Iron Metaoblism And Microcytic Anaemias Flashcards
micro cystic anaemias
Reduced rate of Hb synthesis
Erythrocytes smaller than normal (microcytic)
Cells often paler than normal (hypochromic)
Causes: Thalassaemia Anaemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anaemia
Iron
Essential element in all living cells
Required for:
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
Free iron potentially very toxic to cells
Complex regulatory systems to ensure the safe absorption, transportation & utilisation Important
Body has no mechanism for excreting iron concept!
Ferrous vs Ferric Iron - Iron can exists in a range of oxidation states Ferrous iron (Fe2+) and Ferric iron (Fe3+) most common
Fe2+ is the reduced form Fe3+ is the oxidised form
Dietary iron consists of haem iron (Fe2+) and non-haem (mixture of Fe2+ and Fe3+). Ferric iron must be reduced to ferrous iron (Fe2+) before it can be absorbed from diet
Haem vs non-Haem iron
Need 10-15 mg/day iron in diet
Absorption occurs in duodenum & upper jejunum
Haem iron best source = liver, beef steaks chicken, duck, pork chop, salmon
Non-haem iron = cereals, beans, oats, rice , barley
Some foods fortified with iron e.g. breakfast cereals
Dietary absorption of iron
Factors affecting absorption of non-Haem iron from food
Fe 3+ in the chyme is converted via vitamin C reductase to Fe2+
Fe2+ crosses into the cell in to the enterocyte viva DMT1
Fe2+can then be stored with ferritin (as Fe3+) or be transported into the blood by the channel Ferroportin
When it enters the blood it is converted to 3+ by Hephaestin
Transferrin can then carry 2 Fe3+ molecules around the body
Factors affecting absorption of non-Haem iron from food
Negative influence - Tannins (in tea)
Phytates (e.g. Chapattis, pulses)
Fibre
(The above can bind non-haem iron in the intestine which reduces absorption
Antacids (e.g. Gaviscon)
Positive influence - Vitamin C & Citrate (high in fruits)
Prevent formation of insoluble iron compounds
Vit C also helps reduce ferric to ferrous iron
Functional vs stored iron
Functional (available) iron - Haemoglobin (~2000 mg)
Myoglobin (~300 mg)
Enzymes e.g. cytochromes (~50 mg)
Transported iron (in serum mainly in transferrin) (~3 mg)
Stored iron (~1000 mg) - Ferritin - soluble
Globular protein complex with hollow core
Pores allow iron to enter and be released.
Haemosiderin - insoluble
Aggregates of clumped ferritin particles, denatured protein & lipid.
Accumulates in macrophages, particularly in liver, spleen and marrow.
Cellular iron uptake
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
Iron recycling
Only small fraction of total daily iron requirement gained from the diet.
Most (>80%) of iron requirement met from recycling damaged or senescent red blood cells
Old RBCs engulfed by macrophages (phagocytosis)
Mainly by 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
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. ferroportin
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:
Hepcidin synthesis is increased in iron overload
It’s activated by cytokines
And it is decreased in high erythropoietin activity
Hepcidin induces internalisation and degradation of ferroportin
Anaemia of chronic disease
Long term Inflammatory condition e.g. RA - leads to cytokines (e.g. IL-6) being released by immune cells
This leads to both increased hepcidin (inhibits ferroportin) production by the liver and inhibition of erythropoietin production by the kidneys
Which overall leads to inhibition of erythropoiesis in bone marrow and decreased iron release from RES system/ decreased iron absorption in the gut which also contributes to inhibition of erythropoiesis
Iron deficiency
Most common nutritional disorder worldwide.
1/3rd of world population (2 billion people) are anaemic with at least half of these due to iron deficiency
Iron deficiency is a sign not a diagnosis! Clinician must always seek to determine underlying reason why patient is iron deficient. Could be due to: Insufficient intake/poor absorption Physiological reasons e.g. pregnancy Pathological reason e.g. bleeding
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, gastric bleeding due to chronic NSAID usage
Increased requirement e.g. Pregnancy, rapid growth (at risk groups - infants, women of child bearing age and older people)
Anaemia of chronic disease e.g. Inflammatory bowel disease
Iron deficiency - Signs & Symptoms:
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
Pica (unusual cravings for non-nutritive substances e.g. dirt, ice)
Cold hands and feet
Epithelial changes
Blood parameters and blood film features
FBC results in iron deficiency anaemia: generic patient may have -
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 HaemoglobinmContent (CHr)
Peripheral blood smear results in iron deficiency anaemia:
RBCs are microcytic and hypochromic in chronic cases
Anisopoikilocytosis: change in size and shape
Sometime pencil cells and target cells
Testing and treatment for iron deficiency
Plasma ferritin commonly used as indirect marker of total iron status - ferritin is predominatintly a cytosolic protein but small amount are secreted into 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 - because ferritin levels can also increase considerably in cancer, infection, inflammation, liver disease, alcoholism
CHr (reticulocyte haemoglobin content) recommended by NICE to test for functional iron deficiency
CHr remains low during inflammatory responses etc.
CHr is also low in patients with thalassaemia so can’t be used in this setting
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 poor
Intramuscular iron injections
Intravenous iron
Blood transfusion - only used if severe anaemia with imminent cardiac compromise
Response - Improvement in symptoms
20g/L rise in Hb in 3 weeks
Iron excess is dangerous
Excess iron can exceed binding capacity of transferrin
Excess iron deposited in organs as haemosiderin
Iron promotes free radical formation & organ damage
Hydroxyl and hydroperoxyl Fenton reaction
radicals can cause damage to cells:
Fenton reaction
Fe2+ + H2O2
Transfusion associated haemosiderosis
Repeated blood transfusions give gradual accumulation of iron
400ml blood = 200mg iron
There are problems 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
Accumulation of iron (haemosiderin) in liver, heart & endocrine organs:
Liver cirrhosis - Diabetes mellitus - Hypogonadism - Cardiomyopathy - Arthropathy - “Slate grey” colour of skin
Hereditary haemochromatosis
Autosomal recessive disease caused by mutation in HFE gene (on Chr 6)
HFE protein normally interacts with transferrin receptor reducing its affinity for iron-bound transferrin
Mutated HFE cant bind to transferrin so the negative influence on iron uptake is lost
HFE also has negative influence on hepcidin production so, with no HFE, hepcidin prevents iron from leaving cells (keeps in internalised) again, a negative influence on iron uptake is lost
Too much iron therefore enters cells
Iron accumulates in end organs causing damage
Need to treat with venesection
