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8/13/2019 Megaloblastic Anemia 1
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Megaloblastic Anemia
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Diagnostic approach based on RBCs
indices
MCV < 80 fl 80 fl < MCV < 98 fl MCV > 98 fl
Microcyticanemia
Normocyticanemia
Macrocyticanemia
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Macrocytic Anemia (MCV>100)
Morphology
Peripheral blood & Bone Marrow
Megaloblastic
Vit B12, Folatedeficiency
Non-Megaloblastic
Reticulocyte count
Increased
Hemorrhage
Hemolysis
Cold agglutinins
Decreased/Normal
Alcoholism
Liver Disease
Hypothyroidism
BM failure:
MDS, Aplastic Anemia
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DNA Synthesis DNA
THF
5,10 Methylene THF
DHF
Deoxyuridine
monophosphate
(dUMP)
Thymidine
monophosphate(dTMP)
Methyl B12
Methyl THF(plasma factor)
THF - tetrahydrofolate
DHF - dihydrofolate
Methotrexate blockshere
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B12/Folate deficiency affects all dividing cells
1. Ineffective HematopoiesisIneffective Erythropoiesis Anemia
Ineffective Leukopoiesis Leukopenia
Ineffective Thrombopoiesis Thrombocytopenia
2. RBC survival
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Normal Erythropoiesis (Bone Marrow)
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Megaloblastic Erythropoiesis
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Megaloblastosis (Giant Band Forms in Bone Marrow)
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Megaloblastic Changes Young Megakarocyte (Bone Marrow)
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Normal Megaloblastic Changes
Peripheral Blood (2)
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Normal Megaloblastic Changes
Peripheral Blood
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Peripheral Blood
Hypersegmentation (PMN)
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Megaloblastic Anemia - Etiology
Vitamin B12 deficiency
Folate deficiency
Antimetabolic drugsInborn errors of metabolism
Refractory anemias
Erythroleukemia
95%
5%
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Pernicious Anemia Clinical Presentation
lemon yellow pallor
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Pernicious Anemia Clinical Presentation
Glossitis beefy tongue
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Pernicious Anemia Clinical Presentation
Neurological deficit:
Subacute combined degeneration gait disorders
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Pernicious Anemia Clinical Presentation
Neurological deficit:
Depression, dementia, behavioral changes
(megaloblastic madness)
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Pernicious Anemia Clinical Presentation
Vitiligo
Associated autoimmune disorders:vitiligo, hyper/hypothyroidism etc.
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Megaloblastic Anemias:
Signs & Symptoms (1)
Subjective:
Fatigue, weight loss,gastrointestinal
complaints, sore tongue or mouth
Neurological complaints (may be
irreversible !) : Paresthesias, difficultywalking(?)
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Megaloblastic Anemias:
Signs & Symptoms (2)
Objective:
Pallor & jaundice (lemon yellow) Loss of papillae of tongue (beefy red)
Neurological deficit (Only with B12 def)
( position / vibration sense + romberg /spastic paraparesis)
Can also cause dementia & depression Signs of associated conditions: vitiligo, thyroid
disease etc.
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Megaloblastic Anemia Lab Results
CBC: Hb/Hct, MCV, retics, RDW, WBC, Plts CAUTION: mixed deficiency or concurrent states (iron
deficiency or thal+ megaloblastic anemia) MASKED
SIGNS!Biochemistry:
Bilirubin, LDH, Vit B12
Autoantibodies: anti-parietal cell, anti-thyroid etc.
Other associated: glucose, thyroid function etc.
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B12 is a large, complex molecule with complex
absorption
3 ACTIVE FORMS: CYANO, METHYL AND ADENOSYL
Normal B12 Metabolism (1)
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Normal B12 Metabolism (2)
B12 is present in foods of animal origin
Not in vegetables or plants!!!
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Minimum daily requirement is only 2g/day
Body stores total: 3-4000 g (mainlyhepatic)
Dietary deficiency: rare, in long term strictvegans
Normal B12 Metabolism (3)
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Normal B12
Absorption:a complex process
involving 3
gastrointestinalorgans:
stomach, pancreas,
terminal ileum
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SCHILLING TEST
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Common Etiologies of B12 def. Lack of intrinsic factor
Pernicious anemia Post-gastrectomy (partial / total / bypass)
Congenital
Biological competitiona. Small-bowel bacterial overgrowth
Jejunal diverticuli
Blind loops
Scleroderma, diabetes
b. Fish tapewarmstasis
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Common Etiologies of B12 def.(cont)
Diseases of the ileum
A. Surgical resections
B. Crohns disease
These are differentiated using the Schilling
test !!!
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B12 def - Treatment Oral therapy only if definitive dietary
deficiency (rare) Parenteral injection of B12, 10 injections as a
loading dose and then once a month for life
New!!! Sublingual/
Nasal Vit B12 therapy
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Retics%
Hbg/dl
Plateletsx109/L WBCx103/L
B12 Def. Response to Treatment
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Low B12 level is common Since the introduction of commercial kits,
the finding of a low B12 level is an all-toocommon finding in the workup of patientswith anemia or other syndromes.
Even can be found in patients with LOW
MCV
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Low B12 is common in Israel Reports say that low B12 level is common
in Israel in all ethnic groups Ashkenazi Jews: 22% (Gielchinsky, 2001)
Gaucher patients 40% (Gielchinsky, 2001) Elderly living at home: 12-16% of (only 1-
2% of elderly living in institutions) (Figlin,
2003)
Israeli Olympic team: 1.7% (Eliakim, 2002)
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Confirmation that low B12 level
represents true deficiency
HOW TO CONFIRM?
Metabolic tests:
Methylmalonic acid (MMA) level
Homocysteine (HC) level
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Biochemistry of B12
Association Between Folate, Vit B12
and Homocysteine Metabolism
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Normal Folate Metabolism
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Normal Folate Metabolism (2) Folate is present in fruits, vegetables,
human milk Daily requirement: 50g/day
Well absorbed throughout thejejunum,ileum
Total body stores: 5 mg, only for several
months
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Etiologies of Folate Deficiency Increased requirements (pregnancy,
breastfeeding, hemolysis, exfoliativedermatitis)
Poor diet (longstanding)
Alcoholism, Parenteral feeding etc.
Poor absorption (diffuse intestinal
diseases)
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Folate Deficiency - Treatment Oral folate (pills) for duration of state
leading to deficiency
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Folate supplementation during pregnancyreduces significantly the risk for neuraltube defects
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Association Between Folate, Vit B12
and Homocysteine Metabolism