBC count
  • low serum ferritin, serum iron and %transferrin saturation
  • raised TIBC - total iron binding capacity
  • low reticulocyte Hb (CHr)
35
Q

What does a peripheral blood smear of iron deficient patient show?

A
  • microcytic, hypochromic RBCs in chronic cases
  • anisopoikilocytosis - different sizes and shapes
  • sometimes pencil and target cells
36
Q

What two ways can you test for iron deficiency?

A

plasma ferritin:

  • indirect marker of total iron status - Ferritin is predominantly a cytosolic protein but small amounts are
    secreted into blood where it functions as an iron carrier
  • reduction definitely indicates iron deficiency
  • BUT.. Normal or increased ferritin does not exclude iron deficiency (ferritin levels can also increase considerably in cancer, infection, inflammation, liver disease, alcoholism can mask)

CHr (reticulocyte Hb content):

  • better as it remains low during inflammatory responses
  • however it is also low in patients with thalassaemia so cant be used in this scenario
37
Q

How is iron deficiency treated?

A
  • dietary advice
  • oral supplements (ferrous sulphate) - GI side effects
  • intramuscular iron injections
  • intravenous iron
  • blood transfusion in severe cases, where imminent cardiac compromise is likely
38
Q

What should be the response to iron deficiency treatment?

A
  • improvement in symptoms

- 20g/L rise in Hb in 3 weeks

39
Q

Why is excess iron dangerous?

A
  • excess iron can exceed binding capacity of transferrin
  • Excess iron deposited in organs as haemosiderin
  • iron promotes free radical formation and organ damage through the Fenton reaction
  • hydroxyl and hydroperoxyl radicals cause damage to cells by removing electrons = lipid peroxidation, damage to proteins and DNA
40
Q

What is transfusion associated haemosiderosis?

A
  • repeated blood transfusion = accumulation of iron in liver, heart and endocrine organs
  • 400ml blood contains 200mg iron
  • this can be a problem in transfusion dependent anaemias such as thalassaemia and sickle cell anaemia
  • iron chelating agents such as desferrioxamine can delay but not stop iron overload
41
Q

What are symptoms of transfusion associated haemosiderosis?

A
  • liver cirrhosis
  • diabetes mellitus
  • hypogonadism
  • cardiomyopathy
  • arthropathy
  • slate grey skin colour
42
Q

What is hereditary haemochromatosis?

A
  • autosomal recessive
  • mutation in HFE gene on chromosome 6
  • HFE protein normally interacts with transferrin receptor to reduce its affinity for iron bound transferrin
  • mutated HFE cant bind to transferrin so this negative influence on iron uptake is lost
  • HFE also has a negative influence on hepcidin production so a negative influence on iron uptake is lost once more
  • too much iron enters cells - accumulates causing damage
43
Q

Where does iron build up in haemochromatosis?

A

Liver, pancreas, heart, pit gland, joints, skin

44
Q

What are symptoms of hereditary haemochromatosis?

A
  • liver cirrhosis —> can lead to cancer
  • type 1 diabetes mellitus —> detruction of beta islet cells in pancreas
  • hypogonadism
  • cardiomyopathy —> if absorbed in heart
  • arthropathy - joints
  • increased skin pigmentation - bronze
  • tissue fibrosis
45
Q

How is hereditary haemochromatosis treated?

A

Venesection - periodically draw blood

46
Q

What is haemosiderosis?

A

The process of depositing iron in tissues

47
Q

Why does it take a while for women to be diagnosed with haemochromatosis?

A

Menstrual bleeding - usually diagnosed after menopause

48
Q

What is total iron binding capacity?

A

Blood test taken to see how much more iron the blood can carry

If less capacity, means transferrin is saturated

49
Q

What do blood tests show for haemochromatosis?

A

Transferrin is saturated

Total iron binding capacity decreases

More ferritin produced

50
Q

What are microcytic anaemias?

A

Microcytic anaemias are those anaemias that result in erythrocytes being smaller than normal (i.e. microcytic) due to a reduced rate of haemoglobin synthesis. Cells are often also hypochromic (paler than normal) due to the reduced haemoglobin content.