4b - Iron metabolism and microcytic anaemias Flashcards Preview

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Flashcards in 4b - Iron metabolism and microcytic anaemias Deck (47):
1

What is Microcytic anaemia? 

  • Reduced rate of haemoglobin synthesis 
  • Erythrocytes smaller than normal (microcytic) 
  • Cells often paler than normal (hypochromic) - not as red bc of less

2

  1. What causes Microcytic anaemia? 

  1. Reduced haem synthesis 
  2. Reduced globin chain synthesis: alpha or beta thalassaemia

3

Identify the full list of causes for Microcytic anaemic (hint: acronym - cats have t****)?

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4

Describe some of the functions of iron

  1. Oxygen carriers: Haemoglobin in red cells; Myoglobin in myocytes
  2. Co-factor in many enzymes: Cytochromes (oxidative phosphorylation) Krebs cycle enzymes Cytochrome P450 enzymes (detoxification) Catalase

5

Why is the regulation of iron important? 

  1. Free iron potentially very toxic to cells
  2. Complex regulatory systems to ensure the safe absorption, transportation & utilisation
  3. MOST IMPORTANT - Body has no mechanism for excreting iron  

6

What two common oxidation states does iron exist in? 

  1. Ferrous iron (Fe2+) - Reduced form. ABSORBED FORM
  2. Ferric iron (Fe3+) most common - Oxidised form. 

7

What is dietary iron a mix of? 

Haem iron (Fe2+) and non-haem (mixture of Fe2+ and Fe3+).

8

Identify some sources of haem and non haem iron

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9

Where does the absorption of iron occur? 

•duodeneum and upper jujenum

10

Describe the absorption of dietary iron 

  • Ingestion if iron in the haem form (meat) or non haem form 
  • Duodenum and upper jujenum - intestinal enterocytes – cells where our nutrients are absorbed from the gut BARRIER
  • Chyme is the mixture of food leaving the stomach into the small intestine. Contain haem iron. 
  • Movement: Chyme --> Enterocyte --> Blood 
  • Food must be absorbed across our enterocyte to get them into the blood
  • Haem can be absorbed by the intestinal enterocyte --> HAEM INSIDE OUR CELL 
  • Non haem composed of ferric and ferrous. Can only absorb ferrous (fe2+)
  • So Fe3+ must be converted to Fe2+ - ferrous reductase works in combination with Vitamin c
  • DMT 1 – Divalent metal transporter 1 - two charges – Fe2+ transport. Co transporter – when one iron comes in a H+ ion leaves
  • Fe2+ once in the cell can be stored in the Fe 3+- linked to protein ferritin - function to store iron
  • Ferroportin - allows Fe2+ to pass across the enterocyte into the blood
  • Transferrin – transport molecule. Ferric ion. Two binds sites - can then be tansported around the body

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11

Which factors positively affect the absorption of non-Haem iron from food? 

 

  • Vitamin C and citrate - prevent formation of inbsoluble iron compounds
  • Vit C help reduces ferric to ferrous iron (works with ferric reductase) 

12

Which factors negatively affect the absorption of non-Haem iron from food? 

  • Tannins (in tea)  - found in tea. Combine non haem iron in the intestine. Reduces absorption of iron. Discourage anaemic patients from drinking tea. 
  • Phytates (e.g. Chapattis, pulses) 
  • Fibre 
  • Antacids (e.g. Gaviscon) 

13

What is ferous reductase? 

  • Works in combination with Vitamin C 
  • Catalyses: Fe3+ --> Fe2+ 
  • Found on the apical surfaces of enterocytes

14

What is DMT 1 – Divalent metal transporter 1? 

  • Located on the apical surface of intestinal enterocyte
  • Co transporter - two charges – Fe2+ transport
  • When one iron comes in a H+ ion leaves

15

What is Ferroportin?

  • Found on the basolateral surface of the enterocyte
  • Allows Fe2+ to pass across the enterocyte into the blood

16

What is Transferrin

  • Transport molecule of ferric ion (Fe3+)
  • Two binding sites for Fe3+ - can then be transported around the body

17

What are the two types of iron stores

  1. Functional 
  2. Stored 

18

What functional (available) iron is there? 

  • Haemoglobin (~2000 mg)
  • Myoglobin (~300 mg)
  • Enzymes e.g. cytochromes (~50 mg)
  • Transported iron (in serum mainly in transferrin) (~3 mg)

19

Identify the two main sources of stored iron? 

  1. Ferritin - Soluble 
  2. Haemosiderin - Insoluble 

20

What is Ferritin? 

  • Globular protein complex with hollow core
  • Pores allow iron to enter and be released.

21

What is haemosiderin? 

  • Aggregates of clumped ferritin particles, denatured protein & lipid.
  • Accumulates in macrophages, particularly in liver, spleen and marrow.

22

Describe the uptake of cellular iron? 

  1. Fe3+ bound transferrin binds transferrin receptor and enters the cytosol receptor-mediated endocytosis.
  2. Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+ .
  3. The Fe2+ transported to the cytosol via DMT1. 4
  4. Once in the cytosol, Fe2+ can be stored in ferritin, exported by ferroportin (FPN1), or taken up by mitochondria for use in cytochrome enzymes

23

Describe iron recycling

  • Most (>80%) of iron requirement met from recycling damaged or senescent red blood cells
  • Old RBCs engulfed by macrophages (phagocytosis)
  • Splenic macrophages and Kupffer cells of liver
  • Macrophages catabolise haem released from red blood cells
  • Amino acids reused and Iron exported to blood (transferrin) or returned to storage pool as ferritin in macrophage.

24

Describe the regulation of iron absorption

  • Transporters 
  • Receptors 
  • Cytokines 
  • Hepcidin 
  • Enterocytes - sense dietary iron levels

25

What is Hepcidin

  • Peptide hormone made by the liver 
  • Key negative regulator of iron absorption
  • REDUCES IRON CONCENTRATION (NEGATIVE)
  • Released into bloodstream 
  • Effect ferraportin receptor
  • Causes internalisation and degradisation of ferroportin protein --> blocks transport of iron 

26

Describe the two effects of Hepcidin on iron 

 

  1. Inhibits absorption of iron in the gut 
  2. Release of stored iron in reticuloendothelial system 

27

What is anaemia of chronic disease? 

A common cause of anaemia (2nd worldwide after iron deficiency) associated with chronic inflammatory conditions such as rheumatoid arthritis, chronic infections (e.g. tuberculosis) and malignancy

28

How does chronic disease cause anaemia? 

  • Release of IL6 – can inhibit erythropoesis causing a reduction in RBCs​
  • Reduction in RBC production​
  • Hepcidin – is inhibiting ferroportin ​
  • Reduced amount of iron in the blood plasma

29

Describe  the mechanism of anaemia of chronic disease

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30

Describe the effect of cytokine release in anaemia of chronic disease

  1. Increased hepcidin production - reduced iron absorption and iron release from RES)
  2. Reduced EPO production from the kidney - reduced erythropoeisis 

31

What are some causes of iron deficiency 

  1. Insufficient iron in diet e.g. Vegan & vegetarian diets 
  2. Malabsorption of iron e.g. Vegan & vegetarian diets 
  3. Bleeding e.g. Menstruation, peptic ulcer 
  4. Increased requirement e.g. Pregnancy, rapid growth 
  5. Anaemia of chronic disease e.g. inflammatory bowel disease

32

What groups are most at risk from iron deficiency 

  • Infants
  • Children
  • Women of child bearing age
  • Geriatric age group

33

Identify some peripheral blood smear results arising from iron deficiency anaemia

  • RBCs are microcytic and hypochromic in chronic cases
  • Anisopoikilocytosis: change in size and shape
  • Sometimes pencil cells and target cells

34

Identify some blood film features of iron deficiency anaemia

Full Blood Count 

  • Low MCV
  • Low Hb
  • Low MCHC
  • High Platelet count 
  • Low serum ferritin/ iron/ tranferrin
  • Low reticulocyte count

35

Identify some epithelial changes that occur in anaemia

 

  • Angular cheilitis
  • Koilonychia (spoon nails)
  • Glossy tongue with atrophy of ling

36

Identify some physiological effects of anaemia

  • Tiredness
  • Pallor
  • Reduced exercise tolerance (due to reduced oxygen carrying capacity)
  • Cardiac – angina, palpitations, development of heart failure
  • Increased respiratory rate
  • Headache, dizziness, light-headedness

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38

How do we test for iron deficiency 

  1. Plasma ferritin - decrease definitively indicates iron deficiency BUT.. Normal or increased ferritin does not exclude iron deficiency
  2. CHr - reticulocyte haemoglobin content

39

How do we treat iron deficiency

  • Dietary advice
  • Oral iron supplements
  • Intramuscular iron injections
  • Intravenous iron
  • Blood transfusion

40

Describe the dangers of excess iron

 

  • Exceeds the binding capacity of transferrin
  • Excess iron deposited in organs as haemosiderin
  • Free radical formation & organ damage

41

How does excess iron promote free radical damage 

 

  • Fenton reaction
  • Hydroxyl and hydroperoxyl radicals can cause damage to cells: Lipid peroxidation • Damage to proteins • Damage to DNA

42

43

Describe two examples of excess iron 

  1. Transfusion associated haemosiderosis
  2. Hereditary haemochromostosis (HH)

44

Describe Hereditary Haemochromatosis

Autosomal recessive disease

Mutation in HFE gene which codes for HFE protein

45

In hereditary haemochromatosis, what is the role of the HFE protein (normally) and how is this this altered?

What impact does this have on iron absorption? 

Normal

  • HFE interacts with transferrin receptor
  • It reduces its affinity for iron bound transferrin
  •  

Mutate HFE

  • Cannot bind to transferrin - loss of negative influence uptake
  • Net effect: Too much iron taken up into cells 

 

46

How do we treat hereditary haemochromatosis 

Venesection

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