Intro To Anaemia, B12 And Folate Metabolism And Megaloblastic Anaemia Flashcards
Anaemia Definition
Haemoglobin concentration lower than the normal range
Clinical SIGNS of Anaemia
PALLOR
TACHYCARDIA
Tachypnoea (faster breathing)
SYSTOLIC MURMUR
Hypotension
Anaemia symptoms
Fatigue
Dyspnoea (shortness of breath)
Weakness and lethargy
Headaches
COnfusion
Anaemia is not a diagnosis
It’s a manifestation of an underlying disease state
Important to establish cause of anaemia
Anaemias can occur as a result of abnormalities in RBC what?
Production
Function
Removal
Excessive loss of blood
How are anaemias classified
Depends of how the underlying condition affects the average SIZE of the red cells
How many classifications of Anaemia
3
The 3 Anaemia Classifications
Macrocytic Anaemia (Large Cells)
Microcytic Anaemia (Small Cells)
Normocytic Anaemia (Average/Normal Cells)
Aplastic Anaemia
Reduced erythropoiesis due to Haematopoietic stem cells being unable to make RBCs
Common Cause of Aplastic Anaemia
Chronic Kidney Disease
Kidney make erythropoietin, low levels might not be enough to stimulate erythropoiesis
What is Megaloblastic anaemia?
Inability of precursor RBCs to synthesis DNA
Because of this cell constantly stuck in growth phase so cytoplasm increases in size
Asynchronous maturation between nucleus and cytoplasm
Which category of anaemia is Megaloblastic anaemia?
Macrocytic
Deficiency in which vitamins causes Megaloblastic anaemia?
Vitamin B12
Folate
Different causes of Microcytic Anaemia PNUEMONIC
TAILS
Different Causes of Microcytic Anaemia
T - Thalassaemia
A - Anaemia of chronic disease
I - Iron Deficiency
L - Lead poisoning
S - Sideroblastic anaemia
What is haem iron, what form is the iron in and how is it obtained?
Iron that is associated with a haem group
Ferrous form Fe2+
From animal sources
What is non-haem iron, what form is the iron in and how is it obtained?
Free iron not bound to a haem group
Ferrous (Fe2+) and Ferric form (Fe3+)
Animal and non animal sources (plants)
Good Haem Iron sources
Liver
Kidney
Chicken
Duck
Pork chop
Salmon/Tuna
Beef steak/burger
Good sources of non-haem iron
Beans
Raisins
Figs
Barley
Oats
Rice
Potatoes
How does Iron deficiency lead to anaemia
Iron is needed to synthesise haemoglobin since it is part of the haem group which transports oxygen in RBCs
Iron deficiency treatment
Dietary advice
Intramuscular iron injections
Oral Iron supplements (safest start point)
Intravenous iron
Folate stored where?
Liver
What is folate converted to and stored as in lIver?
Tetrahydrofolate (FH4)
General Role of Tetrahydrofolate (FH4)
Act as one carbon carrier
Provides carbons to other reactions
What is the One-Carbon pool
The wide variety of carbon forms of Tetrahydrofolate FH4
Key reactions which the carbons from Tetrahydrofolate are needed for
Synthesis of Thymidine (T base)
Synthesis of Adenine and Guanine (DNA and RNA Synthesis)
Transfer of methyl groups to Vitamin B12
Problem with Folate deficiency in pregnancy
Foetus can develop Neural Tube Defects
Type of Inheritance for Hereditary Haemochromatosis and what gene is affected?
Autosomal Recessive Inheritance
HFE Gene
WHat is Hereditary Haemochromatosis normally characterised by?
Excess absorption of Dietary Iron
HFE Gene stands for H = High Fe = Iron
THERE IS NO SYSTEM FOR EXCRETION OF EXCESS IRON
What does the normal protein for the affected gene in Hereditarty Haemochromatosis do?
Interacts with transferrin receptor
Reduces affinity for iron bound transferrin so less iron is taken into cells
Promotes Hepcidin production so Ferroportin internalised and degraded so less iron absorbed into blood
What do defects of the HFE Protein cause and why?
Increased cellular uptake of iron
Negative affect of iron uptake into cells lost (no HFE protein to reduce affinity of transferrin rreceptor)
No HFE protein means less Hepcidin so more absorption of Iron into blood since Ferroportin not internalised and degraded
Treatment of Hereditary Haemochromatosis
Therapeutic phlebotomy to remove excess iron (venesection)
Iron deficiency anaemia is what type of anaemia and why?
Microcytic
Less haemoglobin can be synthesised so cell are smaller and hypochromic (paler)
What is an enterocyte?
A cell lining the intestines
Where is iron absorbed?
In the intestines
Specifically the Duodenum and Jejunum
How is haem iron absorbed into the Enterocyte?
Readily
Is absorbed as it is
What happens to the haem iron in the enterocyte?
Enzyme removes the Ferrous Iron from it the haem group (Fe2+)
Fe2+ then oxidised to Ferric Iron (Fe3+) which is stored in the Ferritin complex OR Absorbed straight into the blood by travelling across another transporter
What is Ferritin?
IRON STORAGE MOLECULE
It is a protein which stores Iron in the Ferric form (Fe3+)within the enterocyte
How is NON-Haem Iron absorbed into the enterocyte?
Ferrous Iron (Fe2+) transported in by DMT1
Ferric Iron (Fe3+) reduced to Ferrous iron (Fe2+) by Ferrin REDUCTASE enzyme.
The Ferrous iron (Fe2+) thin enters enterocyte via DMT1
What is DMT1?
Divalent Metal Transporter 1
Divalent = Only liking Fe2+ Ferrous iron
Not liking FerrICK iron, it gives it the ICK
What donates the electron to Ferric iron so it can be reduced to Ferrous iron by the REDUCTASE enzyme?
Vitamin C
Why is Vitamin C important in absorption of non haem iron?
Donates electron (e-) to Fe3+ so it can be reduced to Fe2+ so it can be absorbed into the enterocyte via the DMT1
For non haem iron, what form of Iron does it need to be so it can be absorbed?
FERROUS IRON FE2+ !!!!
What is Ferroportin?
The transporter protein that allows Iron to leave the Enterocyte into the blood in the Ferrous Form (Fe2+)
What form must iron be in to be absorbed into the blood via Ferroportin?
Fe2+ = Ferrous Iron
What is TRANSferrin?
The protein which allows Iron to be TRANSported around in the blood
What form must Iron be in to be TRANSported by TRANSferrin?
Ferric Fe3+
How is Ferrous iron that enters into the blood converted/oxidised into Ferric iron so that it can be transported by Transferrin?
By Protein Hephaestin
Hephaestin function
Facilitates oxidation of Ferrous (Fe2+) into Ferric Iron (Fe3+) so iron can be TRANSported by TRANSferrin in the Blood
What is Hepcidin?
A protein produced by the liver which internalises and degrades Ferroportin
What does Hepcidin do?
Binds to Ferroportin causing it to be internalised into the enterocyte and degraded
What is the significance of Hepcidin Internalising Ferroportin into the cell?
Iron becomes trapped into the Enterocyte so can’t enter the blood
This causes a lack of functional iron in the blood
What other cells does Hepcidin affect besides the Enterocyte and how does it affect the cell?
Macrophages in the Reticuloendothelial system (RES)
Traps iron in them
What 2 forms is Iron Stored in?
Ferritin (Soluble)
Haemosiderin (Insoluble)
Haemosiderin consists of what?
Aggregates (a collection of clumped ferritin, denatured protein and lipids)
Where does Haemosiderin accumulate?
In macrophages in liver (kupffer cells), spleen and bone marrow)
Basic step by step of cell uptake of iron
Fe3+ bound transferrin binds to transferrin receptor
Receptor mediated endocytosis
Fe3+ ——> Fe2+
Leaves endosome via DMT1 into cytoplasm
Fe2+ either stored as ferritin,used by mitochondria or later transported out of cell via Ferroportin
Why is excess iron dangerous?
NO system to remove excess iron from the body
Mechanism on why iron in excess is dangerous
Iron promotes free radical production via the FENTON Reaction
Produces Hydroxyl (OH) and hydroperoxyl (OOH) radicals
How do free radicals cause damage to cells?
Lipid peroxidation
Damage to proteins (cross linking)
Damage to DNA
What is iron needed for in the body?
Proteins (Haemoglobin)
Cytochromes in ETC (why mitochondria take up iron)
Catalase enzyme (Protects from oxidative stress, breaks down H202)
Why does the body only experience mild symptoms when anaemia develops slowly over a long period of time?
Body has time to adjust to lower [Hb]
Increased cardiac stroke volume
Increased levels of 2,3-bisphosphoglycerate in erythrocytes to promote oxygen dissociation (reduces Hb affinity for 02)
Acute onset anaemia symptoms
Fatigue
Dyspnoea
Palpitations
Headaches
Angina
Vitamin B12 source
Animal origin
Vegans need supplements
Vitamin B12 absorption quick overview
B12 binds to haptocorrin
B12 haptocorrin complex digested by pancreatic proteases in small int
B12 binds to intrinsic factor
b12 - Intriinsic factor complex binds to Cubam receptor
Receptor mediated endocytosis into enterocyte
B12 moves into blood and binds to transcobalamin (transport protein)
What causes vitamin B12 deficiency?
Lack of B12 in diet
Lack of Intrinsic factor (pernicious anaemia)
Disease of ileum (Chron’s disease)
Lack of transcobalamin (Transport of B12)
Chemical inactivation of B12
Pernicious Anaemia
Lack of intrinsic factor causing reduced B12 absorption, often die to an autoimmune disease
How are B12 and Folate linked
B12 needed in Methionine cycle (Methionine produces cysteine)
Methyltetrahydrofolate needed as cofactor for Methionine cycle to work
So lack of B12 causes lack of folate since it stays trapped as Methyltetrahydrofolate
Simple link between B12 and folate
Low B12 causes low available Tetrahydrofolate
Methionine cycle ceases (low B12) so all Folate gets stuck as Tetrahydrofolate
Subacute combined degeneration of the cord is caused by what
B12/Folate Deficiency
Where demyelination of the cord occurs due to lacking B12
B12 is needed for myelin sheath production
AFfects nervous system
Metabolic defects in RBCs that might cause anaemia
Glucose-6-Phosphate Dehydrogenase deficiency (G6PDH Deficiency)
Pyruvate Kinase deficiency
Why would G6PDH Deficiency cause anaemia?
Pentose-Phosphate pathway can’t replenish NADPH
RBCs vulnerable to oxidative stress since GSH can’t be reduced to active form
Cross linking of inappropriate disulphide bonds between haemoglobin chains causes Heinz bodies to form
Leads to haemolysis
Why would pyruvate kinase deficiency cause anaemia?
RBC dependant of Glycolysis for ATP (no mitochondria)
Glycolysis pathway defective
RBC can’t produce ATP
Haemolysis
5 reasons why Iron deficiency anaemia might occur?
Increased blood loss
Increased requirements (pregnancy, growth spurt)
Decreased absorption
Anaemia of chronic disease (lack of functional iron)
Diet
Anaemia of Chronic disease/inflammation occurs due to increased production of what?
Cytokines
Cytokines do what to contribute to anaemia
Increased Hepcidin production (Liver) (affecting Ferroportin)
Macrophages retain iron, also less iron absorbed into the blood from gut
Inhibit Erythropoietin production by kidney inhibiting erythropoiesis
Cytokines also directly inhibit erthyropoiesis
Macrocytic anaemia causes
Folate/B12 Deficiency (Megaloblastic anaemia)
Alcohol consumption (has antifolate effect)
Liver disease
How do you treat pernicious anaemia?
Intramuscular injection of hydroxycobalamine
What type of anaemia does Koilonychia and Angular Stomatitis suggest?
What does Koilonychia mean?
What does Angular Stomatitis mean?
Iron deficiency anaemia
Koilonychia = spoon shaped nails
Angular Stomatitis = inflammation of corners of mouth
What is Glossitis?
What type of anaemia is this indicative of?
Inflammation and depapillation of tongue
Vit B12 deficiency
