L8: Iron metabolism and microcytic anaemias Flashcards
What are microcytic anaemias?
Erythrocytes are smaller
Reduced rate of haemoglobin synthesis
Cells paler (hypochromic)
What causes microcytic anaemias?
Reduced haem synthesis
-Anaemia of chronic disease –> Hepcidin result in functional iron deficiency (plenty of it but cant be used)
-Iron deficiency–> required for haem synthesis
-Lead poisoning–> acquired defect
-Sideroblastic anaemia–> inherited defect in haem synthesis
Reduced globin chain synthesis
- Thalassaemia –> α and β
–> α –> deletion or loss of one or more of α globin genes
–> β –> mutation in β globin genes leading to reduction or absence of the β globin
Mnemonic –> TAILS
What is iron? Whats its function?
Element
Essential in all living cells
Free iron–> potentially toxic to cells
Complex regulatory system–> safe utilisation, absorption and transport
Required for:
- O2 carriers –> haemoglobin in red cells
–> myoglobin in myocytes
-Cofactor in many enzymes–> cytochromes (OP), Krebs cycle enzymes, cytochrome P450 enzymes (detoxification), catalase
Body has no mechanism for excreting iron
What is the difference between ferrous and ferric?
Ferrous Fe2+ –> reduced form–> absorbed from diet in this form
Ferric Fe3+ –> oxidised form
How is ferric reduced to ferrous and vice versa?
Ferric (Fe3+) + e- –> Ferrous (Fe2+) reduction low pH (acid)
Ferrous (Fe2+) –> Ferric (Fe3+) + e- oxidisation high pH (alkaline)
What is the difference between haem and non-haem iron?
Haem–> associate with globin–> haemoglobin
Come from animals–> liver, kidney, steak, beef burgers etc
Easily/readily absorbed
Non-haem –> Ferrous or ferric form–> fortified cereals, raisins, beans, figs, barely, oats, rice and potatoes
Converted to ferrous for absorption
How much iron is needed in the diet and where is it absorbed?
10-15 mg/day
Absorbed in the duodenum and upper jejunum
How is iron absorbed into the bloodstream?
- Chyme enter duodenum/ upper jejunum
- a) Haem–> readily absorbed by the enterocytes
- inside Fe2+ released by haem oxygenase
b) Non Haem–> Fe3+ –> Fe2+ via reductase enzymes in brush border
–> Requires Vit C as electron donor
–> Fe2+ –> enters enterocyte through DMT1 (divalent metal transporter 1)- H+ ion out - Fe2+ stored- storage protein ferritin in Fe3+ form
OR - Enters bloodstream through ferroportin
- Transported- Fe3+ form- converted by Hephaestin
- Fe3+ binds to transferrin—> transported around the blood
What inhibits the role of ferroportin?
Hepcidin
Peptide hormone
Produced by liver
Bind to ferroportin–> degradation
What factors affect the absorption of non-haem iron from food?
Negative influences–> Tannis (in tea), phytates (pulses), fibre and antacids (gavison)
- -> bind to non-heam iron in the intestine reduce absorption
- -> need acidic environment to convert Fe3+–> Fe2+
Positive influences–> Vit C and citrate–> prevent formation of insoluble iron compounds
VitC require for conversion of Fe3+–> Fe2+
What is the difference between functional and stored iron?
Functional iron–> available
- Heamoglobin (2000mg)
- Myoglobin (300mg)
- Enzymes- cytochromes (50mg)
- Transported iron (transferrin) (3mg)
Stored iron (1000mg)
How can iron be stored?
Ferritin–> soluble form
- -> stored in enterocyte
- -> globular protein complex with hollow core–> pores allow iron to enter and be released
Haemosiderin –> insoluble form
- -> Aggregates of clumped ferritin particles, denatured protein and lipid
- -> Accumulates in macrophages, particular in liver and spleen
How is iron taken up into cells?
1- Fe3+ bound trasferrin binds transferrin receptor and enters the cytosol receptor-mediated endocytosis
2- Fe3+ within the endosome released by acidic microenvironment and reduced to Fe2+
3- The Fe2+ transported to the cystol via DMT1
4- Once in cystol Fe2+ can be:
- stored in ferritin
-exported by ferroportin (FPN1) or
-taken up by mitochondria - cytochrome enzymes
What is meant by iron recycling?
Small intake in diet Most (>80%) - recycled from damaged or senescent RBC Phagocytosis by macrophages Splenic macrophages and kupffer cells - Liver Catabolise haem released from RBC AA reused and iron: - exported to blood - transferrin - stored - Ferritin - macrophages
How is iron absorption regulated?
Determined by: dietary factors, iron stores, erythropoiesis
Sensed by enterocytes
Controlled mechanisms
- Regulation of transporter- ferroportin
- Regulation of receptors- Transferrin receptor and HFE protein (homeostatic iron regulator)
- Hepcidin and cytokines
- Crosstalk between the epithelial cells and other cells like macrophages
How does hepcidin regulate iron absorption?
Negative regulator
Synthesis increased in iron overload
Decreased by high erythropoietic activity
Induces the internalisation and degradation of ferroportin
What is meant by anaemia of chronic disease?
Anaemia caused by inflammation
Inflammatory condition–> cytokine release (IL-6)
Main effect–> increased hepcidin production–> inhibition of ferroportin–> decreased iron released from reticuloendothelial cells and reduced absorption from diet–> plasma iron reduced–> inhibition of erythropoiesis in bone marrow–> anaemia (less RBC)
Minor pathway–> Inhibition of erythropoietin production and inhibition of erythropoeisis–anaemia
What type of deficiency is anaemia of chronic disease?
Functional deficiency
enough iron in body but cannot utilise it
How much iron is lost from the body each day and how? Is iron excretion regulated?
1-2 mg/day - desquamation of epithelia - menstural bleeding - sweat - pregnancy--> 3.5mg/day No--> no mechanisms to control excretion
What is significant about iron deficiency?
Most common nutritional disorder
1/3rd population anaemic- 1/2 iron deficient
Sign not a diagnosis
What are the causes of iron deficiency?
Insufficient iron in diet Malabsorption Bleeding Increased requirement (pregnancy) Anaemia of chronic disease
Why is the iron requirement for females 19-50 greater than males of similar age?
Females of this age lose lots of blood during menstruation each month
What groups are at risk?
Children
Infants
Women of child bearing age
Geriatric age group (elderly)
What are the signs and symptoms of anaemia?
- Tiredness, pallor, reduced exercise tolerance, cardiac (angina, palpitations, development of HF), increased resp rate, headache, dizziness, light-headedness
- Pica (unusual cravings)–> non-nutritive substances
- Cold hands and feet
- Epithelial changes (angular cheilitis, glossy tongue with atrophy of linguinal papillae), Koilonychia (spoon nails)
