megaloblastic anemia. marrow failure metabolically highly active, 2º to rapid cell turnover...
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MEGALOBLASTIC ANEMIA
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MARROW FAILURE
• Metabolically highly active, 2º 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
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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
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FOLIC ACIDOH
N
NN
N
NH
CONH
COCH2
CH2CHCOOH
(GLU)n
Pteridine PABA Glutamic Acids
H2N
12
34 5
6
7
8
9
10
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FOLIC ACIDOH
N
NH
N
N
NH
CONH
COCH2
CH2CHCOOH
(GLU)n
H2N
12
34 5
6
7
8
9
10
NH
NH
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FOLIC ACIDOne Carbon Fragment Forms
NH
NH
CH2
N5,10 methylene THF
Thymidylatebiosynthesis
NH
NH2
CH3
N5 methyl THFTransport
N NH
NH
NH
CH
HC
O
N5,
10-m
ethe
nyl T
HF
N10
- form
yl T
HF
H2O
Purine biosynthesis
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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
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FOLATE DEFICIENCYManifestations
• Megaloblastic anemia• Glossitis/stomatitis• GI malabsorption 2º 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
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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
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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
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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
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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
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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
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FOLATE/COBALAMINProperties
Property Folic Acid Cobalamin
Food Source Almost all foods Animal protein only
Water soluble Yes Yes
Site of absorption Duodenum/Jejunum IleumMech of absorption Deconjugation of
poly-GluUptake of IF-Cblcomplex
Metabolic Function One Carbontransfers
Unknown
Body stores 4-5 months 2-12 yearsDietary deficiency Common RareDeficiency states
Megaloblasticanemia
Yes Yes
Neurologicdisease
No Yes
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MEGALOBLASTIC ANEMIA Diagnosis /Therapy
• Draw levels at first suspicion of problem,BEFORE ANY THERAPY
• Once levels drawn, begin treatment with both B12 and 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 30 35 40 45 50 55 600
10
20
30
40
50
Re
tic
(%
), H
em
ato
cri
t (%
)
Days
Retic (%) Hematocrit (%)
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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