HEMATOLOGY|CHAPTER 21

MEGALOBLASTIC ANEMIA
Interns: Garcia, Gelito, & Galit | Central Philippine University | CMLS
 At the end of this presentation, the interns
OBJECTIVES should have been able to KNOW:
• The relationships among macrocytic anemia,
megaloblastic anemia, and pernicious anemia, and
classify anemias appropriately.
• The physiologic roles of folate and vitamin B12 in
DNA production.
• The absorption and distribution of vitamin B12,
including carrier proteins and the biologic activity of
various vitamin-carrier complexes.
• The biochemical basis for development of anemia
with deficiencies of vitamin B12 and folate, and
explain the cause of the accompanying
megaloblastosis.
• The individuals at risk for megaloblastic anemia by
virtue of age, dietary habits, or physiologic
circumstance such as pregnancy, drug regimens, or
pathologic conditions.
 At the end of this presentation, the
OBJECTIVES interns should have been able to KNOW:
• The complete blood count, reticulocyte count,
red and white blood cell morphologies, and bone
marrow findings consistent with megaloblastic
anemia.
• The results of tests measuring levels of serum
vitamin B12, serum methylmalonic acid, serum
folate, plasma or serum homocysteine, and
antibodies to intrinsic factor, determine the likely
cause of a patient’s deficiency.
• The results of bilirubin and lactate
dehydrogenase tests that are consistent with
megaloblastic anemia and explain why the test
values are elevated in this condition.
 INTRODUCTION
Impaired deoxyribonucleic acid
(DNA) metabolism causes systemic
effects by impairing production of
all rapidly dividing cells of the body
namely;
1. Skin
2. Epithelium of the
gastrointestinal tract
3. Hematopoietic tissue
 INTRODUCTION
Patients may experience symptoms in
any of these systems, but the blood
provides a ready tissue for analysis.
The hematologic.effects, especially
megaloblastic anemia, have come to be
recognized as the hallmark of the
diseases affecting DNA metabolism.
 ETIOLOGY
The root cause of megaloblastic
anemia is impaired DNA synthesis. The
anemia is named for the very large cells
of the bone marrow that develop a
distinctive morphology due to a
reduction in the number of cell
divisions. Megaloblastic anemia is one
example of a macrocytic anemia.
 ETIOLOGY

Understanding the etiology of

megaloblastic anemia requires a
review of DNA synthesis with
particular attention to the roles of:
1. Vitamin B12 (cobalamin)
2. Folic acid (folate)
 PHYSIOLOGIC ROLES OF VITAMIN B12 & FOLATE

Vitamin B12 is a coenzyme in two

biochemical reactions in humans.

1. Isomerization of methylmalonyl
coenzyme A (CoA) to succinyl CoA,
which requires vitamin B12 (in the
adenosylcobalamin form) as a cofactor
In the absence of vitamin B12, the impaired
and is catalyzed by the enzyme activity of methylmalonyl CoA mutase leads
to a high level of serum methylmalonic acid
methylmalonyl CoA mutase. (MMA), which is useful for the diagnosis of
vitamin B12 deficiency
 PHYSIOLOGIC ROLES OF VITAMIN B12 & FOLATE

2. The transfer of a methyl group from 5-

methyltetrahydrofolate (5-methyl THF) to
homocysteine, which thereby generates
methionine. This reaction is catalyzed by
the enzyme methionine synthase and uses
vitamin B12 (in the methylcobalamin form)
as a coenzyme.

Methylcobalamin is synthesized through reduction and methylation of vitamin B12. This reaction represents the link between
folate and vitamin B12 coenzymes and appears to account for the requirement for both vitamins in normal erythropoiesis.
 PHYSIOLOGIC ROLES OF VITAMIN B12 & FOLATE

Folate is the general term used for

any form of the vitamin folic acid. Folic
acid is the synthetic form in
supplements and fortified food.
Folates consist of a pteridine ring
attached to para-aminobenzoate with
one or more glutamate residues. The function of folate is to transfer carbon units in the form of
methyl groups from donors to receptors. In this capacity, folate
plays an important role in the metabolism of amino acids and
nucleotides. Deficiency of the vitamin leads to impaired cell
replication and other metabolic alterations.
OTHER CAUSES OF MEGALOBLASTOSIS

1. Dysplastic erythroid cells in

myelodysplastic syndrome (MDS)

2. Congenital dyserythropoietic
….anemia (CDA) types I and III
SYSTEMIC MANIFESTATIONS OF FOLATE AND VITAMIN B12 DEFICIENCY

a. Weakness, fatigue and shortness of breath

from anemia

b. Sore tongue (glossitis) – severe cases are

very painful, tongue appears “beefy red”

c. Skin: lemon-yellow color (pallor + mild

icterus); blotchy, brownish pigmentation
with patches of vitiligo may appear

d. Others: Gastritis, nausea, constipation,

weight loss due to anorexia difficulty
walking
SYSTEMIC MANIFESTATIONS OF FOLATE AND VITAMIN B12 DEFICIENCY

NEUROLOGIC SYMPTOMS

• Pronounced in Vitamin B12 deficiency, absent in folate

deficiency anemia)
• Nervous System Findings
***Demyelinization of spinal cord and peripheral nerves

1. Paresthesias (prickling, tingling, “pins and needles” sensation in

the hands and feet)
2. Memory loss, loss of balance, weakness, clumsiness, spasticity
3. Megaloblastic madness – infrequent; personality changes and
psychosis (hallucinations, maniacal outbursts, paranoia,
schizophrenia)
 REFERENCE
Rodak, B. F., Fritsma, G. A., & Keohane, E. M. (2016). Hematology:
Clinical principles and applications (5th ed.). St. Louis, Mo.: Elsevier
Saunders.