Iron and Anaemia Flashcards
List the 3 functions of iron
- Haemoglobin formation for gaseous exchange and acid-base balance
- Enzymatic reaction
- Energy reaction in muscles
Can iron be excreted and if not what will happen if it overloads
*There is no physiological way to excrete iron. Iron overload is toxic = hemochromatosis.
List the 2 forms in which iron exist
Fe2+ (ferrous ) and Fe3+ (ferric)
free iron is toxic to the body and needs to be bound to protein
List the 2 forms of sources of iron
- Haeme iron (Fe2+): found in animal protein and is easily absorbed = more available to the body
- Non-haem iron (Fe3+): found in vegs, eggs, and nuts, and cashew, it is less available to the body
How is iron distributed in the body, from most to least
Hg in RBC (65) > Ferritin (Ferritin is a universal intracellular protein that stores iron and releases it in a controlled fashion)and haemosiderin (30%)> Myoglobin (in muscles) 4% > Haem enzymes eg cytochromes ,catalase ,peroxidase 1% > Transferrin bound iron 1%
Discuss iron absorption , also differentiate between heme and non heme iron absorption
1.Heme iron is moved across the enterocyte brush border membrane by the iron transporter divalent metal-ion transporter 1,
> The heme iron is either stored mucosal ferritin,
which can be lost by shedding
or
> Excreted in the form of ferrous and transformed into ferritin by hephaestin / copper-containing ceruplasmin and transported into the blood attached to plasma transferrin
- Non-heme (ferritin ) is transformed into ferrous by duodenal cytochrome B
*The ferrous then enters the cell through Divalent metal transported 1
The ferrous is either stored mucosal ferritin,
which can be lost by shedding
or
> Excreted in the form of ferrous and transformed into ferritin by hephaestin / copper-containing ceruplasmin and transported into the blood attached to plasma transferrin
Transferrin unbound to iron is called apoferritin
Cellular uptake of iron
TF binds receptor >endocytosed > endosome >Fe3+ released in low PH/affinity lost & STEAP3 > converted Fe2+ by ferri-reductase > transported via DMT1 > labile pool > mitoferritin (MFRN) transfers iron into mitochondria and used for haem synthesis (protophorphyrin ring + iron)
Excess iron stored as ferritin
Iron reuptake depends on :
Transferrin (TF) only taken up by cells through binding transferrin receptors on cell surfaces. TFR1. TFR2.
85% TF has taken up by erythroid precursor cells.
Increased demand for iron cells have more TRF receptors and uptake more ironRapidly dividing cells, erythroid precursors cells
In conditions that cannot make functional Hg eg Thalassaemia and cannot make use of iron, what happens to the iron
> stored as ferritin and accumulates in mitochondria seen as siderotic granules on BMA iron stain1(BLUE in color)
or
Formed by the partial digestion of ferritin aggregates by lysosomal enzymes.
Predominantly found in macrophages
An important source of iron to new erythroid cells in the bone marrow around the nucleus for hg formation
Stained on bone marrow samples with Perl’s stain to assess iron stores in this compartment
Factors favoring iron absorption
Iron source (haem)
Acids
Vitamin C
Reduced serum hepcidin (e.g Iron deficiency state)
Ineffective erythropoiesis
Increased expression DMT1 (e.g increased demand e.g infancy, pregnancy)
Hereditary hemochromatosis
Factors decreasing iron absorption
Iron source (non-haem)
Antacids
Bowel surgery
Raised hepcidin (e.g infective state, excess iron stores)
Decreased expression DMT-1 by duodenal enterocytes
Tea, phyates
What is the function of hepcidin
Negatively regulates iron release from cells (NB duodenal and macrophages) by binding to Ferroportin
Causes Ferroportin to be internalized and degraded
It acts to inhibit:
Iron absorption
Iron release from macrophages to newly produced erythroid cells
Iron transport across the placenta
What is the difference between absolute iron deficiency and functional iron deficiency
ABSOLUTE IRON DEFICIENCY
No iron in stores
Ferroportin present but nothing to be released
no absorption of iron, chronic blood loss (HB iron)
FUNCTIONAL IRON DEFICIENCY/IRON TRAPPING
Iron PRESENT in stores
No ferroportin to release iron from stores due to increased hepcidin levels
E.g chronic kidney disease, chronic infective states
FUNCTIONAL IRON DEFICIENCY/HIGHER DEMAND vs SUPPLY
Mismatch of iron supply due to increased red cells
Ineffective erythropoiesis- Mismatch of demand vs supply:
o Increased erythroid drive/stressed erythropoiesis due to increased erythropoietin and iron present unable to meet demand
o Ineffective erythropoiesis due to B-thalassaemia, or myelodysplastic syndrome results in erythroid progenitors that can’t function and are destroyed before they can become mature red cells. Lack of mature red cells in circulation results in “anemic state” ( also stimulates EPO production and increased iron absorption with resultant iron overload) remember hepcidin will be inhibited by increased EPO and red cell mass through erythroferrone
REGULATION OF HEPCIDIN Synthesis
- Bone morphpgenoc protein (BMP) and haemojuvelin (HJV) > hepatocytes activation > hepicidin synthesis
- Haemachromatosis (HFE) and Transferrin receptor 2 (TFr2) needs to be a complex before activating the BMP-HJV complex
- Under low iron states ,HFE bound to TFr1 > no formation of hepcidin
- Under high iron states > excess transferrin > competes and overpowers HFE binding with TFr1 > HFE released and free to bind to TFR2 > hepcidin formation and decreased absorption of iron .IL6 can also stimulate hepcidin synthesis
- Martipase is an enzyme whoes activity is increased in iron def ,its function is to breakdoen HJV > In no HJV - BMP complex > no hepcidin formation
- Formation of martipase 2 controlled by TRMPSS6 gene > patients with iron refractory iron deficiency anaemia and d not respond to oral iron > They have a mutation in the TRMpSS6 gene causing no expression of martipase and persistant hepcidin formation.
Decreased iron > decreaed erythropiesis > increased erythroietin EPO synthesis > decreased hepcidin
Clinical features of anemia
- Headache,vertigo, syncope
- Cognitive impairment in children and adults
- Fatigue, tachycardia, cardiac murmur dyspnoea
- Poor physical activity and quality of life
- Increased hospitalization and decreased exercise intolerance
- Increased risk of preterm, low neonatal weight, perinatal complications, and maternal mortality in pregnancy
- Haemodynamic instability and decreased immune response
- Koilonychia, oral lesions and paleness
