Anamia And Vit B12 And Folate Flashcards
Anaemia
Definition - A haemoglobin concentration lower than the normal range.
Normal range will vary with age, sex and ethnicity so the point at which a patient becomes anaemic depends on these parameters
Signs and symptoms - Haemoglobin carries O2. General signs and symptoms therefore related to insufficient delivery of O2 to tissues
Symptoms:- Shortness of breath, Palpitations, Headaches, Claudication, Angina, Weakness & Lethargy, Confusion
Signs - Pallor, Tachycardia, Systolic flow murmur, Tachypnoea and Hypotension
Specific signs associated with the cause of anaemia
Koilonychia (Spoon shaped nails) Iron deficiency
Angular stomatitis - (Inflammation of corners of the mouth) Iron deficiency
Glossitis (inflammation & depapillation of tongue) - Vitamin B12 deficiency
Abnormal facial bone development - Rare in recent times as preventable with early diagnosis Thalassaemia
Key clinical point - anaemia in itself is not a diagnosis but a manifestation of an underlying disease state and it is important to establish the cause of the anaemia
Why might anaemia develop?
Problem with the bone marrow - Reduced or dysfunctional erthyropoiesis, Abnormal Haem synthesis, abnormal globin chain synthesis
Problem with the peripheral red blood cells - abnormal structure, mechanical damage (e.g. heart valve stenosis) and abnormal metabolism
Removal of RBC from blood/body - excessive bleeding or increased removal by reticuloendothelial (RES) system present int the spleen and liver
Reduced or dysfunctional erythropoiesis
Anaemia can result from lack of Input response in the haemostatic loop e.g. in chronic kidney disease the kidney stops making erythropoietin
Anaemia can result from marrow being unable to respond to EPO e.g. after chemotherapy, toxic insult or sense hypoxia and parvovirus infection
If marrow is infiltrated by cancer cells or fibrous tissue (myelofibrosis) the number of normal haemopoietic cells is reduced
In Anaemia of chronic disease e.g. in erythroblasts in rheumatoid arthritis, iron is not made available to marrow for rbc production
In rare forms of blood cancer called myelodysplastic syndromes abnormal clones of marrow stem cells limit the capacity to make both red and red cells in blood white blood cells
Defects in Hb synthesis
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 result in a functional iron deficiency (sufficient iron in body Haemoglobin but not made available for erythropoiesis)
Mutations in the genes encoding the globin chain proteins -
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Abnormal structure and mechanical damage results in haemolytic anaemia
This could be: Inherited -
Mutations in the genes coding for proteins involved in interactions between the plasma membrane and cytoskeleton
Cause cells to become less flexible and more easily damaged
RBC could break up in the circulation or be removed more quickly by RES
E.g. Hereditary spherocytosis: - the proteins that keep the concave shape of the RBC dont function properly so leads to abnormal structure
Or Acquired damage -
Microangiopathic haemolytic anaemias result from mechanical damage e.g.
Shear stress as cells pass through a defective heart valve (e.g. MAHA in aortic valve stenosis)
Cells snagging on fibrin strands in small vessels where increased activation of clotting cascade has occurred (e.g. in Disseminated Intravascular coagulation)
Heat damage from severe burns
Osmotic damage (drowning in freshwater)
Defects in Red cell metabolism
Pyruvate kinase deficiency -
Pyruvate kinase is the final enzyme in glycolysis
Rare genetic defects in this enzyme occur in some patients
As red cells lack mitochondria they depend on glycolysis for energy production
A defective glycolytic pathway causes red cells to rapidly become deficient in ATP and they undergo haemolysis
Or
G6PDH deficiency -
Decreased G6PDH activity limits amount of NADPH
NADPH is required for reduction of oxidised glutathione (GSSG) back to glutathione (GSH)
Lower GSH means less protection against damage from oxidative stress (infection, drugs)
This increase in stress can lead to lipid peroxidation and protein damage (aggregates of cross-linked Hb form (Heinz bodies)
These red cells are recognised as defective by RES and removed from blood
Excessive bleeding
Acute blood loss - Injury - Surgery - Childbirth - Ruptured blood vessel.
Chronic NSAID usage - Aspirin Ibuprofen Naproxen
Nonsteroidal anti-inflammatory drugs (NSAIDs) commonly used for treatment of conditions with pain and inflammation can Induce GI injury/bleeding via - Inhibition of cyclooxygenase (COX) activity Direct cytotoxic effects on epithelium
Chronic bleeding - A small amount of bleeding continuing over a long time may result in a significant blood loss e.g.
Heavy menstrual bleeding
Repeated nosebleeds
Haemorrhoids
Occult gastrointestinal bleeding (blood lost in stool)
Ulcers (stomach or small intestine)
Diverticulosis
Polyps in large intestine
Intestinal cancer
Kidney or bladder tumours (blood lost in urine)
Role of the reticuloendothelial system
In haemolytic anaemias red cells are destroyed more quickly as they are abnormal or damaged
Damage can occur within the blood vessels (intravascular haemolysis) or within the RES system (extravascular haemolysis)
In autoimmune haemolytic anaemias autoantibodies bind to the red cell membrane proteins as they think they are foreign which causes them to be recognised by macrophages in the spleen and destroyed (splenomegaly often occurs with haemolytic anaemias as the spleen is doing extra work)
Anaemia is often multifactoral
E.g. Myelofibrosis - proliferation of mutated haematopoietic stem cells results in reactive bone marrow fibrosis
This fibrosis means that there is little space for haemopoiesis in the bone marrow
Mutated progenitor cells from marrow can also colonise liver and spleen leading to extramedullary haemopoiesis
Such patients often show an enlarged liver and spleen
E.g. Thalassemia - inherited disorders resulting from decreased or absent alpha or beta globin chain production (alpha - and Beta - thalassaemia respectively)
Imbalance in composition of the haemoglobin alpha2 beta2 tetramers results in defective microcytic hypochromic red cells
Severity depends on type of disease e.g. lack of 3 or 4 alpha globin genes leads to haemoglobin H disease characterised by severe splenomegaly as well a as microcytosis and haemolysis
Evolution of anaemia
2 key features can help to work out the cause of an anaemia:
The rbc size – macrocytic, microcytic, normocytic (big, small, normal)
The presence or absence of reticulocytosis (has the marrow responded normally?)
What are reticulocytes? - Immature red blood cells (i.e. those which have just been released from the marrow into blood) - No nucleus & eliminate remaining mitochondria
Typically compose ~1% of all red blood cells and take ~ 1 day to mature into erythrocytes
Reticulocyte are slightly larger than mature red blood cells so an increase in reticulocyte number will - increase MCV
Reticulocyte count very useful in evaluating anaemia
Shows if marrow is capable of responding (would expect anaemia to cause an increase in reticulocyte count if marrow is working normally)
Macrocytic anaemia
Anaemias where the average RC size is greater than normal
Megaloblastic anaemia - interference with DNA synthesis during erythropoiesis causes retard development of nucleus - causes delay of cell division leading to megloblasts forming leader to larger RBC e.g. seen in VitaminB12 and Folate deficiency and anti cancer drugs (these interfere with DNA synthesis)
Macronormoblastic erythropoiesis - nucleus and cytoplasm size is normal but RBC are just large than normal e.g. seen in liver disease and alcohol toxicity
Stress erythropoiesis - conditions associated with high reticulocyte count (as reticulocyte are larger than RBCs) e.g. recovery from blood loss during haemorrhage
Folate and folate deficiency
Synthesised in bacteria and plants
Present in a wide variety of animal and vegetable food sources.
Particularly abundant in green leafy vegetables (“foliage”).
Absorption mainly from duodenum and jejunum.
Converted to tetrahydrofolate (FH4) by intestinal cells
Taken up by liver which acts a store.
Metabolic role to provide carbons for other reactions.
Recipient reactions include synthesis of nucleotide bases required for DNA& RNA synthesis.
Folate deficiency:
Causes - Dietary deficiency (Poor diet), Increased requirements e.g. Pregnancy, Increased erythropoiesis e.g. haemolytic anaemia, Severe skin disease (e.g. psoriasis, exfoliative dermatitis), Disease of the duodenum and jejunum (e.g. coeliac disease, Crohn’s disease), Drugs which inhibit dihydrofolate reductase (e.g. Methotrexate), Alcoholism (poor diet and damage to intestinal cells), Urinary loss of folate in liver disease and heart failure
Symptoms - Those related to anaemia Reduced sense of taste Diarrhoea Numbness and tingling in feet and hands Muscle weakness Depression
Key clinical point: Folic acid taken
Vitamin B12
Largest and most structurally complex of all vitamins
Water soluble vitamin
Essential cofactor for DNA synthesis (due to its role in folate metabolism)
Required for normal erythropoiesis
Essential for normal function and development of CNS
Produced by bacteria (NOT plants or animals)
Largely obtaining from foods of animal origin (meat , fish, eggs, cheese, milk)
Essential that people on a vegan diet eat foods fortified with vit B12 or take a B12 supplement daily
Vitamin B12 absorption:
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 (produced by gastric parietal cells).
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 basolateral membrane through MDR1
Then it binds to transcobalamin in blood and is transported around bloodstream
Majority of B12 is stored in the liver (store enough to provide B12 requirements for ~3-6 year)
Vitamin B12 deficiency
Causes
Dietary deficiency
Why do VitB12 and folate deficiency cause macrocytic (megaloblastic) anaemia ?
Treatment of these deficiencies
Both folate and B12 deficiency ultimately lead to thymidine deficiency
In the absence of thymidne, uracil is incorporated into DNA instead
DNA repair enzymes detect these errors and constantly repair by excision
Results in asynchronous maturation between nucleus & cytoplasm.
Nucleus does not fully mature,
Cytoplasm matures at the normal rate
Vitamin B12 and folate are both necessary for nuclear division and maturation.
When B12 and folate are deficient, nuclear maturation and cell divisions lag behind cytoplasm development.
Leads to large red cell precursors with inappropriately large nuclei and open chromatin.
The mature red cells are also large leading to a macrocytic anaemia
As B12/folate deficiency progresses a pancytopenia can also develop - i.e. low platelets and neutrophils as well
Treatment of Vit B12 and folate deficiency:
Beware of hypokalaemia at beginning of treating severe pernicious anaemia.
This is due to increased K+ requirement as erythropoiesis increases back to its normal rate.
Vitamin B12
For Pernicicous anaemia - Hydroxycobalamine (not oral) for life)
For other causes of B12 deficiency: Oral cyanocobalamine
Blood transfusion in patients with severe anaemia caused by vitamin B12 deficiency can cause high output cardiac failure.
If absolutely required transfuse smaller volume with care
