2. INTRODUCTION
Impaired DNA synthesis
Cells affected have relatively rapid turnover
Hematopoietic precursors
Gastrointestinal epithelial cells
Cell division is slow but cytoplasmic
development progresses normally
Cells tend to be large
Increased ratio of RNA to DNA
3. INTRODUCTION
Megaloblastic eythroid progenitors destroyed
in the marrow
Marrow cellularity often increased
RBC production decreased ineffective
erythropoiesis
Most cases due to deficiency of:
Cobalamin
Folic acid
4. DIAGNOSIS
Significant macrocytosis (MCV > 100 fl)
If MCV > 110 fl, megaloblastic anemia is
more likely
Low reticulocyte count, decreased leukocyte
and platelet count especially in severely
anemic patients
PBS: marked anisocytosis, poikilocytosis
with macroovalocytes
5. DIAGNOSIS
Nucleated RBC’s, hypersegmented nucleus of the
neutrophils
Hypercellular bone marrow with decreased
myeloid/erythroid ratio and abundant stainable iron
RBC precursors abnormally large, nuclei appear
much less mature
Nuclear chromatin condenses in a fenestrated pattern
Ineffective erythropoiesis
RBC folate level better than serum folate level as an
index of folate stores
7. FOLIC ACID DEFICIENCY
Sources: fruits and vegetables
Destroyed by cooking
Requirement: 50 ug/day
Increased during pregnancy
Absorbed in proximal jejunum
Plasma folate: N5 – methyltetrahydrofolate
Normal: 5-20mg in various body stores, half
in the liver
8. FOLIC ACID DEFICIENCY
Transfer methyl and formyl groups to organic
compounds to form metabolic intermediates
used in the synthesis of:
Purines
Deoxythymidylate monophosphate (dTMP)
methionine
9. FOLIC ACID DEFICIENCY
Some drugs inhibit dihydrofolate reductase-
producing folate deficiency despite normal
tissue folate concentrations
Patients more malnourished
GIT manifestations more severe
Diarrhea often present
May have cheilosis and glossitis but neurologic
abnormalities do not occur
Due to inadequate intake, increased demand or
malabsorption
10. FOLIC ACID DEFICIENCY
INADEQUATE INTAKE
Alcoholics
Narcotic addicts malnutrition
Indigent or elderly individuals on canned foods
or “tea or toast”
Teenagers junk food
Food supplementation
11. FOLIC ACID DEFICIENCY
INCREASED DEMAND
Pregnant women neural tube defects in
the fetus
Folate food supplementation has
decreased neural tube defects by 50%
Infancy
Adolescence
Chronic dialysis
12. FOLIC ACID DEFICIENCY
MALABSORPTION
Tropical sprue
Improved symptoms upon taking folic acid
or antibiotics
Also in non-tropical sprue and alcoholics
Primary small bowel disorders
13. FOLIC ACID DEFICIENCY
TREATMENT
Folate 1 mg/day PO
Up to 5 mg/day in malabsorption
Reticulocytosis after 4 days
Correction of anemia at 1-2 months
In hemolytic anemia and malabsorption or
chronic malnutrition: oral folic acid indefinitely
14. FOLIC ACID DEFICIENCY
DRUGS
Interfereswith DNA synthesis
Direct inhibitors of DNA synthesis
Purine analogues (6-
mercaptopurine)
Pyrimidine analogues (5-FU)
Others (hydroxyurea)
Zidovudine (AZT)
16. FOLIC ACID DEFICIENCY
DRUGS
Interferes
with DNA synthesis
OTHERS:
Mild megaloblastic anemia
May affect intestinal absorption of
folate:
Phenytoin
Primidone
phenobarbital
17. COBALAMIN DEFICIENCY
Cannot be synthesized in the human body
Must be supplied in the diet
Animal products: meat and dairy foods
Minimum daily requirement: 2.5ug/day
Absorbed in distal ileum
Requires binding to intrinsic factor from parietal
cells of the stomach
Transport is via the transcobalamin II
transporter
18. COBALAMIN DEFICIENCY
Liver: 2mg
Another 2 mg elsewhere in the body
3-6 years for a normal person to develop
deficiency if absorption stops
Cofactor for: methionine synthase and
methylmalonyl-CoA synthase
19. COBALAMIN DEFICIENCY
Exists in 2 forms:
Methylcobalamin
required for methionine synthase
Conversion of homocysteine to
methionine
Synthesis of choline from methionine
Neurologic deficits
20. COBALAMIN DEFICIENCY
Exists in 2 forms:
Adenosylcobalamin
Conversion of methymalonyl CoA to
succinyl CoA
21. COBALAMIN DEFICIENCY
CLINICAL DISORDERS
Alcoholics
Pernicious anemia
Tropical sprue
Diphyllobothrium latum
Cobalamin almost always due to malabsorption
Folic acid- decreased dietary intake, increased
metabolic demand, malabsorption
Severe deficiency of one can lead to malabsorption
of the other
22. COBALAMIN DEFICIENCY
Blood, GIT, nervous system
Anemia
Rarely purpura
Pale, slightly icteric skin and eyes, jaundice
Heart may be enlarged
Systolic flow murmur
Sore, smooth and beefy tongue
Anorexia, weight loss, diarrhea
23. COBALAMIN DEFICIENCY
Folate supplementation may increase the
likelihood of neurologic symptoms
Anemia may be very severe but well-
tolerated because it develops slowly
People > 70 years cannot absorb from food
but can absorb form crystalline form
PPI’s inhibit release of cobalamin from food
24. COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA
Most common cause
Absence of intrinsic factor due to atrophy of gastric
mucosa or autoimmune destruction of parietal cells
Less common in Europeans and Asians
Males=females
Presents near age 60, rare under age 30, can be
seen in children under age 10
Increased in immunologic diseases
Graves’
disease, myxedema, thyroiditis, vitiligo, hypoparathyroidism
, idiopathic adrenocortical insufficiency
25. COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA
Abnormal circulating antibodies
90% anti-parietal cell antibody against HK-
ATPase
60% anti-IF antibody, absent in patients with
gastric atrophy but no pernicious anemia
Relatives have increased incidence
Common in agammaglobulinemia
Glucocorticoids may reverse the disease
Gastric atrophy with antral sparing
26. COBALAMIN DEFICIENCY
PERNICIOUS ANEMIA
Insidious onset
hypergastrinemia, hematologic abnormalities
Nervous system changes may be irreversible
Subject to gastric polyps and 2x the normal
incidence of cancer
27. COBALAMIN DEFICIENCY
Postgastrectomy/ extensive damage to
gastric mucosa
Intestinal organisms
Bacterial overgrowth consume cobalamin
Tetracycline, ampicillin
D. latum competes for cobalamin
29. COBALAMIN DEFICIENCY
Nitrous Oxide
Destroys endogenous cobalamin
Repeated or protracted use (>6 hours)
Especially in the elderly
30. COBALAMIN DEFICIENCY
TREATMENT
Generally given parenteral (IM cyanocobalamin)
1000 ug cobalamin/ week for 8 weeks followed by
1000 ug IM every month for the rest of the patient’s
life or 2 mg crystalline B12/day
Increase in strength, improved sense of well-being
Marrow morphology reverts to normal within a few
hours
Reticulocytosis after 4-5 days, peaks at day 7
Anemia resolves over the next several weeks
Hypokalemia, salt retention, thrombocytosis may be
seen
31. COBALAMIN DEFICIENCY
TREATMENT
Severe anemia- emergency transfusion
Neurologic symptoms may not be fully corrected
Folate may improve anemia without improving or
even worsening of neurologic symptoms
0.1 mg oral crystalline cobalamin prophylaxis
daily in people over 65 years old
