Microcytic anaemia and Iron metabolism

Question 1

microcytic anaemias

Answer 1

• Reduced rate of haemoglobin synthesis
• Erythrocytes smaller than normal (microcytic)
• Cells often paler than normal (hypochromic)
  
  • Less haemoglobin

Question 2

microcytic anaemias are due to

Answer 2

1) reduced haem synthesis
2) reduced glonbin chain synthesis

Question 3

1) Reduced haem synthesis causes

Answer 3

• Iron deficiency
  
  • Insufficient iron for haem synthesis
• Lead poisoning (rare)
  
  • Acquire defect
  • Lead inhibits enzymes involved in haem synthesis
• Anaemia of chronic disease
  
  • Hepcidin results in functional iron deficiency
• Sideroblastic anaemia
  
  • Inherited defect in haem synthesis

Question 4

2) Reduced globin chain synthesis causes

Answer 4

• Alpha thalassaemia
  
  • Deletion or loss of function of one or more of the 4 alpha globin genes
• Beta thalassaemia
  
  • Mutation in B globin genes leading to reduction or absence of the B globin

Question 5

acronymn for microcytic anaemia

Answer 5

TAILS

Question 6

T

Answer 6

thalassaemia

Question 7

A

Answer 7

anaemia of chronic disease

Question 8

I

Answer 8

iron deficiency

Question 9

L

Answer 9

lead poisoning

Question 10

S

Answer 10

sideroblastic anaemia

Question 11

iron is an essential element in all livign cells. Required for

Answer 11

• Oxygen carriers
  
  • Hb in red cells
  • Myoglobin in myocytes
• Co-factor in many enzymes
  
  • Cytochrome (oxidative phos)
  • Kreb cycle enzymes
  • Cytochrome P450 enzymes (detoxification)
  • Catalase

Question 12

free iron is

Answer 12

potnetially very toxic

• Complex regulatory systems to ensure the safe absorption, transportation and utilisation
• Body has no mechanism for excreting iron- important concept

Question 13

iron can exist in a rnage of oxidation states- what are the most common

Answer 13

ferrous iron (Fe2+) and ferric iron (Fe3+

Question 14

Fe2+

Answer 14

ferrous iron

• reduced form

Question 15

Fe3+

Answer 15

ferric iron

oxidised form

Question 16

dietary iron consists of

Answer 16

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

Question 17

what must happen to ferric (Fe3+) iron before it can be absorbed from the diet

Answer 17

must be reduced to ferrous (Fe2+)

Question 19

where does absorption of ferrous iron (Fe2+) occur

Answer 19

duodenum and upp jejunum

Question 20

is haem or non-haemi iron best

Answer 20

haem iron (pure Fe2+)

Question 21

good source of haem iron

Answer 21

liver, kidney, beef steak, chicken, duck, salmon/tuna

Question 22

good soruce of non-haem iron

Answer 22

fortified cereals

rasiins

beans

figs

barley

oats

rice

potatoes

Question 23

Dietary absorption of iron

Answer 23

• In the upper duodenum region that absorption occurs
• Haem iron (Fe2+ ferrous) can be absorbed without transporters
• Non haem iron needs transporter
  
  • Fe3+ à Fe2+
  • Reductase uses vitamin C to reduce ferric to ferrous
  • Fe2+ can then be absorbed via DMT1 (divalent (meaning 2- fe2+) metal transporter 1) cotransporter
• Haem is degraded within the enterocyte to release Fe2+ (haem oxygenase)
  
  • Iron can be stored as ferritin (Fe3+)
  • Iron can be transported into the blood via ferroportin
• To transport iron around the body it is bound to a protein called Transferrin (binds 2 ferric Irons – Fe3+)
  
  • Hephaestin converts Fe2+ to Fe3+
• Hepcidin inhibits the function of ferroportin

Question 24

factors affecting absorption of Non-haem iron from foods:

Negative influence

Answer 24

Tannins (tea)

• Phytates (e.g. chapattis, pulses)
• Fibres
• Antacids (e.g. Gaviscon)

Question 25

factors affecting absorption of Non-haem iron from foods: ## Footnote **Positive influence**

Answer 25

* Vitamin C and citrate * Prevent formation of insoluble iron compound * Vit C also help reduce ferric to ferrous irons * E.g. take iron tablets with orange juice

Question 26

**Functional iron (3350mg)**

Answer 26

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

Question 27

Stored iron (around 1000 mg)x

Answer 27

**Ferritin (soluble)** o Globular protein complex with hollow core o Pores allow iron to enter and be release **Hemosiderin (insoluble)** o Aggregates of clumped ferritin particles, denatured protein and lipid o Accumulates in macrophages, particularly in liver, spleen and marrow

Question 28

cellular uptake of iron from the blood

Answer 28

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. Once in the cytosol, Fe2+ can be **stored** in ferritin, **exported** by ferroportin (FPN1), or taken up by **mitochondria** for use in cytochrome enzymes

Question 29

ferritin structure

Answer 29

iron storage mocluel with iron mineral core (found within cells)

Question 30

**Iron recycling**

Answer 30

* Only small fraction of daily iron requirement gained from diet * Most (80%) of iron requirement met from recycling damaged or senescent red blood cells

Question 31

features of iron recyling

Answer 31

* Old RBCs engulfed by **macrophages** via **phagocytosis** * Mainly s**plenic macrophages and Kupffer cells of liver** * Macrophages **catabolise haem r**eleased from RBC * Amino acids reused and iron exported to blood (transferrin) or returned to storage pool as ferritin in macrophage

Question 32

**Regulation of iron absorption**

Answer 32

* Depends on dietary factors, body iron stores and erythropoiesis * Dietary iron levels sensed by enterocytes * Control mechanisms * Regulation of transporters e.g. ferropotin * Regulation of receptors e.g. transferrin receptor & HFE protein (interacts with transferrin receptor) * Hepcidin and cytokines * Crosstalk between the epithelial cells and other cells like macrophages

Question 33

hepcidin

Answer 33

a key negative regulator of iron absorption

Question 34

how does hepcidin work

Answer 34

* During iron overload hepcidin synthesis is increased * Induced internalisation and degradation of ferroportin

Question 35

hepcidin synthesis is decreased by

Answer 35

high erytrhopoieric activity

Question 36

anaemia of chronic disease is what sort of iron deficiency

Answer 36

functional iron deficiency

Question 37

mechanism of anaemia of chronic disease

Answer 37

1. Main mechanism: cytokine **IL-6** released by immune cell due to inflammatory condition such as arthritis 2. I**L-6 increases the production of Hepcidin by liver** * Inhibition of ferroprotein * Decreased iron released from retinoendothelial system * Decreased iron absorption in the gut * Plasma iron reduced * Inhibition of erythropoiesis in bone marrow 3. **IL-6 also inhibits erythropoietin**, further inhibiting erythropoiesis

Question 38

summary of iron homeostasis

Answer 38

Question 39

**Iron deficiency**

Answer 39

* Most common nutritional disorder worldwide * 1/3^rd of world population are anaemic with at least half of these due to iron deficiency

Question 40

iron defiicnecy is a ..... not a ......

Answer 40

sign not a diagnosis need to seek underlying reason why patient is iron deficiency

Question 41

causes of iron deficiency

Answer 41

* **Could be due to:** * **Insufficient intake/ poor absorption** * Vegan and vegetarian diets * **Physiological reasons** e.g. pregnancy and rapid growth (increased requirement) * **Pathological reasons** e.g. bleeding * Menstruation * Gastric bleeding due to chronic NSAID usage * **Anaemia of chronic disease e.g. IBD**

Question 42

groups at risk of iron deficiency

Answer 42

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

Question 43

physiological effects of iron deficiency (same as anaemia)

Answer 43

* 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

Question 44

other symptoms of iron deficiency

Answer 44

* **Pica** – unusual cravings for non-nutritive substances e.g. dirt and ice * **Cold hands and feet** * **Epithelial changes**

Question 45

sings of iron deficiency

Answer 45

angular cheilitis glossitis koilonychia (spoon nails)

Question 46

Iron deficiency anaemia: FBC results

Answer 46

* Low mean corpuscular volume (MCV) * Low mean corpuscular haemoglobin concentration (MCHC) * Often elevated platelet count (\>450,000/μL) * Normal or elevated white blood cell count * Low serum ferritin, serum iron and %transferrin saturation, raised TIBC * Low Reticulocyte Haemoglobin Content (CHr)

Question 47

**Peripheral blood smear results in iron deficiency anaemia**

Answer 47

* RBC are microcytic and hypochromic in chronic cases * Anisopoikilocytosis- change in size and shape * Sometimes pencil cells and target cells

Question 48

**Testing for iron deficiency**

Answer 48

* Plasma **ferritin** commonly used as indirect marker of total iron status * Ferritin predominantly a cytosolic protein but small amounts are secreted into the blood where it functions as an iron carrier * **Reduced** plasma ferritin definitively indicates iron deficiency * **BUT..** Normal or increased ferritin does **not** exclude iron deficiency * **Ferrtitin levels can also increase considerably in cancer, infection, inflammation, liver disease and alcoholism** * **CHr** (reticulocyte haemoglobin content) recommended by NICE to test for functional iron deficiency * CHr remains low during inflammatory responses etc. (also low in those with thalassaemia)

Question 49

**Treatment of iron deficiency** *

Answer 49

* Dietary advice * Oral iron supplements * Safest, first-line therapy for most patients but many experience GI side effects and compliance with treatment * Intramuscular iron injections * Intravenous iron * Blood transfusion- only used if severe anaemia with imminent cardiac compromise

Question 50

iron excess is

Answer 50

dangerous * Excess iron can exceed binding capacity to transferrin * Excess iron deposited in organs as **haemosiderin** * Iron promotes free radical formation and organ damage * E.g. plays a role in the **Fenton reaction** which creates free radicals

Question 52

causes of iron excess

Answer 52

* Transfusion associated hemosiderosis * Hereditary hemochromatosis (HH)

Question 53

**Transfusion associated hemosiderosis** is caused by

Answer 53

* **Repeated blood transfusions** give gradual accumulation of iron * 400ml blood = 200mg iron * **Problem with transfusion dependent anaemias such as thalassaemia & sickle cell anaemia** * Iron chelating agents such as ***desferrioxamine*** can delay but do not stop inevitable effects of iron overload

Question 54

transfussion asscoaited hemosiderosis leads to

Answer 54

Accumulation of iron (hemosiderin) in the liver, heart and endocrine organs: * Liver cirrhosis * Diabetes mellitus * Hypogonadism * Cardiomyopathy * Arthropathy * Slate great colour skin

Question 55

**Hereditary heamochromatosis**

Answer 55

Autosomal recessive disease caused by mutation in **HFE gene** (on Chr 6)

Question 56

HFE protein and hereditary haemochromatosis

Answer 56

* HFE protein normally **interacts** with **transferrin receptor** reducing its affinity for iron-bound transferrin * HFE also promotes **hepcidin** expression through activation of signalling pathways in liver * Mutated HFE therefore results in loss of **negative influences** on iron uptake and absorption * Too much iron enters cells and accumulates in end organs causing **damage**

Question 57

results of HH

Answer 57

* Liver cirrhosis * Diabetes mellitus * Hypogonadism * Cardiomyopathy * Arthropathy * Increased skin pigmentation