Review Article

Megaloblastic Anemia: An Updated Review

Atul Khajuria, Raju Sehrawat
NIMS College of Paramedical Technology, NIMS University, Jaipur, Rajasthan, India
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Abstract
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Megaloblastic anemia is a kind of anemia, which is triggered by means of inhibition of DNA synthesis at some point of erythropoiesis.
The most frequent motive of defects in red blood cell DNA synthesis is vitamin deficiency, especially vitamin B12 deficiency or folic
acid deficiency. Micronutrient loss can additionally be a cause. Moderate deficiency can consist of swollen tongue and neurological
problems, inclusive of peculiar sensations such as a tingling sensation, whereas severe deficiency can encompass reduced coronary
heart feature and greater serious neurological issues

Keywords: Folic acid deficiency, megaloblastic anemia, pernicious anemia, treatment, vitamin B12 deficiency

Introduction Red blood cells (RBCs) in megaloblastic anemias have an

atypical nuclear maturation and an imbalance between
Macrocytic anemias are characterized with the aid of
nuclear and cytoplasmic maturation. The absence of vitamin
giant red cells with a diameter of greater than 9μ and a
B12 or folates impairs DNA synthesis, which slows nuclear
mean corpuscular quantity of >100 fL. The motives of
replication and delays every step of maturation. The premitotic
macrocytic anemias may also be broadly divided into
interval is prolonged. These effects in a giant nucleus increased
megaloblastic and non-megaloblastic relying on the look
cytoplasmic RNA and early synthesis of hemoglobin. Many
of developing red cell precursors in the bone marrow
cells in no way endure mitosis and breakdown in the bone
megaloblastic anemias can be classified into two main
marrow, producing extraordinarily multiplied stages of serum
categories. The foremost divisions are vitamin B12
lactic dehydrogenase. This deficiency can impair maturation
(cobalamin, Cbl) deficiency and folic-acid deficiency.
in myelogenous white blood cells and megakaryocytes,
The time period megaloblastic refers to the abnormal
producing leukopenia with neutrophilic hypersegmentation
marrow erythrocyte precursor viewed in processes, such
and thrombocytopenia. Megakaryocyte fragments and large
as pernicious anemia, related to altered DNA synthesis.
platelets may additionally be considered on peripheral blood
Macrocytes can show up in the absence of a megaloblastic
smears. Megaloblastic anemias such as pernicious anemia
process. For example, an expanded mean corpuscular
are additionally characterized by energetic intramedullary
volume (MCV) can result actually from enlargement
hemolysis.
in the wide variety of circulating reticulocytes, which
are larger than mature erythrocytes. The most frequent
motives of megaloblastic anemia are acquired, although Etiology
congenital types exist. Deficiencies in cobalamin, folate, Megaloblastic anemia prompted via diet B12 deficiency is
or each account for the majority of cases. The most associated with
frequent disease of cobalamin deficiency is pernicious
anemia. Less-frequent manifestations can manifest as
Address for correspondence: Dr. Atul Khajuria,
the end result of a gastrectomy, inflammatory problems Medical Laboratory Technology, NIMS College of Paramedical Technology,
of the terminal ileum, or infestation with fish tapeworm NIMS University, Jaipur, Rajasthan, India.
Diphyllobothrium latum. Folic-acid deficiency is normally E-mail: atul.khajuria@nimsuniversity.org
brought on by inadequate dietary intake.[1]
Received: 23-May-2022, Revised: 16-Aug-2022, Accepted: 29-Aug-2022,
Published: 16-Nov-2022
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DOI:
10.4103/DYPJ.DYPJ_40_22 How to cite this article: Khajuria A, Sehrawat R. Megaloblastic
anemia: An updated review. D Y Patil J Health Sci 2022;10:63-6.

      © 2022 D Y Patil Journal of Health Sciences | Published by Wolters Kluwer - Medknow 63  
 Khajuria and Sehrawat: Megaloblastic anemia

• Increased utilization of vitamin B12 due to the fact of Physiology

parasitic infections such as D. latum (tapeworm) and
Normal red cell maturation is based on many hematological
pathogenic bacteria in issues such as diverticulitis and
factors; two of which are the vitamin B12 coenzymes (also
small bowel structure.
known as cobalamin) and folates. Megaloblastic dyspoiesis
• Malabsorption syndrome brought on by means of
occurs when one of these elements is absent. Vitamin B12
gastric resection, gastric carcinoma, and some varieties
and a range of structurally comparable compounds, known
of celiac disorder or sprue.
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as cobalamin analogs, that lack the functional coenzyme

• Nutritional deficiency or diminished furnish of
recreation of the vitamin appear in nature as a product of
vitamin B12. Cobalamin is synthesized by way of
sure microorganisms. It will become available to people via
microorganism and is found in soil and contaminated
the meals chain. Approximately one-third of the body’s
water. Foods of animal origin (e.g., meat, eggs, and
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common whole of 5,000 mg is saved in the liver. The

milk) are the fundamental dietary sources. The
average loss of nutrition B12 is approximately 5 mg/day. An
quantity of cobalamin in the common Western diet
adult requires approximately 5 mg of diet B12 per day to
(5–15 mg/day) is extra than sufficient to meet normal
balance this loss, with an increased need for the duration of
requirements. The body can save giant quantities of
uncommon intervals such as pregnancy. An everyday food
cobalamin. Because of this, it can take 2–5 years for a
regimen carries 5–30 mg. Folates are ample in yeast, many
deficiency to improve even in the presence of extreme
leafy vegetables, and organ meats such as liver and kidneys.
malabsorption.
The human body stores little folic acid. Storage quantities
• Chronic atrophic gastritis can occur due to the deficiency
would final approximately 3–4 months if an entire absence
of pernicious anemia as well as megaloblastic anemia.
of dietary folates existed. However, a chronically insufficient
• Abnormal absorption prompted by means of celiac
eating regimen can produce folic acid deficiency anemia.
disorder or sprue.
In addition to a negative diet, alcohol is the most frequent
• Increased utilization brought on by way of being
pharmacological motive of folic-acid deficiency. However,
pregnant or some acute leukemias.
folic-acid antagonists, such as positive drugs used to deal
• Treatment with ant metabolites that act as folic acid
with leukemias and oral contraceptives, show up to reduce
antagonists.
the absorption of folic acid.

Epidemiology
Epidemiological research on megaloblastic anemia
in Nigeria and in Africa is sparse. However, the
frequency of megaloblastosis is best possible in nations
in which malnutrition is rampant and events vitamin
supplementation for aged people and pregnant women
is no longer available. Faulty preparations of meals and
extended demand for folate in the course of pregnancy
are the most frequent reasons for megaloblastic
anemias.
Approximately 1 in 7,500 humans develops pernicious
anemia in the USA per year; however, this has been
modified by modern-day fortification of meals and diet
vitamins in aged sufferers in the USA. International
records confirmed that pernicious anemia and folate
deficiency typically occur in persons older than 40 years
and the occurrence will increase with older populations.
The incidence of pernicious anemia is stated to be greater
in Sweden, Denmark, and United Kingdom than in
different developed international locations.[2] Research
studies have currently documented that 1.9% of persons
older than 60 years have undiagnosed pernicious anemia.
Earlier research advised that pernicious anemia is restricted
to Northern Europeans; however, more recent studies
report the disorder in each Blacks and Latin Americans.
The median age at analysis is 60 years. A slightly greater
number of women than men are affected.
Pathophysiology
The two vitamins, that is, folate and cobalamin, act
synergistically in producing the thymidylic acid used for
DNA synthesis. Therefore, in cobalamin deficiency, the
megaloblastic arrest is actually brought on by means
of a deficit in folate utilization. As shown in Figure 1
(activated methyl cycle), methionine is generated by
means of switch of methylene team from N5-methyl
tetrahydrofolate (FH4) to homocysteine the use of the
enzyme methyl transferase (Methionine synthase). In this
biochemical process, methylcobalamin is the element that
assists in methyl transfer as coenzyme form of cobalamin.
This is why the morphological abnormalities emanating
from either cobalamin or folate deficiency show up
precisely alike.
Clinical Features
Megaloblastic anemias, irrespective of the cause, share
sure widely widespread features. The anemia develops
slowly with little or no signs and symptoms till the
hematocrit is severely depressed and at this point, signs
such as weakness, palpitation, fatigue, mild headedness,
and shortness of breath occur. Severe pallor and mild
jaundice mix to produce a telltale lemon yellow skin.
Slight variations appear in clinical signs and symptoms
of megaloblastic anemia depending on whether or not
it is prompted by using folate deficiency or by means of

      
64 64  D Y Patil Journal of Health Sciences ¦ Volume 10 ¦ Issue 2 ¦ April-June 2022
 Khajuria and Sehrawat: Megaloblastic anemia
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Figure 1: Role of vitamin B12 as a enzyme in megaloblastic anemia
vitamin B12 deficiency. In folate deficiency, fundamental
clinical aspects consist of anemic syndrome, pallor, icterus,
hunter’s syndrome, nail pigmentation, alternate of hair
shade (early graying), and splenomegaly in approximately
10%–15% of patients. In addition to the aforementioned
features, cobalamin deficiency manifests with neurological
symptoms, which encompass loss of joint role feel in
the second toes, loss of vibration experience in toes and
fingers, paraesthesia, hypoesthesia, tingling sensation,
gait abnormalities, loss of coordination, muscle weakness,
spasticity, optic neuropathy, urinary and fecal incontinence,
erectile dysfunction, dementia, and reminiscence loss.
These neuropathies are symmetric and solely have an
effect on decreased extremities. Demonstrable signs
include fine Romberg’s sign, Babinsky reflex, Lhermitte’s
sign, spasticity, hyporeflexia, and clonus.
Laboratory Diagnosis
Pernicious anemia, the most frequent megaloblastic anemia,
is a prototype of the complete group. The hematological
picture is the identical whether or not the motive is diet
B12 or folic acid deficiency. However, assisting laboratory
assays will vary for a number megaloblastic anemias. The
hemoglobin and red cell counts are generally extremely
low in this anemia. However, the microhematocrit (packed
cell volume) can also no longer reflect the real minimize
in erythrocytes because of the enlarged dimension of the
pink cells. This increase in red cell measurement is usually
reflected in the suggested corpuscular volume (MCV), which
may also be as excessive as 130 fL. The mean corpuscular
hemoglobin (MCH) usually varies in approximately 90%
      D Y Patil Journal of Health Sciences ¦ Volume 10 ¦ Issue 2 ¦ April-June 2022
of cases. Concurrent conditions that limit the MCV, such
as thalassemia or iron deficiency, may reason the MCV to
be normal. The imply corpuscular hemoglobin attention
(MCHC) is commonly normal. In this anemia, platelet
counts are normally somewhat decreased. The complete
white blood cell count number will classically show a
leukopenia, especially a neutropenia.[1] Examination of a
peripheral blood smear exhibits a moderate-to-significant
anisocytosis and poikilocytosis with many macrocytic,
ovalocytic red cells. Erythroid precursors, incredibly
metarubricytes, may additionally be observed. Red cell
inclusions such as basophilic stippling, Howell–Jolly bodies,
and Cabot rings might also be observed. Abnormalities in
leukocytes may additionally consist of hypersegmented
(more than four lobes) neutrophils and an extension in the
percentage of eosinophils (eosinophilia). The number of
platelets are also reduced. The reticulocyte count is much
less than 1% in untreated pernicious anemia and is low for
the degree of anemia. However, subsequent to nutrition
B12 treatment, assuming that the patients no longer have
antibodies toward interferon (IFN), the reticulocyte count
can amplify up to 25% in 5–8 days.
Pancytopenia may also be considered in superior cases. In
severe anemia with a hematocrit of much less than 20%,
promegaloblasts and nucleated erythrocytes might also
be seen, precipitated by extramedullary hematopoiesis in
the spleen and very early marrow release. A dimorphic
population of red cells might also be present with
concurrent iron deficiency. The red cell distribution width
is high. The bone marrow is normally hypercellular with
megaloblastic modifications in both the erythroid line
or all lines; however, it can be hypocellular and mimic
aplastic anemia.[3]
Erythrocyte precursors are enlarged with a reduced nuclear-
cytoplasmic ratio. Nuclear-cytoplasmic asynchrony, with
the relative immaturity of the nucleoplasm, is typical.
Changes give red cells a dysplastic appearance, and a
wrong diagnosis of myelodysplastic syndrome can be
made. Granulocytic precursors can also additionally
show nuclear-cytoplasmic dissociation and enlargement.
Characteristically, massive metamyelocytes with large,
incompletely segmented nuclei are seen.
Treatment
The trendy cure for nutrition B12 deficiency is regular
monthly intramuscular injections of at least a 100 mg
of vitamin B12 to right the diet deficiency. This regimen
corrects the anemia and may additionally right the
neurological complications if administered quickly
after the onset of symptoms. A similar advice is that
aged sufferers with gastric atrophy must take capsules
containing 25–1 mg of vitamin B12 each day to forestall
vitamin B12 deficiency. This recommendation supposes
that approximately 1% of vitamin B12 is absorbed by using
65  
 Khajuria and Sehrawat: Megaloblastic anemia
mass motion in the absence of IF. A profitable response
to therapy with cobalamin (vitamin B12) or folate starts
within 8–12 h in the bone marrow, with a decision of
megaloblastic hematopoiesis. The reticulocyte count starts
to increase 2–3 days after therapy and peaks in 5–8 days;
greater and later peaks happen in extra severe anemia.
The hematocrit starts to increase in approximately 1 week
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and will normalize within 4–8 weeks. The MCV typically
increases for the first 3–4 days, most likely due to the fact
of reticulocytosis, and then starts to decrease. The regular
reference range is predicted to be reached in 25–78 days.
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Resolution of neurological abnormalities is structured
on the length of loss. Most neurological signs will exhibit
maximal improvement within 6 months of initiation of
therapy. Serum iron levels will start to fall within 24 h of
profitable treatment, but the affected person ought to be
located over the subsequent 2–3 weeks.[2]
Conclusion
Megaloblastic anemia is a kind of anemia induced by the
inhibition of DNA synthesis during erythropoiesis. The
most frequent motive of defects in RBC DNA synthesis
66 66  D Y Patil Journal of Health Sciences ¦ Volume 10 ¦ Issue 2 ¦ April-June 2022
is vitamin deficiency, mainly vitamin B12 or folic acid
deficiency. On average deficiency, tongue inflammation
and neurological issues may begin. Megaloblastic
anemias are characterized by impaired DNA synthesis
and wonderful RBC precursors megaloblasts in the bone
marrow and macrocytic red cells in the peripheral blood.
The megaloblasts are large, ordinary precursors of RBCs,
which exhibit nuclear-cytoplasmic asynchrony.
Financial support and sponsorship
Not applicable.
Conflicts of interest
There are no conflicts of interest.
References
1. Turgeon ML. Megaloblastic anemias. In: Clinical Hematology:
Theory and Procedures. 4th ed. Philadelphia, PA: Lippincott
Williams & Wilkins; 1999. p. 181.
2. Chanarin I. The Megaloblastic Anaemias. 2nd ed. Oxford, England:
Blackwell Scientific Publishers; 1979.
3. McClatchey KD. Clinical Laboratory Medicine. 2nd ed.
Philadelphia, PA: Lippincott Williams & Wilkins; 2002.