Haemopoiesis, Erythropoiesis and Iron

Question 1

What is haemopoiesis

Answer 1

Production of blood cells in the bone marrow

Question 2

Briefly outline the steps in the formation of different blood cells

Answer 2

• Platelets bud of large megakaryocyte
• Erythrocytes develop through erythropoiesis
• Myeloblasts differentiate into granulocytes and monocytes
  
  • Granulocytes include basophils, eosinophils and neutrophils
• Lymphocytes develop further in the fetal liver and bone marrow

Question 3

Discuss the negative feedback loop of erythropoiesis

Answer 3

1. Reduced oxygen concentration detected in interstitial peritubular cells in kidney
2. Increased production of erythropoietin (hormone) released from kidneys
3. Erythropoietin stimulates maturation, where erythroblasts extrude their nucleus and most of their organelles forming reticulocytes (immature red blood cells) which are released into the circulation
4. Reticulocytes extrude their remnants including mitochondria and ribosomes and mature to red blood cells
5. Haemoglobin rises and plasma oxygen concentration rises
6. Erythropoietin production falls

Question 4

Outline the reticuloendothelial system

Answer 4

• Reticuloendothelial system - controls and removes blood cells
  
  • Network in blood and tissues containing phagocytic cells - monocytes, macrophages, kupffer cells, microglial cells
  • Phagocytose blood cells and recycle as much as possible
  • Main organs are spleen and liver
  • As blood passes through spleen, it can dispose of blood cells - especially old or damaged
    
    • Globin portion degraded to amino acids and haem portion metabolised to bilirubin
      - Bilirubin travels to liver and conjugated and secreted as bile

Question 5

Describe the structure and role of the red cell membrane

Answer 5

• Red cell membrane contains proteins spectrin, Ankryin, band 3 and protein 4.2
  
  • Facilitate vertical interactions with the cytoskeleton of the cell to maintain biconcavity
    
    • Gene mutations in membrane proteins can result in disease such as hereditary spherocytosis which cause red blood cells to lose their biconcavity

Question 6

Explain the structure of haemoglobin

Answer 6

• Haemoglobin - tetramer of 2 pairs of globin chains each with its own haem group (α2ß2 tetramer)
  
  • Globin chains protect haem molecule from oxidation, confer solubility and permits variation in oxygen affinity
  • Exist in the R and T state
  • T state - tense state - heme group not exposed so difficult to bond
  • R state - relaxed state - exposed group (more common form)
  • Oxygen binding promotes stabilisation of the R state (higher affinity state)
    
    • Promote oxygen to higher level, allowing new oxygen to bind at high affinity (cooperative bonding)
  • Oxygen binding curve for haemoglobin sigmoidal due to cooperative binding of oxygen
    
    • Binding affinity for oxygen increases as more oxygen molecules bind to haemoglobin subunits
    • Sigmoidal binding curve means that oxygen can be efficiently carried from the lungs to the tissues

Question 7

What factors cause a rightward shift of the oxygen dissociation curve

Answer 7

Increase in:

• CO2
• Acidity
• DBG (2,3-bisphosphoglycerate)
• Exercise
• Temperature

Question 8

What is the significance of foetal haemoglobin

Answer 8

• HbF is the major haemoglobin in foetal blood

- Higher binding affinity for oxygen than HbA which allows transfer of oxygen to foetal blood supply from the mother

Question 9

When is iron in the stored or functional form

Answer 9

• Functional form - haemoglobin, myoglobin, tissue iron, transported iron
• Stored form - ferritin (soluble), hemosiderin (macrophage iron, insoluble)

Question 10

Where does iron come from within the body

Answer 10

• Most (80%) active iron comes from recycling within the body
  
  • Macrophages ‘eat’ old senescent red blood cells
  • Mainly splenic macrophages and Kupffer cells of the liver
  • 95% of stored iron in liver tissue is found in hepatocytes as ferritin
  • Hemosiderin constitutes remaining 5% and found mainly in Kupffer cells

Question 11

What is the difference between haem and non-haem iron

Answer 11

• Eating meat takes in haem iron (red blood cells)
  
  • Present in the ferrous form (Fe2+)
• Non-haem iron sources include grains and pulses
  
  • Present in the ferric form (Fe3+) - needs to be converted to ferrous form before being transported across intestinal equilibrium

Question 12

Outline iron metabolism

Answer 12

• Iron exposed to stomach acid where Fe3+converted to Fe2+ and binds to transferrin
• Taken up in duodenum and jejunum where it can be converted to ferritin or enters blood stream
• Iron exported out of cell by ferroportin
• Iron in blood stream bound to transferrin and transported to bone marrow for erythropoiesis or taken up by macrophages in reticuloendothelial system as a storage pool
• Foetal enterocytes have receptors for lactoferrin - primary source of iron in infants

Question 13

In what condition is iron absorption at its best

Answer 13

• Absorption of iron best in acidic conditions - iron tablets taken with orange juice
  
  • Some foods precipitate iron and inhibits absorption such as tea

Question 14

How is iron absorption regulated

Answer 14

• Primarily regulated by hepcidin whichh is expressed in the liver
  
  • Bind to ferroportin resulting in its degradation and thus prevents iron from leaving cell into blood
• Also depends on dietary factors, body iron stores and erythropoiesis
• Dietary iron levels are sensed by the villi of enterocytes

Question 15

In what forms are iron stored as

Answer 15

Ferritin and haemosiderin

Question 16

How is iron deficiency caused and what are its symptoms

Answer 16

• Iron deficiency can be due to insufficient intake or increased use (pregnancy, bleeding)
  
  • Symptoms include tiredness, reduced oxygen carrying capacity, cardiac symptoms (angina, heart failure), brittle nails

Question 17

How will cells look in iron deficiency

Answer 17

• Cells will look small and pale (pallor)
  
  • Hypochromic - low haemoglobin content
  • Microcytic - small red blood cells, low mean cell volume
  • Change in size and shape
  • Low reticulocyte haemoglobin content (CHR)

Question 18

How do you test for iron deficiency

Answer 18

• Ferritin common measure for iron levels
  
  • Low ferritin means they are iron deficient
  • Normal or increased levels do not mean iron excess as increased in inflammation, alcoholism etc
• CHR remains low during inflammation, better test but CHR low in patients with thalassaemia

Question 19

How is iron deficiency treated

Answer 19

• Dietary advice, oral iron supplements, intravenous iron, transfusion
  
  • Iron supplements taken on an empty stomach to allow it to be absorbed
  • Many negative side effects including diarrhoea and constipation

Question 20

What is the pathogenesis of hereditary haemochromatosis

Answer 20

• Autosomal recessive
• Mutation in HFE gene on chromosomes 6
• HFE protein competes with transferrin to bind with transferrin receptor
• Mutated HFE cannot bind so transferrin has no competition
  
  • Excessive absorption of dietary iron into cells
  • No system for iron excretion - iron accumulation in tissues disrupts function

Question 21

What are the most affected sites and therefore symptoms of hereditary haemochromatosis

Answer 21

• Most susceptible organs are liver, adrenal glands, heart, joints, pancreas
• Present with cirrhosis, adrenal insufficiency, heart failure, arthritis, diabetes

Question 22

What is the treatment for hereditary haemochromatosis

Answer 22

Treat with venesection (remove blood) to remove iron