HEMATOLOGY LECTURE

Disorders of DNA Metabolism

(Chapter 21 of Rodaks Hematology)

macrocytic (MCV > 100 fL) and megaloblastic

anemias
primarily caused by vitamin B12 and folate deficiency

ROLES OF VITAMIN B12 AND FOLATE

- vitamin B12 (cobalamin) is used as a cofactor in two
biochemical reactions
o isomerization of methylmalonyl-CoA into
succinyl-CoA
deficiency of vitamin B12 causes serum
methylmalonic acid useful in diagnosis
o transfer of methyl group from 5methyltetrahydrofolate (5-THF) to homocysteine
for generation of methionine
link between importance of vitamin B12 and
folate
- folate primarily functions to transfer methyl groups
o important in the metabolism of proteins and
nucleic acids
o deficiency leads to impaired cell replication
o folate exists mostly as 5-THF (inactive form) and
becomes its active form, THF upon
demethylation
- 5-THF THF 5,10-methylene THF + dUMP
dTMP
- dTMP serves as a precursor for dTTP (a nucleotide)
MEGALOBLASTIC ANEMIA DUE TO VITAMIN B12 AND
FOLATE DEFICIENCY
- causes impaired DNA synthesis
- instead of thymidine, uridine is used in DNA
o causes gaps in the DNA sequence
o creates nonfunctional DNA
o leads the cell to apoptosis
- shows nuclear-cytoplasmic asynchrony slower
maturation of nucleus as compared to the cytoplasm
CAUSES OF VITAMIN DEFICIENCY
1. Folate Deficiency
o inadequate dietary uptake

/sqg

increased need pregnant and lactating

women, growing children
o impaired absorption - sprue and celiac disease
o impaired use inhibited by anti-epileptic drugs
and some anti-cancer drugs
o excessive loss by renal dialysis
2. Vitamin B12 Deficiency
o inadequate dietary uptake
o increased need pregnant and lactating
women, growing children
o impaired absorption
failure to separate vitamin B12 from food
proteins
failure to separate vitamin B12 from
haptocorrin caused by lack of trypsin
lack of intrinsic factor may be caused by
pernicious anemia and H. pylori infection
malabsorption sprue and celiac disease
o inherited errors Imerslund-Grasbeck syndrome
DIAGNOSIS OF MEGALOBLASTIC ANEMIA
1. Screening
o complete blood count
Hgb, Hct
MCV, MCH, RDW
o absolute reticulocyte count -
o manual differential count hypersegmented
neutrophils, oval macrocytes
o serum bilirubin and serum LDH -
megaloblastic anemia may also be a
hemolytic anemia
2. Diagnostic
o bone marrow exam presence of megaloblasts
o serum vitamin B12 and serum folate
o serum methylmalonic acid and serum
homocysteine
o

TREATMENT
- vitamin B12 can be administered orally or
intramuscularly (for treatment of pernicious anemia)
- folic acid can be administered orally
- iron may also be supplemented