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Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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MEGALOBLASTIC ANEMIA
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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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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Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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)n
H2N
12
34 5
6
78
9
10
NH
NH
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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 2º to impaired GI
epithelium (rare)
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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)
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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!!!!!
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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MEGALOBLASTIC ANEMIADiagnosis /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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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
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
Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am
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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