Megaloblastic Anemias

Causes:
• Folate deficiency Required for the
synthesis of
thymidylate, which is
required for DNA
replication.
• Vitamin B12 deficiency
 Megaloblastic anemia stems
Mechanism:
from metabolic defects that
lead to inadequate biosynthesis Many red cell progenitors are so defective in
of thymidine, one of the DNA synthesis that they undergo apoptosis in
building blocks of DNA. the marrow (ineffective hematopoiesis).

Others mature into red cells but do so after

Abnormalities in rapidly dividing fewer cell divisions, further diminishing the
cells throughout the body, but output of red cells
the hematopoietic marrow
is most severely affected.
Granulocyte and platelet
Precursors are also affected resulting in
segmented granulocytes, macrocytic
The synthesis of RNA and
anemia, pancytopenia (anemia,
cytoplasmic elements proceeds
thrombocytopenia,
at a normal rate which outpaces
and granulocytopenia).
the nucleus, the hematopoietic
precursors show nuclear-
cytoplasmic asynchrony.
 Folate Deficiency:- Causes
Inadequate dietary intake

Increased metabolic demands

Problems with absorption or metabolism:

Food
Drugs
Malabsorptive disorders
 • Folate is present in nearly all foods, it is
destroyed by 10 to 15 minutes of cooking, so
Diet stores are marginal
• poor diet is seen in the economically
deprived, the indigent, and the elderly)

Metabolic • Pregnant women.

• Chronic hemolytic anemias, such as sickle cell
demands disease
Defects with absorption or metabolism:
• Food folates are predominantly in polyglutamate
form and must be split into monoglutamates for
Diet absorption, a conversion that is inhibited by acidic
foods and substances found in beans and other
legumes.

• Phenytoin (dilantin), interfere with folate

Drugs absorption,
• Methotrexate inhibit folate metabolism.

Malabsorpti • Celiac disease and tropical sprue, that affect

the upper third of the small intestine where
ve disorders folate is absorbed, impair folate uptake.
 Pathogenesis:
• Helps in conversion within cells from dihydrofolate to
tetrahydrofolate by dihydrofolate reductase.

• Tetrahydrofolate acts as an acceptor and donor of one-

carbon units in several reactions that are required for the
synthesis of deoxythymidine monophosphate (dTMP).

• If intracellular stores of folate fall, insufficient dTMP is

synthesized and DNA replication is blocked, leading to
megaloblastic anemia.
 Vitamin B12 deficiency:
• Sources:
• Vitamin B12 is widely present in foods, is resistant to
cooking and boiling, and is even synthesized by gut flora.
• Thus, unlike folate, vitamin B12 deficiency is virtually
never caused by inadequate intake except in vegetarians
who scrupulously avoid milk and eggs.

• Deficiencies typically arise from some abnormality

that interferes with vitamin B12 absorption
 Defects in absorption:
Peptic digestion releases dietary vitamin B12, allowing it to bind a salivary
protein called haptocorrin.
On entering the duodenum, haptocorrin–B12 complexes are processed by
pancreatic proteases; this releases B12, which attaches to intrinsic factor
secreted from the parietal cells of the gastric fundic mucosa.
The intrinsic factor–B12 complexes pass to the distal ileum and attach to
cubilin, a receptor for intrinsic factor, and are taken up into enterocytes.
The absorbed vitamin B12 is transferred across the basolateral membranes
of enterocytes to plasma transcobalamin, which delivers vitamin B12 to the
liver and other cells of the body.
After absorption, the body stores it in the liver, which normally contains
reserves sufficient to support bodily needs for 5 to 20 years.
Because of these large liver stores, clinical presentations of vitamin B12
deficiency typically follow years of unrecognized malabsorption.
 Causes of malabsorption:
Name of Disease Reasons
• Pernicious Anemia • Autoimmune attack on the gastric mucosa that
suppresses theproduction of intrinsic factor.
Histologically, there is a chronic atrophic gastritis
marked by a loss of parietal cells, a prominent
infiltrate of lymphocytes and plasma cells, and
megaloblastic changes in mucosal cells similar to
thosefound in erythroid precursors. Primary cause
of the gastric pathology; rather, it seems that an
autoreactive T cell response initiates gastric
mucosal injury and triggers the formation of
autoantibodies. When the mass of intrinsic factor-
secreting cells falls below a threshold (and
reserves of stored vitamin B12 are depleted),
anemia develops.
 Causes of malabsorption:
Name of Disease Reasons
• Gastrectomy • Loss of intrinsic factor–producing cells.
• Ileal resection • Loss of intrinsic factor–B12 complex–absorbing
cells
• Crohn disease, • Loss of intrinsic factor–B12 complex–absorbing
tropical sprue, and cells
Whipple disease.
• Gastric atrophy and • There is interference with the production of acid
achlorhydria seen and pepsin, which are needed to release the
in older persons vitamin B12 from its bound form in food
 Pathogenesis
• The metabolic defects responsible for the anemia of vitamin B12
deficiency are intertwined with folate metabolism.
• Vitamin B12 is required for recycling tetrahydrofolate, which is the
form of folate that is needed for DNA synthesis.
• The main neurologic lesions associated with vitamin B12 deficiency
are demyelination of the posterior and lateral columns of the spinal
cord, sometimes beginning in the peripheral nerves
 Clinical features:
Folate deficiency:
• Weakness and easy
fatigability.
• Sore tongue.
(Because the cells lining the
gastrointestinal tract, like the
hematopoietic system, turn
over rapidly)
• Unlike in vitamin B12
deficiency neurologic
abnormalities do not occur.
Vitamin B12 deficiency:
• Pallor, easy fatigability,
• In severe cases, dyspnea and even congestive
heart failure.
• Mild jaundice: The increased destruction of
erythroid progenitors because of ineffective
erythropoiesis.
• The spinal cord disease (subacute degeneration
of spinal cord) begins with symmetric numbness,
tingling, and burning in the feet or hands,
followed by unsteadiness of gait and loss of
position sense, particularly in the toes due to
demyelination of the posterior and lateral
columns of the spinal cord, sometimes beginning
in the peripheral nerves. In time, axonal
degeneration may supervene.
 Investigations:
Folate deficiency
• The anemia of folate deficiency is
best distinguished from that of
vitamin B12 deficiency by
measuring serum and red cell
folate and vitamin B12 levels.
Vitamin B12 deficiency
• Low serum vitamin B12 levels
• Normal or elevated serum folate
levels.
• Moderate to severe macrocytic
anemia
• Leukopenia with hypersegmented
granulocytes.
• Dramatic reticulocytic response
(within 2 to 3 days) to parenteral
administration of vitamin B12.
• Pernicious anemia is associated
with all of these findingsplus the
presence of serum antibodies to
intrinsic factor.
 Treatment:
Folate deficiency Vitamin B12 deficiency
• Folic acid supplements • Vitamin B12 supplements