CLASSIFICATION OF ANAEMIA:Macrocytic Anaemia
Lazarela Vucinic 2009
Macrocytic anaemias
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Macrocytic anaemia(MCV>RR)
Megaloblasticanaemia
Non-megaloblasticanaemia
- B12 deficiency- Pernicious anaemia
- Folate deficiency- B12/Folate
- Liver disease- Alcoholism
- MDS- Drug induced- Reticulocytosis- Others
-Oval macrocytes-Hypersegmented neutrophils
Round macrocytes
Lazarela Vucinic 20093
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
B12 absorption
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www.uq.edu.au/vdu/HDUAnaemiaMegaloblastic.htm
Accessed 14.04.08
Mouth:Unbound B12 may be absorbed
Stomach:
Protein-bound B12 detaches R-Protein picks up B12 IF secreted
Upper small intestine:
R-protein releases B12. IF picks up B12
Lower small intestine:
IF-B12 attaches to receptor Some unbound B12 absorbed
Intestinal cells: B12 attaches to transcobalamin II
http://www.veganhealth.org/b12/images/b12absorption1.gif Accessed 14.04.08
Blood:
Transcobalamin II carries B12 to cells OR to liver for storage (transcobalamin III)
Liver:
B12 is stored and released into small intestine via the bile
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
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B12 function
http://emedicine.medscape.com/article/1152670-overview Accessed180309
B12 function
7http://emedicine.medscape.com/article/1152670-media Accessed 140309
Lazarela Vucinic 2009
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
Causes of B12 deficiency
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B12 deficiency
Inadequate intake
Increased need
Impaired absorption
Lack of IF Failure to separate from haptocorrin
Malabsorption
Competition for B12
Gastrectomy
Perniciousanaemia
Pernicious anaemia
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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
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 preventseven out of 10 births of babies affected by a neural tube defect
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Folate• Before folate can be used, the following
reactions occur:
• Occurs as conjugate of one or multiple glutamic acids– Folic monoglutamates & polyglutamates exist
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FolateDihydrofolate
FH2
TetrahydrofolateFH4
Dihydrofolate reductase
Folate absorption
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1. Unconjugatedor conjugated dietary folate
2. All polyglutamates
are deconjugated
3. Monoglutamatestransported across
intestinal epithelium
4. FH4 formation inintestinal epithelium
5. Monoglutamatescirculate in blood& are transported
into cells
6. Polyglutamatesformation inside cells
Folate function
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http://www.pubmedcentral.nih.gov/picrender.fcgi?artid=1519435&blobtype=pdf Accessed 150408
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)
Causes of folate deficiency
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Increased need
Excessive loss
Folatedeficiency
Impaired absorption
Inadequate intake
Impaired utilisation
Symptoms of B12 & folate deficiency
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Anaemia Weakness Fatigue SOB Pallor – may be severe
Loss of epithelium Glossitis Gastritis Constipation
Neurologic symptoms May appear before
anaemia Memory loss Loss of balance Numbness in toes and
fingers Depression “Megaloblastic madness”
Jaundice Weight loss
Megaloblastic anaemia
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FBE 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
Lazarela Vucinic 2009
Megaloblastic anaemia
Lazarela Vucinic 2009
Megaloblastic anaemia
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 varyIs NOT performed unless there is a suspicion of megaloblastic
anaemia in a child
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Diagnosis of B12/Folate deficiency
• Bilirubin• LDH• Haptoglobin• Homocystine• IF of parietal cell antibodies• ? Methylmalonic acid – serum or urine
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Evidence of haemolysis
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
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
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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
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Lazarela Vucinic 2009
Liver disease
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
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Lazarela Vucinic 2009
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
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.
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