MEGALOBLASTIC ANEMIA

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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 gt 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 ACID
OH
N
1
8
N
2
7
(GLU)n
6
9
COCH2CH2CHCOOH
3
5
4
N
N
H2N
10
NH
CONH
Pteridine
PABA
Glutamic Acids
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FOLIC ACID
OH
N
1
8
N
2
7
(GLU)n
6
9
COCH2CH2CHCOOH
3
5
4
N
N H
H2N
10
NH
CONH
NH
NH
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FOLIC ACIDOne Carbon Fragment Forms
NH
NH
NH
NH
N
NH2
N5,10-methenyl THF
CH2
CH
CH3
N5,10 methylene THF
N5 methyl THF
Thymidylatebiosynthesis
Transport
H2O
N10-formyl THF
NH
NH
Purine biosynthesis
HC O
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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 CoAto succinyl CoA

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COBALAMINStructure
-groupsCN - Cyano inactiveOH - Hydroxyl
inactiveMethyl - Folate metabolismAdenosyl -
Mutase activity
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COBALAMIN REACTIONS
Methylmalonyl CoA
Homocysteine
Methionine
MethylCobalamin
AdenosylCobalamin
THF
NH
NH
CH3
Succinyl CoA
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GI ABSORPTION OF COBALAMIN
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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
THF
Cbl
Conjugated folates
N5-methyl-THF
THF
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
  folateDON'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
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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
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SCHILLING TEST
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MEGALOBLASTIC ANEMIASSummary

• Deficiency in folate or B12
• Macrocytic anemia other cytopenias
• Slowly developing anemia, usually
  wellcompensated
• Response to therapy rapid and dramatic
• Treatment essential to avoid other complications
• Anemia is secondary to an underlying disease
  process