Microcytic anaemia and Iron metabolism Flashcards
microcytic anaemias
- Reduced rate of haemoglobin synthesis
- Erythrocytes smaller than normal (microcytic)
- Cells often paler than normal (hypochromic)
- Less haemoglobin
microcytic anaemias are due to
1) reduced haem synthesis
2) reduced glonbin chain synthesis
1) Reduced haem synthesis causes
-
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
2) Reduced globin chain synthesis causes
-
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
acronymn for microcytic anaemia
TAILS
T
thalassaemia
A
anaemia of chronic disease
I
iron deficiency
L
lead poisoning
S
sideroblastic anaemia
iron is an essential element in all livign cells. Required for
- 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
free iron is
potnetially very toxic
- Complex regulatory systems to ensure the safe absorption, transportation and utilisation
- Body has no mechanism for excreting iron- important concept
iron can exist in a rnage of oxidation states- what are the most common
ferrous iron (Fe2+) and ferric iron (Fe3+
Fe2+
ferrous iron
- reduced form
Fe3+
ferric iron
oxidised form
dietary iron consists of
haem iron (Fe2+) and non-haem iron (mixture of Fe2+ and Fe3+)
what must happen to ferric (Fe3+) iron before it can be absorbed from the diet
must be reduced to ferrous (Fe2+)

where does absorption of ferrous iron (Fe2+) occur
duodenum and upp jejunum

is haem or non-haemi iron best
haem iron (pure Fe2+)
good source of haem iron
liver, kidney, beef steak, chicken, duck, salmon/tuna
good soruce of non-haem iron
fortified cereals
rasiins
beans
figs
barley
oats
rice
potatoes
Dietary absorption of iron
- 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

factors affecting absorption of Non-haem iron from foods:
Negative influence
Tannins (tea)
- Phytates (e.g. chapattis, pulses)
- Fibres
- Antacids (e.g. Gaviscon)
factors affecting absorption of Non-haem iron from foods:
Positive influence
- 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
Functional iron (3350mg)
- Haemoglobin (~2000 mg)
- Myoglobin (~300 mg)
- Enzymes e.g. cytochromes (~50 mg)
- Transported iron (in serum mainly in transferrin) (~3 mg)
Stored iron (around 1000 mg)x
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

cellular uptake of iron from the blood
- 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.
- Once in the cytosol, Fe2+ can be stored in ferritin, exported by ferroportin (FPN1), or taken up by mitochondria for use in cytochrome enzymes

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

Iron recycling
- Only small fraction of daily iron requirement gained from diet
- Most (80%) of iron requirement met from recycling damaged or senescent red blood cells
features of iron recyling
- Old RBCs engulfed by macrophages via phagocytosis
- Mainly splenic macrophages and Kupffer cells of liver
- Macrophages catabolise haem released from RBC
- Amino acids reused and iron exported to blood (transferrin) or returned to storage pool as ferritin in macrophage

Regulation of iron absorption
- 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
hepcidin
a key negative regulator of iron absorption
how does hepcidin work
- During iron overload hepcidin synthesis is increased
- Induced internalisation and degradation of ferroportin
hepcidin synthesis is decreased by
high erytrhopoieric activity

anaemia of chronic disease is what sort of iron deficiency
functional iron deficiency
mechanism of anaemia of chronic disease
- Main mechanism: cytokine IL-6 released by immune cell due to inflammatory condition such as arthritis
- IL-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
- IL-6 also inhibits erythropoietin, further inhibiting erythropoiesis

summary of iron homeostasis

Iron deficiency
- Most common nutritional disorder worldwide
- 1/3rd of world population are anaemic with at least half of these due to iron deficiency
iron defiicnecy is a ….. not a ……
sign not a diagnosis
need to seek underlying reason why patient is iron deficiency
causes of iron deficiency
-
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
-
Insufficient intake/ poor absorption
groups at risk of iron deficiency
- Infants
- Children
- Women of child bearing age
- Geriatric age group
physiological effects of iron deficiency (same as 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
other symptoms of iron deficiency
- Pica – unusual cravings for non-nutritive substances e.g. dirt and ice
- Cold hands and feet
- Epithelial changes
sings of iron deficiency
angular cheilitis
glossitis
koilonychia (spoon nails)
Iron deficiency anaemia: FBC results
- 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)
Peripheral blood smear results in iron deficiency anaemia
- RBC are microcytic and hypochromic in chronic cases
- Anisopoikilocytosis- change in size and shape
- Sometimes pencil cells and target cells

Testing for iron deficiency
- 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)
Treatment of iron deficiency
*
- 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
iron excess is
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
causes of iron excess
- Transfusion associated hemosiderosis
- Hereditary hemochromatosis (HH)
Transfusion associated hemosiderosis is caused by
- 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
transfussion asscoaited hemosiderosis leads to
Accumulation of iron (hemosiderin) in the liver, heart and endocrine organs:
- Liver cirrhosis
- Diabetes mellitus
- Hypogonadism
- Cardiomyopathy
- Arthropathy
- Slate great colour skin
Hereditary heamochromatosis
Autosomal recessive disease caused by mutation in HFE gene (on Chr 6)
HFE protein and hereditary haemochromatosis
- 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
results of HH
- Liver cirrhosis
- Diabetes mellitus
- Hypogonadism
- Cardiomyopathy
- Arthropathy
- Increased skin pigmentation