distinctive morphologic appearances of the developing red cells in the bone marrow

1. MEGALOBLASTIC ANEMIAS
ZIV H OSPITA L 2 0 2 1
SAMEER SAWAED , MD

2. INTRODUCTION
distinctive morphologic appearances of the developing red
cells in the bone marrow.
• cause is usually a deficiency of either cobalamin (vitamin
B12) or folate
• genetic or acquired abnormalities

3. CAUSES OF MEGALOBLASTIC ANEMIA

4. COBALAMIN
• Cobalamin (vitamin B12) exists in a number of different
chemical forms.
• 2-deoxyadenosyl (ado) form, which is located in
mitochondria. It is the cofactor for the enzyme L-
methylmalonyl coenzyme A (CoA) mutase
• The other major natural cobalamin is methylcobalamin,
the form in human plasma and in cell cytoplasm.

5. DIETARY SOURCES AND
REQUIREMENTS
• Cobalamin is synthesized solely by microorganisms
• The only source for humans is food of animal origin, for
example, meat, fish, and dairy products.
• daily requirements are also about 1–3 μg.

6. ABSORPTION
• Two mechanisms exist for cobalamin absorption:
• One is passive, occurring equally through buccal,
duodenal, and ileal mucosa; it is rapid but extremely
inefficient, with <1% of an oral dose being absorbed
by this process.

7. ABSORPTION
The normal physiologic mechanism is active
• It occurs through the ileum and is efficient for small (a
few micrograms) oral doses of cobalamin, and it is
mediated by gastric intrinsic factor (IF).

8. IF
produced in the gastric parietal cells of the fundus and
body of the stomach
• The cobalamin-IF complex enters the ileal cell, where
IF is destroyed.
• cobalamin appears in portal blood attached to
transcobalamin (TC) II.

9. FOLATE
Folic (pteroylglutamic) acid
• The highest concentrations are found in liver, yeast,
spinach, other greens, and nuts (>100 μg/100 g).
• Folate is easily destroyed by heating, particularly in
large volumes of water.
• Daily adult requirements are ~100 μg

10. FOLATE ABSORPTION
Folates are absorbed rapidly from the upper small
intestine
• converted to 5-methylTHF (5-MTHF) within the small
intestinal mucosa before entering portal plasma
• Folate is transported in plasma; about one-third is
loosely bound to albumin, and two-thirds is
unbound.

11. COBALAMIN-FOLATE RELATIONS
• Methylmalonyl- CoA isomerization requires adocobalamin
• The methylation of homocysteine to methionine requires
both methylcobalamin and 5-MTHF
• folate polyglutamate synthase can use only THF, not
MTHF, as substrate.
• This has been termed THF starvation
• why the anemia of cobalamin deficiency responds to folic
acid in large doses.

13. CLINICAL FEATURES
raised mean corpuscular volume (MCV) on a routine blood
count.
• anemia
• Glossitis, angular cheilosis, a mild fever in more severely
anemic patients, jaundice (unconjugated)
• The anemia and low leukocyte count may predispose to
infections, particularly of the respiratory and urinary
tracts.

14. NEUROLOGIC MANIFESTATIONS
Vitamin B12 is needed for the myelination of the central
nervous system.
• bilateral peripheral neuropathy or degeneration
• The patient, more frequently male, typically presents with
paresthesias, muscle weakness, or difficulty in walking
but sometimes with the dementia, psychotic
disturbances, or visual impairment.

15. DEFICIENCY IN INFANCY
• In infancy there may be feeding difficulties, lethargy, and
coma.
• Convulsions and myoclonus have been described.
• tests for pernicious anemia (PA) by serum gastrin level
and for antibodies to IF or parietal cells
• vitamin B12, vitamin B6, and folic acid alone or in
combination did not improve cognitive function.

16. ADVANCED DISEASES
• Neural Tube Defects Folic acid supplements at the time
of conception and in the first 12 weeks of pregnancy
reduce by ~70% the incidence of neural tube defects
(NTDs)
• Cardiovascular Disease Children with severe
homocystinuria
• Meta-analysis showed an 18% reduction in strokes.

17. ADVANCED DISEASES
• Malignancy Prophylactic folic acid in pregnancy has
been found in some but not all studies to reduce the
subsequent incidence of acute lymphoblastic leukemia
(ALL) in childhood.

18. HEMATOLOGIC FINDINGS
• The MCV is usually >100 fL
• neutrophils are hypersegmented (more than five
nuclear lobes).
• leukopenia due to a reduction in granulocytes and
lymphocytes
• platelet count may be moderately reduced

21. PERNICIOUS ANEMIA
• defined as a severe lack of IF due to gastric atrophy.
• other organ-specific autoimmune diseases, for example,
thyroid diseases, vitiligo, hypoparathyroidism, Type 1
diabetes, and Addison’s disease. It is also associated
with hypogammaglobulinemia, with premature graying or
blue eyes, and persons of blood group A.

22. PERNICIOUS ANEMIA
• IF antibodies also have been detected in gastric juice in
~80% of PA patients.
• Parietal cell antibody is present in the sera of almost
90% of adult patients with PA but is frequently present in
other subjects.
• Type 1 + type 2

23. ANTI FOLATE DRUGS
The drugs that inhibit DHF reductase :
methotrexate, pyrimethamine, and trimethoprim.
The antidote to these drugs is folinic acid (5-formyl-THF).

24. TREATMENT
• Treat the underlying cause of cobalamin deficiency
• The indications for starting cobalamin therapy are a well-
documented megaloblastic anemia or other
hematologic abnormalities and neuropathy due to
the deficiency.

25. TT
• Replenishment of body stores should be complete with
six 1000-μg IM injections of hydroxocobalamin given at
3- to 7-day intervals.
• For maintenance therapy, 1000 μg hydroxocobalamin IM
once every 3 months is satisfactory.

26. • large daily oral doses (1000–2000 μg) of
cyanocobalamin are used in PA for replacement
(especially in Canada and Sweden)
PA

27. FOLATE DEFICIENCY
• Oral doses of 5–15 mg folic acid daily are satisfactory
• Before large doses of folic acid are given, cobalamin
deficiency must be excluded and, if present, corrected
•
• Long-term folic acid therapy is required when the
underlying cause of the deficiency cannot be corrected
and the deficiency is likely to recur, for example, in
chronic dialysis or hemolytic anemias.