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Macrocytic anaemia


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Classification of Anaemia

Classification of Anaemia

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  • 1. CLASSIFICATION OF ANAEMIA: Macrocytic Anaemia
  • 2. Macrocytic anaemias Macrocytic anaemia (MCV>RR) Megaloblastic Non-megaloblastic anaemia anaemia -Oval macrocytes Round macrocytes -Hypersegmented neutrophils -Liver disease-B12 deficiency -Alcoholism -Pernicious anaemia -MDS-Folate deficiency -Drug induced-B12/Folate -Reticulocytosis -Others Lazarela Vucinic 2009 2
  • 3. Vitamin B12 (Cobalamin)• Synthesized by some microorganisms• Food that contains cobalamin is from animal origin• Average daily diet contains ~ 5-30ug – 1-5ug is absorbed• ~2-5mg are stored – Liver – Kidneys Lazarela Vucinic 2009 3
  • 4. aemiaMegaloblastic.htm B12 absorption Accessed 14.04.08Mouth:Unbound B12 Stomach:may be absorbed Protein-bound B12 detaches R-Protein picks up B12 IF secreted Upper small intestine:Liver: R-protein releases B12. IFB12 is stored and picks up B12released into smallintestine via the bile Lower small intestine: IF-B12 attaches to receptor Some unbound B12 absorbedBlood: Intestinal cells:Transcobalamin II B12 attaches tocarries B12 to cells OR transcobalamin IIto liver for storage(transcobalamin III) Accessed 14.04.08 4
  • 5. Transcobalamins• Transcobalamin II – Synthesised by the liver, vascular endothelium, enterocytes, macrophages and fibroblast – Half – life ~ 90min – Mainly circulates as apoTCII – Carries 6-25% of B12 & takes it to the tissues – Binds to TC II-R and is internalised by receptor-mediated endocytosis & is not recycled• Transcobalamin I and III (TCI & TCIII) – Synthesised in the liver – 75% of plasma B12 binds to TCI • Storage protein for B12 5
  • 6. B12 function Accessed180309
  • 7. B12 function Accessed 140309 7
  • 8. B12 deficiency• Folate trapping – Abnormal DNA synthesis• Homocysteine – Plasma toxicity – Deterioration of inner lining of arteries and veins – => leads to risk for CHD, PVD and stroke• ? of S-adenosylmethionine (SAM) – Shown to help treat depression – ?Abnormal neuronal conduction• Leads to development of methylmalonic aciduria – Associated with neurological symptoms and learning deficiencies Lazarela Vucinic 2009
  • 9. Causes of B12 deficiencyInadequate Increased need intake Malabsorption B12 deficiency Competition Impaired for B12 absorptionGastrectomy Lack of IF Failure to separate from haptocorrin Pernicious anaemia 9
  • 10. Pernicious anaemia Mean age of onset is 60 years Impaired absorption of B12 due to a lack of IF Autoimmune disorder  ? genetic predisposition Lymphocyte mediated destruction of parietal cells => IF not secreted Antibodies block IF action  Blocking Abs detectable in serum Leads to development of atrophic gastritis 10
  • 11. Folate• Normal daily intake = 650 μg• Amount lost = 13 μg (urine)• Daily requirements = 200 μg• Storage = 5mg• Food sources include green leafy vegetables , bananas, strawberries, nuts, liver, yeast• Lots of food has been fortified with folate• Vulnerable to heat and dissolves in water - so cooking can reduce the levels Research indicates that increased folate intake can prevent seven out of 10 births of babies affected by a neural tube defect 11
  • 12. Folate• Before folate can be used, the following reactions occur: Dihydrofolate Tetrahydrofolate Folate FH4 FH2 Dihydrofolate reductase• Occurs as conjugate of one or multiple glutamic acids – Folic monoglutamates & polyglutamates exist 12
  • 13. Folate absorption1. Unconjugated or conjugated 3. Monoglutamates dietary folate transported across 2. All intestinal epithelium polyglutamates are deconjugated 4. FH4 formation in intestinal epithelium6. Polyglutamates 5. Monoglutamates formation circulate in blood inside cells & are transported into cells 13
  • 14. Folate function The principal function of folate coenzymes is to accept or donate one- carbon units in key metabolic pathways Folate-requiring reactions include:  those involved in phases of amino acid metabolism  purine and pyrimidine synthesis  formation of the primary methylating agent, S- adenosylmethionine (SAM) Accessed 150408 14
  • 15. Causes of folate deficiency Increased need Inadequate intake Folate deficiency Impaired absorptionExcessive loss Impaired utilisation 15
  • 16. Symptoms of B12 & folate deficiency Anaemia  Neurologic symptoms  Weakness  May appear before anaemia  Fatigue  Memory loss  SOB  Loss of balance  Pallor – may be severe  Numbness in toes and fingers  Depression Loss of epithelium  “Megaloblastic madness”  Glossitis  Gastritis  Jaundice  Constipation  Weight loss 16
  • 17. Megaloblastic anaemiaFBE Results: Hb/RCC/Hct MCV RDW Plt/WCC  =>Pancytopenia may develop Oval macrocytes Hypersegmented neutrophils No polychromasia Poikilocytosis, tear drops In severe megaloblastic anaemia  Basophilic stippling  Howell Jolly bodies 17
  • 18. Megaloblastic anaemia Lazarela Vucinic 2009
  • 19. Megaloblastic anaemia Lazarela Vucinic 2009
  • 20. Bone Marrow• Shows megaloblastic changes• Nuclear-cytoplasmic asynchrony• Hypercellular• M:E = 1:1 – Intramedullary haemolysis due to ineffective erythropoiesis• Giant WBC precursors – Metamyelocytes and bands• Megakaryocytes vary Is NOT performed unless there is a suspicion of megaloblastic anaemia in a child 20
  • 21. Diagnosis of B12/Folate deficiency• Bilirubin• LDH Evidence of haemolysis• Haptoglobin• Homocystine• IF of parietal cell antibodies• ? Methylmalonic acid – serum or urine 21
  • 22. Treatment of megaloblastic anaemia• Directed at specific vitamin deficiency – Treating B12 deficient patient with folate may increase neurological symptoms• Folate and B12 tablets administered orally – Iron may be supplemented• B12 may be administered intramuscularly – No need for IF – Lifelong administration for PA patients• Sublingual or nasal B12 available – Expensive
  • 23. Liver disease• Anaemia – Macrocytes (round) & target cells • Due to abnormalities of RBC membrane lipids – anisocytosis & poikilocytosis than in megaloblastic anaemia – reticulocytes• Thrombocytopenia – Often mild and due to hypersplenism – If due to alcohol • May have abnormal platelet aggregation and secretion • Direct marrow suppression• Coagulopathy – Lack or malabsorption of VitK – Decreased synthesis of coagulation proteins – Synthesis of abnormal proteins 23
  • 24. Alcoholic liver disease• The effects of alcohol may be: – Direct – seen in the BM – Indirect – liver disease or due to nutritional abnormalities• Anaemia (? haemolytic) + impaired RC production• Leucopenia + neutropenia – Suppression of growth factors – Splenomegaly• Concurrent infection/inflammation that may give rise to ACD – Abnormal N function and decrease Ab production• Thrombocytopenia – Ineffective thrombopoiesis• May lead to development of (reversible) sideroblastic anaemia• Folate and iron deficiencies are common 24
  • 25. Liver disease Lazarela Vucinic 2009
  • 26. Diagnosis of liver disease• Abnormal LFT• Coagulation – PT • Prolonged even in mild liver disease • fVII and fX particularly affected – APTT – Fibrinogen • May be elevated in early liver disease (acute phase reactant) • May be structurally abnormal – Folate and Iron storage may be low 26
  • 27. Learning objectives• Be able to describe different types of macrocytic anaemias and their causes• Understand the function and metabolism of B12 and folate and the causes and impact of deficiency in either one• Show an understanding of tests and expected results that may be performed in order to diagnose B12/Folate deficiency• Be able to explain other causes of macrocytosis (liver disease, MDS and drug induced) Lazarela Vucinic 2009
  • 28. Study Questions• What are the expected results in a patient with megaloblastic anaemia and why?• Why do we need B12 and Folate and what effect will the deficiency of either one have?• What is pernicious anaemia, what is its cause and how is it diagnosed?• How would you diagnose liver disease?• List the causes of macrocytosis and briefly explain the pathophysiology of each. Lazarela Vucinic 2009 28