MEGALOBLASTIC ANEMIA - Anemia Thursday, February 12, 2004 ... PERNICIOUS ANEMIA ... 032406heme-Diugui

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  • Megaloblastic Anemia Thursday, February 12, 2004 9:00 am

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    MEGALOBLASTIC ANEMIA

    MARROW FAILURE

    Metabolically highly active, 2 to rapid cell turnover White cell life span 12-24 hours Platelet life span 7 days Red blood cell lifespan 120 days

    Any slowing of DNA production marrow failure

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    MEGALOBLASTIC ANEMIA

    Hemoglobin production probably normal Defect in nuclear replication & division Affects all marrow elements

    MEGALOBLASTIC ANEMIA

    Trademark cell: Oval macrocyte, (MCV > 100 fl) Hypersegmented neutrophils - 98% Pancytopenia, esp if anemia severe Reticulocytopenia LDH elevated (90%) Serum Fe normal or elevated Serum B12 or folate low Marrow classic megaloblastic changes

  • Megaloblastic Anemia Thursday, February 12, 2004 9:00 am

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    FOLIC ACIDOH

    N

    NN

    N

    NH

    CONH

    COCH2CH2CHCOOH

    (GLU)n

    Pteridine PABA Glutamic Acids

    H2N

    12

    34 5

    6

    78

    9

    10

    FOLIC ACIDOH

    N

    NH

    N

    N

    NH

    CONH

    COCH2CH2CHCOOH

    (GLU)nH2N

    12

    34 5

    6

    78

    9

    10

    NH

    NH

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    FOLIC ACIDOne Carbon Fragment Forms

    NH

    NH

    CH2N5,10 methylene THF

    Thymidylatebiosynthesis

    NH

    NH2

    CH3N5 methyl THFTransport

    N NH

    NH

    NH

    CH

    HC

    O

    N5,

    10-m

    ethe

    nyl T

    HF

    N10

    - form

    yl T

    HF

    H2O

    Purine biosynthesis

    FOLATE ABSORPTION

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    FOLATE DEFICIENCYCauses

    Folate-poor diet Alcoholism Severe poverty

    Increased folate requirement Pregnancy Severe hemolytic anemia Severe Psoriasis

    Drug therapy Malabsorption

    Tropical sprue

    FOLATE DEFICIENCYManifestations

    Megaloblastic anemia Glossitis/stomatitis GI malabsorption 2 to impaired GI

    epithelium (rare)

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    COBALAMIN (Vitamin B12)Functions

    Folate metabolism - Required for demethylation of methyl-THF

    Methylation of myelin Conversion of methylmalonyl CoA

    to succinyl CoA

    COBALAMINStructure

    Co

    Nucleotide

    -groupsCN - Cyano; inactiveOH - Hydroxyl; inactiveMethyl - Folate metabolismAdenosyl - Mutase activity

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    COBALAMIN REACTIONS

    NH

    NH

    CH3

    THF

    Homocysteine Methionine

    Methyl

    Cobalamin

    Methylmalonyl CoA

    Succinyl CoA

    AdenosylCobalamin

    GI ABSORPTION OF COBALAMIN

    IF

    R

    Cbl

    R-Cbl

    R-CblR

    IF-Cbl

    IF-Cbl IF-Cbl TCII

    IF Cbl

    TCII-Cbl TCII-Cbl

    Cbl TCII

    Stomach

    Duodenum

    Terminal Ileum

    TCI-Cbl

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    COBALAMIN DEFICIENCYCauses

    Gastric Failure Pernicious Anemia Total gastrectomy

    Ileal Failure Regional enteritis (Crohn's disease) Ileal resection Tropical sprue

    Competing organisms Bacterial overgrowth (Blind loop) Diphyllobothrium latum

    PERNICIOUS ANEMIA Autoimmune destruction of parietal cells Antibodies vs. parietal cells, intrinsic factor Achlorhydria is universal Increased incidence of gastric cancer Increased incidence American blacks,

    northern Europeans Often associated with other immune diseases

    (eg Hashimoto's thyroiditis)

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    COBALAMIN DEFICIENCYPeripheral Folate Depletion

    N5-methyl-THF

    N5-methyl-THF THF Conjugated folates

    THF

    Cbl

    Homocysteine Methionine

    COBALAMIN DEFICIENCYPeripheral Manifestations

    Megaloblastic anemia - Indistinguishablefrom folate deficiency & due to intracellularfolate deficiency

    Stomatitis/glossitis GI Mucosa alterations Can correct all of the above with high dose

    folate;

    DON'T DO THIS!!!!!DON'T DO THIS!!!!!

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    COBALAMIN DEFICIENCYManifestations-Central

    Both brain and spinal cord Brain:

    Dementia Psychological disturbances

    Spinal cord: Demyelinating disease Loss of posterior & lateral columns-

    hence name "Combined system disease" Neurologic disease stabilized with treatment,

    but usually not reversed Treatment with folate does nothing for neurologic

    disease

    SUBACUTE COMBINED DEGENERATION

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    COBALAMIN DEFICIENCYUsual Sequence of Events

    Serum homocysteine & methylmalonicacid rise

    Serum cobalamin falls MCV rises; neutrophil hypersegmentation MCV rises above normal Anemia Symptoms

    FOLATE/COBALAMINProperties

    P ro p e rty F o lic A c id C o b a la m in

    F o o d S o u rce A lm o s t a ll foo d s A n im a l p ro te in o n ly

    W ate r so lub le Y e s Y e s

    S ite o f ab so rp tion D u o d en um /Je ju n um Ile umM e ch o f a b so rp tion D e co n ju ga tion o f

    p o ly-G luU p ta ke o f IF -C b lco m p le x

    M e ta bo lic F u n c tion O n e C a rb o ntra n s fe rs

    U n kn o w n

    B o d y s to re s 4 -5 m o n th s 2 -1 2 ye a rsD ie ta ry d e fic ie n cy C o m m o n R a reD e fic ien cy s ta te s

    M e ga lo b la s tica n em ia

    Y e s Y e s

    N e u ro lo g icd ise a se

    N o Y e s

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    MEGALOBLASTIC ANEMIADiagnosis /Therapy

    Draw levels at first suspicion of problem,BEFORE ANY THERAPY

    Once levels drawn, begin treatment with both B12and folate

    Once levels are back, can stop the normal vitamin

    Transfusions to be avoided unless hemodynamic compromise is present, or patient having angina

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    MEGALOBLASTIC ANEMIAResponse to Therapy

    0 5 10 15 20 25 3035 40 45 50 55 60

    0

    10

    20

    30

    40

    50

    Ret

    ic (%

    ), H

    emat

    ocrit

    (%)

    Days

    Retic (%) Hematocrit (%)

    SCHILLING TESTCause of Cobalamin Deficiency

    Part I Without IF

    Part II With IF

    Part III After Ab

    Pernicious Anemia

    Low Normal Not needed

    Bacterial Overgrowth

    Low Low Normal

    Ileal dysfunction

    Low Low Low

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    MEGALOBLASTIC ANEMIASSummary

    Deficiency in folate or B12 Macrocytic anemia; other cytopenias Slowly developing anemia, usually well

    compensated Response to therapy rapid and dramatic Treatment essential to avoid other complications Anemia is secondary to an underlying disease

    process

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