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
- What causes Microcytic anaemia?
- Reduced haem synthesis
- Reduced globin chain synthesis: alpha or beta thalassaemia
Identify the full list of causes for Microcytic anaemic (hint: acronym - cats have t****)?
Describe some of the functions of iron
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
Why is the regulation of iron important?
- Free iron potentially very toxic to cells
- Complex regulatory systems to ensure the safe absorption, transportation & utilisation
- MOST IMPORTANT - Body has no mechanism for excreting iron
What two common oxidation states does iron exist in?
- Ferrous iron (Fe2+) - Reduced form. ABSORBED FORM
- Ferric iron (Fe3+) most common - Oxidised form.
What is dietary iron a mix of?
Haem iron (Fe2+) and non-haem (mixture of Fe2+ and Fe3+).
Identify some sources of haem and non haem iron
Where does the absorption of iron occur?
•duodeneum and upper jujenum
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
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)
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)
Antacids (e.g. Gaviscon)
What is ferous reductase?
- Works in combination with Vitamin C
- Catalyses: Fe3+ --> Fe2+
- Found on the apical surfaces of enterocytes
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
What is Ferroportin?
- Found on the basolateral surface of the enterocyte
- Allows Fe2+ to pass across the enterocyte into the blood
What is Transferrin
- Transport molecule of ferric ion (Fe3+)
- Two binding sites for Fe3+ - can then be transported around the body
What are the two types of iron stores
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)
Identify the two main sources of stored iron?
- Ferritin - Soluble
- Haemosiderin - Insoluble
What is Ferritin?
- Globular protein complex with hollow core
- Pores allow iron to enter and be released.
What is haemosiderin?
- Aggregates of clumped ferritin particles, denatured protein & lipid.
- Accumulates in macrophages, particularly in liver, spleen and marrow.
Describe the uptake of cellular iron?
- Fe3+ bound transferrin binds transferrin receptor and enters the cytosol receptor-mediated endocytosis.
- Fe3+ within endosome released by acidic microenvironment and reduced to Fe2+ .
- The Fe2+ transported to the cytosol via DMT1. 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
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.
Describe the regulation of iron absorption
- Enterocytes - sense dietary iron levels
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
Describe the two effects of Hepcidin on iron
- Inhibits absorption of iron in the gut
- Release of stored iron in reticuloendothelial system
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
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
Describe the mechanism of anaemia of chronic disease
Describe the effect of cytokine release in anaemia of chronic disease
Increased hepcidin production - reduced iron absorption and iron release from RES)
Reduced EPO production from the kidney - reduced erythropoeisis
What are some causes of iron deficiency
- Insufficient iron in diet e.g. Vegan & vegetarian diets
- Malabsorption of iron e.g. Vegan & vegetarian diets
- Bleeding e.g. Menstruation, peptic ulcer
- Increased requirement e.g. Pregnancy, rapid growth
- Anaemia of chronic disease e.g. inflammatory bowel disease
What groups are most at risk from iron deficiency
- Women of child bearing age
- Geriatric age group
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
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
Identify some epithelial changes that occur in anaemia
- Angular cheilitis
- Koilonychia (spoon nails)
- Glossy tongue with atrophy of ling
Identify some physiological effects of anaemia
- Reduced exercise tolerance (due to reduced oxygen carrying capacity)
- Cardiac – angina, palpitations, development of heart failure
- Increased respiratory rate
- Headache, dizziness, light-headedness
How do we test for iron deficiency
Plasma ferritin - decrease definitively indicates iron deficiency BUT.. Normal or increased ferritin does not exclude iron deficiency
CHr - reticulocyte haemoglobin content
How do we treat iron deficiency
- Dietary advice
- Oral iron supplements
- Intramuscular iron injections
- Intravenous iron
- Blood transfusion
Describe the dangers of excess iron
- Exceeds the binding capacity of transferrin
- Excess iron deposited in organs as haemosiderin
- Free radical formation & organ damage
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
Describe two examples of excess iron
- Transfusion associated haemosiderosis
- Hereditary haemochromostosis (HH)
Describe Hereditary Haemochromatosis
Autosomal recessive disease
Mutation in HFE gene which codes for HFE protein
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?
- HFE interacts with transferrin receptor
- It reduces its affinity for iron bound transferrin
- Cannot bind to transferrin - loss of negative influence uptake
- Net effect: Too much iron taken up into cells
How do we treat hereditary haemochromatosis