Megaloblastic Anemia 1

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    Megaloblastic Anemia

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    ""

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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