S4 Anaemia, Vitamin B12 and Folate Metabolism Flashcards
What is anaemia?
A Hb concentration lower than normal range (parameters vary dependent on age, sex and ethnicity)
Is anaemia a diagnosis?
No, it is a manifestation of an underlying disease state (so it is important to establish the cause of anaemia)
What are some signs associated with the cause of anaemia?
- koilonychia (spoon shaped nails) - iron deficiency
- angular stomatitis (inflammation of corners of mouth) - iron deficiency
- glossitis (inflammation and depapillation of the tongue) - vitamin B12 deficiency
- abnormal facial bone development (rare due to early diagnosis) - thalassaemia
What are general signs and symptoms of anaemia related to?
Related to insufficient delivery of oxygen to tissues as Hb Carrie oxygen
What are 7 symptoms (noticed by the patient) of anaemia?
- Shortness of breath
- Palpitations
- Headaches
- Claudication (cramping in leg induced by exercise)
- Angina
- Weakness and lethargy
- Confusion
What are 5 signs (noticed by healthcare professional) of anaemia?
- Pallor
- Tachycardia
- Systolic flow murmur
- Tachypnoea (abnormal rapid breathing)
- Hypotension
Why might anaemia develop? Answer based off the life cycle of RBC and would could happen at each stage.
- bone marrow - reduced/dysfunctional erythropoiesis, abnormal haem synthesis, abnormal globin chain synthesis
- peripheral RBCs - abnormal structure, mechanical damage, abnormal metabolism
- excessive bleeding
- removal - increased removal by RES
How can reduced or dysfunctional erythropoiesis lead to anaemia?
- lack of response in the haemostatic loop (kidney stops making erythropoietin in chronic kidney disease)
- bone marrow unable to respond to EPO (after chemotherapy, toxic insulin or parvovirus infection)
- if marrow is infiltrated by cancer/fibrous tissue (myelofibrosis), number of haemopoietic cells is reduced
- in anaemia of chronic disease (rheumatoid arthritis - iron not made available to marrow for RBC production)
- in blood cancers (myelodysplastic syndromes - abnormal clones of marrow stem cells limit capacity to make RBCs and WBCs)
What cells in the kidneys sense hypoxia and produce EPO in response?
Pericytes
What does EPO do in the bone marrow?
Binds to receptors on erythroblasts to stimulate RBC production
How can defects in Hb synthesis lead to anaemia?
- defects in the haem synthetic pathway can lead to sideroblastic anaemia
- insufficient iron in diet can lead to iron deficiency anaemia (not enough iron to make haem)
- anaemia of chronic disease can lead to functional iron deficiency (enough iron in body but it’s not available for erythropoiesis
- mutations in genes coding for globin chain proteins (alpha and beta Thalassaemia and sickle cell disease)
How can inherited abnormal structure and mechanical damage result in haemolytic anaemias?
Mutations in the genes coding for proteins involved in interactions between the plasma membrane and cytoskeleton of RBCs - cells become less flexible and are more easily damaged - so they break up in the circulation or a removed more quickly by the RES
E.g. hereditary spherocytosis
How can acquired abnormal structure and mechanical damage result in haemolytic anaemias?
- microangiopathic haemolytic anaemias - mechanical damage due to shear stress as cell passed through defective heart valance or snag on fibrin strands in small vessels where DIT has occurred
- heat damage from severe burns
- osmotic damage e.g. from drowning in fresh water
What are cell fragments resulting from mechanical damage called?
Schistocytes
What proteins can you get defects in leading to hereditary spherocytosis?
- band 3
- protein 4.2
- ankyrin
- spectrin
How can defects in RBC metabolism lead to anaemia?
- G6PDH deficiency - less NADPH, less GSH, more oxidative damage, haemolysis - formation of Heinz bodies - RBC seen as defective so removed by RES
- pyruvate kinase deficiency - RBC rely on glycolysis, without pyruvate kinase, less ATP produced, heamolysis
How can excessive bleeding occur that leads to anaemia?
- acute blood loss - injury, surgery, childbirth, ruptured blood vessel
- chronic NSAID usage - aspirin, ibuprofen, naproxen (induce GI injury and bleeding)
- chronic bleeding - small amount of bleeding over a long time - menstrual bleeding (heavy), nosebleeds, GI bleeding, kidney/bladder tumours (blood lost in urine)
How does the reticuloendothelial system play a role in anaemia?
- haemolytic anaemia - RBCs destroyed more quickly as abnormal/damaged
- autoimmune haemolytic anaemias - autoantibodies bind to RBCs so recognised by macrophages in spleen and are destroyed
What 2 key features can help work out the cause of an anaemia?
- RBC size - Macrocytic? Microcytic? Normocytic?
* presences or abscence of reticulocytosis (increased in reticulocytes - has marrow reacted normally?)
What are reticulocytes?
Immature RBCs (just even released from marrow into blood)
Have no nucleus
Take 1 day to mature into an erythrocyte
Slightly larger than erythrocytes
Why is reticulocyte count useful in evaluating anaemia?
Shows if marrow is capable of responding (would increase count if working normally)
If RBCs are microcytic what types of anaemia is it?
Thalassaemia Anaemia of chronic disease Iron deficiency Lead poisoning Sideroblastic anaemia
TAILS
If RBCs are macrocytic what types of anaemia is it?
Vitamin B12 deficiency Folate deficiency Myelodysplasia Live disease Alcohol toxicity
If RBCs are normocytic what types of anaemia is it?
Primary bone marrow failure
Secondary bone marrow failure
If haemolysis has occurred, what time of anaemia is it?
Autoimmune MAHA Haemoglobinopathies Enzyme defects Membrane defects
If there is an increased or no increase in reticulocyte count, which pathway do you look at for each?
Increase - haemolysis? Bleeding?
No increase - what do the RBCs look like?
What are macrocytic anaemias?
Anaemias where the average RBC size is greater than normal (increased mean cell/corpuscle volume (MCV))
What are the 3 types of macrocytic anaemias?
- Megaloblastic anaemias
- Macronormoblastic erythropoiesis
- Stress erythropoiesis
What is megaloblastic anaemia? How does it occur?
- interference with DNA synthesis during erythropoiesis means development of nucleus is inhibited in relation to cytoplasm maturation - so cell division is delayed so erythroblasts continue to grow to form megaloblasts - lead to larger RBCs
What can cause megaloblastic anaemias?
- vitamin B12/folate deficiency
- drugs that interfere with DNA synthesis e.g. anti cancer drugs
- erythroid leukaemias (where DNA synthesis in inhibited)
How does macronormoblastic erythropoiesis occur? What can cause it?
- normal relationship between development of nucleus
- cytoplasm is retained
- erythroblasts are just larger than normal
Liver disease, alcohol toxicity, myelodysplastic syndromes
What is stress erythropoiesis? What can cause it?
Conditions associated with high reticulocyte count - high level of erythropoietin leads to accelerated and increased erythropoiesis
Recovery from blood loss due to haemorrhage
Recovery from haemolytic anaemias
Where is folate synthesised? Where is it absorbed in the GI tract?
Bacteria and plants
Duodenum and jejunum
What is folate converted to by intestinal cells? What is folate taken up by?
Tetrahydrofolate
The liver which acts as a store
What is the metabolic role of folate? What is a reaction folate is involved in?
Provide carbons for other reactions
Synthesis of nucleotide bases for DNA and RNA synthesis
What can cause folate deficiency?
- dietary deficiency
- increased requirements e.g. pregnancy, skin disease (lost due to shedding), increased erythropoiesis
- disease of the duodenum or jejunum
- drugs
- alcoholism (poor diet and damage to intestinal cells)
- urinary loss of folate - liver disease and heart failure
What are the 6 symptoms of folate deficiency?
- Anaemia symptoms
- Reduced sense of taste
- Diarrhoea
- Numbness and tingling in feet and hands
- Muscle weakness
- Depression
What is the advantage of taking folic acid before conception and during the 1st 12 weeks of pregnancy?
Prevents majority of neural tube defects in babies
What is vitamin B12? What is the importance of B12?
A water soluble vitamin
It is an essential cofactors for DNA synthesis (involved in folate metabolism) so it is required for erythropoiesis
Essential for normal function/development of CNS
What produces B12? What part of the diet has the most B12?
Bacteria
Foods of animal origin
How is B12 absorbed?
- Released from food proteins by proteolysis in stomach, binds to haptocorrin (produced by salivary glands)
- Haptocorrin-B12 complex is digested by pancreatic proteases in small intestine, this releases B12 which binds to intrinsic factor (produced by gastric parietal cells)
- Intrinsic factor-B12 complex binds to cubam receptors which mediates uptake of complex by receptor-mediated endocytosis into enterocytes
- Once released in enterocytes, B12 exits via basolateral membrane through MDR1
- B12 binds to transcobalamin in the blood and is transported through bloodstream
- Most B12 is stored in the liver (enough is stored to provide requirements for 3-6 years)
What can cause B12 deficiency?
- dietary deficiency
- lack of intrinsic factor
- disease of ileum
- lack of transcobalamin (congenital)
- chemical inactivation of B12
- parasitic infection (can trap B12)
- drugs can chelate intrinsic factor
What is pernicious anaemia?
- decreased/absence of intrinsic factor - exhaustion of B12 reserves
- autoimmune disease - blocking antibody (blocks binding of B12 to IF) or binding antibody (prevents receptor mediated endocytosis)
What are the 6 symptoms of vitamin B12 deficiency?
- Anaemia symptoms
- Glossitis and mouth ulcers
- Diarrhoea
- Paraesthesia (numbness and tingling)
- Disturbed vision
- Irritability
What is subacute combined degeneration of the cord?
- irreversible nervous damage
* degeneration of posterior and lateral columns of spinal cord
How does vitamin B12 and folate deficiencies affect the nervous system?
Folate - in pregnancy can cause neural tube defects
B12 - associated with focal demyelination
What are the symptoms of subacute combined degeneration of the cord?
- gradual onset weakness, numbness and tingling in arms, legs and trunk which gets worse over time
- changes in mental state
How are B12 and folate linked?
A lack of B12 will keep folate as methyltetrahydrofolate, preventing it from its use in reactions like the synthesis of thymidine for DNA synthesis
Why do B12 and folate deficiencies lead to megaloblastic anaemia?
- Folate and B12 deficiencies both result in thymidine deficiency
- In the absence of thymidine, uracil is incorporated into DNA instead
- DNA repair enzymes detect the error and constantly repair with excision
- This results in asynchronous maturation between the nucleus and cytoplasm
What can you see on the blood film of megaloblastic anaemia?
- macrocytic RBCs
- hypersegmented neutrophils
- ovalocytes
- tear drop RBCs
- anisopoikilocytosis (variation in size and shape)
- eventually… pancytopenia
How can you treat vitamin B12 and folate deficiencies?
B12 - for pernicious anaemia: intramuscular hydroxycobalamine, other causes: oral cyanocobalamine, if necessary small volume blood transfusion
Folate - oral folic acid
Why are blood transfusions in patients with B12 deficiency not commonly used?
Can cause high output cardiac failure
What do you need to be aware of when treating pernicious anaemia (with hydroxycobalamine)?
Hypokalaemia at the start due an increased requirement for K+ as erythropoiesis increases back to normal rate
What is high in megaloblastic anaemia investigations?
- MCV
- serum ferritin
- plasma lactate dehydrogenase (LDH)
- bilirubin
What is low in megaloblastic anaemia investigations?
- Hb
- erythrocyte count
- reticulocyte count
- leukocyte count
- platelet count
Why is LDH raised in megaloblastic anaemia?
Due to increased cell destruction and increased cell production
