Megaloblastic Anemia Thursday, February 12, 2004 – 9:00 am 1 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
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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
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!!!!!
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