7. Introduction To Anaemia Vit B12 And Folate Flashcards
What is anaemia?
A haemoglobin concentration lower than the normal range
Normal range varies with age, sex and ethnicity
What are the symptoms of anaemia?
Shortness of breath Palpitations Headaches Claudication Angina Weakness and lethargy Confusion
What are the signs of anaemia?
Pallor Tachycardia Systolic flow murmur Tachypnoea Hypotension Koilonychia (spoon shaped nails) Angular stomatitis (inflammation of corners of mouth) Gloss it is (inflammation and shiny tongue) Abnormal facial bone development
Why might anaemia develop due to bone marrow?
Reduced or dysfunctional erythropoiesis
Abnormal haem synthesis
Abnormal globin chain synthesis
Why might anaemia develop due to peripheral red blood cells?
Abnormal structure
Mechanical damage
Abnormal metabolism
Why might anaemia develop due to removal?
Excessive bleeding
Increased removal by reticuloendothelial system
Describe the haemostatic loop
Low blood oxygen
Pericytes in kidney sense hypoxia and produce erthyropoietin (EPO)
EPO binds to receptors on erythroblasts in bone marrow and stimulates red cell production
Increased number of red cell in blood
High blood oxygen
Negative feedback
How can anaemia develop from reduced or dysfunctional erythropoiesis?
Lack of response in haemostatic loop
Marrow being unable to respond to EPO
Marrow is infiltrated by cancer cells or fibrous tissue number of normal haemopoietic cells reduced
Anaemia of chronic diseases
Blood cancer called myelodysplastic syndromes
Why might anaemia develop due to defects in haemoglobin synthesis?
Mutation in genes encoding globin chain proteins (alpha and beta thalassaemia, sickle cell disease)
Insufficient iron in diet (not enough iron to make haem)
Defects in haem synthetic pathway (sideroblastic anaemia)
What can cause haemolytic anaemia to develop that is inherited?
Mutations in genes coding for proteins involved in interactions between plasma membrane and cytoskeleton
Cause cells to become less flexible and more easily damaged
Break up in circulation or removed more quickly by RES
E.g. hereditary spherocytosis
What can cause haemolytic anaemia to develop due to acquired damage?
Microangiopathic haemolytic anaemias result from mechanical damage
E.g. shear stress as cells pass through defective heart valves or a blood clot, cells snagging on fibrin strands in small vessels
Heat damage from sever burns
Osmotic damage
Forms fragments called schistocytes
What defects in red cell metabolism may cause anaemia to develop?
G6PDH deficiency - causes Heinz bodies, aggregates of cross-linked haemoglobin, red cells recognised as defective by RES and removed
Pyruvate kinase deficiency - red cells lack mitochondria so rely on glycolysis, causes RBC to rapidly become deficient in ATP
Why might anaemia develop due to excessive bleeding?
Acute blood loss - injury, surgery, childbirth
Chronic NSAID usage - induce GI injury/bleeding
Chronic bleeding - heavy menstrual bleeding, occult GI bleeding (ulcers, diverticulitis, cancer), repeated nosebleeds
What happens in autoimmune haemolytic anaemias?
Autoantibodies bind to the red cell membrane proteins causing them to be recognised by macrophages in the spleen and destroyed
Splenomegaly often occurs as spleen doing extra work
What 2 features can help to work out the cause of anaemia?
RBC size - macrocytic, microcytic, normocytic
The presence or absence of reticulocytosis (has the marrow responded normally)
What are reticulocytes?
Immature red blood cells
No nucleus and eliminate remaining mitochondria
Slightly larger than mature red blood cells so an increase in number will increase MCV
Shows if marrow capable of responding (would expect anaemia to cause an increase in reticulocyte count)
What can cause macrocytic RBC?
Vit B12 deficiency Folate deficiency Myelodysplasia Liver disease Alcohol toxicity
What are megaloblatic anaemias?
Interference with DNA synthesis during erythropoiesis causes development of nucleus to be regarded in relation to maturation of cytoplasm
Cell division delayed, erythrocytes continue to grow to form megaloblasts
Give examples of megaloblastic anaemias
Vitamin B12/folate deficiency
Drugs that interfere with DNA synthesis
Some erythroid leukaemias where DNA synthesis is retarded
What is macronormoblastic erythropoiesis?
Normal relationship between development of ncleus and cytoplasm is retained but erythroblastosis are larger than normal and give rise to lager red cells
E.g. live disease, alcohol toxicity
What is stress erythropoiesis?
Conditions associated with a high reticulocyte count
High even of erythropoietin leads to expanded and accelerated erythropoiesis
E.g. recovery form blood loss due to haemorrhage, recovery from haemolytic anaemia
What is folate?
Synthetic form = folic acid
Synthesised in bacteria and plants
Present in wide variety of animal and vegetable food sources
Absorption mainly from duodenum and jejunum
Taken up by liver which acts as a store
Metabolic role to provide carbons for other reactions
What are the causes of a folate deficiency?
Dietary deficiency
Increased requirements - pregnancy, increased erythropoiesis, sever skin disease
Disease of duodenum and jejunum
Drugs which inhibit dihydrofolate reductase
Alcoholism
What are the symptoms of a folate deficiency?
Those related to anaemia Reduced sense of taste Diarrhoea Numbness and tingling in feet and hands Muscle weakness Depression
When should folic acid supplements be taken?
Before conception
During first 12 weeks of pregnancy to prevent majority of neural tube defects in babies
What is vitamin B12?
Water soluble vitamin Essential cofactor for DNA synthesis Required for normal erythropoiesis Essential for normal function and development of CNS Produced by bacteria
What are good sources of vitamin B12?
Meat Fish Milk Cheese Eggs Yeast extract
Describe how vitamin B12 is absorbed from dietary intake
- B12 released from food proteins by proteolysis in stomach where it then binds to haptocorrin
- Haptocorrin B12 complex digested by pancreatic proteases in small intestine releasing B12 which then binds intrinsic factor
- Intrinsic factor-B12 complex binds to cubam receptor which mediates uptake of complex by receptor-mediated endocytosis into enterocytes
- After lysosomal release in enterocytes, B12 exits via absolute real membrane through MDR1
- Binds to transcobalamin in blood and transported around bloodstream
- Majority of B12 stored in liver
How many years supply of B12 is in liver?
3-6 years
What are the causes of vitamin B12 deficiency?
Dietary deficiency
Lack of intrinsic factor (pernicious anaemia)
Diseases of the ileum
Lack of transcobalamin (congenital defect)
Chemical inactivation of B12
Parasitic infestation
Some drugs can chelate intrinsic factor
What is pernicious anaemia?
Decreased or absent intrinsic factor causes progressive exhaustion of B12 reserves
Autoimmune disease
2 types of antibody (Ab):
- blocking Ab bock binding of B12 to IF
- binding Ab prevents receptor mediated endocytosis
What are the symptoms of vitamin B12 deficiency?
Those related to anaemia Glossitis and mouth ulcers Diarrhoea Paraesthesia Disturbed vision Irritability
How can B12/folate deficiency affect the nervous system?
Folate deficiency in pregnancy can cause neural tube defects
Vitamin B12 deficiency associated with focal demyelination
B12 deficiency more often results in a reversible peripheral neuropathy
Can also result in serious condition called subacute combined degeneration fo the cord involving degeneration of posterior and lateral columns of the spinal cord
What are the symptoms of subacute combined degeneration of the cord?
Gradual onset weakness, numbness and tingling in arms, legs and trunk which progressively worsens
Changes in mental state
How does lack of B12 cause problems in DNA synthesis?
Lack of B12 2ill trap folate in the stable methyltetrahydrofolate form preventing its use in other reactions such as synthesis of thymidine for DNA synthesis
Why do B12 and folate deficiency cause a megaloblastic anaemia?
Both folate and B12 deficiency ultimately lead to thymidine deficiency
In the absence of thymidine uracil is incorporated into DNA instead
DNA repair enzymes detect these errors and constantly repair by excision
Results in asynchronous maturation between nucleus and cytoplasm
What are the megaloblastic features in a peripheral blood film?
Variance in size and shape Tear drop red cells Ovalocytes (oval shape) Hypersegmented neutrophils (6 or more lobes in nuclei) Macrocytic
What can happen as B12/folate deficiency progresses?
A pancytopenia can develop (low platelets, neutrophils and red blood cells)
What is the treatment for folate deficiency?
Oral folic acid
What is the treatment for vitamin B12 deficiency for pernicious anaemia?
Hydrocycobalamine intramuscular (not oral) for life
- beware of hypokalaemia at beginning of treating severe pernicious anaemia as increased K+ requirement as erythropoiesis increases
- not oral as won’t be absorbed
What is the treatment for vitamin B12 deficiency for most causes?
Oral cyanocobalamine
Blood transfusion in patients with severe anaemia can cause high output cardiac failure as body has compensated for low levels with an enlarged heart
