Amir Humza

Lecturer pathology
NWIHS
Red cells become larger in size than normal. Its diameter is 9u or
above.MCV is increased. MCH &MCHC are normal. Hb in each cell
appear to be low.
Causes: Megaloblastic erythropoiesis in bone marrow:
It is caused due to deficiency of Vit B12 & folic acid which may occur in
the following conditions:
 Dietary deficiency
 Drugs
 intestinal malabsorption
 Pernicious anemia
 Pregnancy
Non-megaloblastic erythropoiesis:
It is found in case of:
 Hemolytic anemia
 Post hemorrhagic anemia
 In which large no of reticulocytes are released in circulation which
accounts for macrocytosis.
 Macrocytosis occasional:
It may be found in the following conditions:
 Alcoholism
 Liver disease
 Acute leukemia
 Myelodysplastic syndrome
 Multiple myeloma
 Lymphoma
 Cytotoxic drugs
Macrocytosis with megaloblastic changes
 Vit B12 deficiency
 Folic acid deficiency
Macrocytosis without megaloblastic changes
 Vit B12 & Folic acid level normal
A. Physiological
 Pregnancy
 Newborn
B. Pathological
 Alcohol excess
 Liver disease
 Reticulocytosis
 Hypothyroidism
 Megaloblastic anemia
 Megaloblastic anemia is characterized by the presence of erythroblasts
in bone marrow with delayed nuclear maturation b/c of defective DNA
synthesis. These erythroblasts are large in size therefore called
megaloblasts.

 Etiology:
 Vit B12 deficiency

 Folic acid deficiency

 Pathogenesis
 For the proliferation of hemopoietic tissue DNA is required in large amount. Both Vit B12
& folic acid are necessary for DNA synthesis. Therefore deficiency of either B12 or folic
acid leads to reduced DNA synthesis which results in delayed or stopped cell division in
bone marrow. Cell division is sluggish, but cytoplasmic development progresses
normally, therefore megaloblastic cells tend to be large, with an increased ratio of RNA to
DNA.

 Megaloblastic erythroid cells tend to be destroyed in the marrow. Thus the marrow
cellularity is often increased but production of RBC’s is decreased (this abnormality is
called inefective erythropoiesis ).

 Associated with changes in red cells, changes also occur in WBC precursors (giant
metamyelocytes) & in megakaryocytes. The massive destruction of marrow cells from
dyserythropoiesis liberates large quantities of enzymes including LDH, which rises to
very high levels in blood.
 Vit B12 Metabolism
 Vit B12 is found in meat, fish, egg and milk but not in plant.
 After engulf VB12 make complex with R-protein present in saliva.
 When it pass small intestine R-protein are degraded by protease.
 Its absorption from lower ileum is facilitated by gastric intrinsic factor,
synthesized by gastric parietal cells. The intrinsic factor form complex with
Vit B12.
 This complex is taken up at special binding sites in the ileum where Vit
B12 is released into the ileum cells; intrinsic factor is not absorbed.
 After absorption Vit B12 is bound to a carrier protein in the plasma &
transported to tissues & taken up by cells as required. Vit B12 is stored in
liver.
 Causes of Vit B12 deficiency

 Low dietary intake

In true vegetarians
 Impaired absorption
1. Stomach
o Intrinsic factor deficiency due to pernicious anemia, gastrectomy
o Congenital deficiency of intrinsic factor without gastric atrophy (rare)
2. Small Intestine
o Crohn’s disasee, ileal resection
o Vit B12 may be removed from gut by bacterial overgrowth in stagnant loops
o Parasites such as fish tapworm
 Pernicious anemia
 It is the megaloblastic anemia due to Vit B12 deficiency as a result of failure of
intrinsic factor by stomach due to atrophy of gastric mucosa.

 It is an autoimmune disease & in about 50% of patients antibodies to intrinsic

factor can be detected.

 There is an association with other autoimmune diseases particularly thyroid

disease, Addison’s disease &. vitiligo

 It is the commonest cause of Vit B12 deficiency.

 Age incidence: 45 – 60yrs

 Clinical Features
 Features of megaloblastic anemia due to Vit B12 deficiency:
Symptoms
1. Onset----- insidious
2. Features of anemia e.g. Pallor, weakness, tachycardia & dyspnea.
Anemia may be severe.
3. Yellow discoloration: Due to mild jaundice caused by excessive
breakdown of hemoglobin due to ineffective erythropoiesis in bone
marrow.
4. Mucosal changes: Red sore tongue due to glossitis & angular stomatitis
may be present. Diarrhea & anorexia due to changes in GI mucosa.
o Spleen may be palpable
o Purpura due to thrombocytopenia may be present.

o Low grade fever due to anemia itself or due to infection.

o CNS examination shows signs of a polyneuropathy.

 Investigations
 Blood picture

 Hemoglobin----- low

 MCV---- raised usually between 110-140 fl. However it is possible to have B12
deficiency with a normal MCV. When iron deficiency & thalassemia coexist
with B12 deficiency MCV is usually normal. Peripheral film shows anisocytosis
& poikilocytosis.

 WBC & paltelet count may be low showing pancytopenia.

 Neutrophils are hypersegmented ( 6 lobes)

 Reticulocyte count is low.

 Investigations
 Bone marrow
 It shows marked erythroid hyperplasia, abnormally large cell size, giant
metamyelocytes.

 Serum Vit B12

 it is usually low below the normal level of 150-350 pg/ml. Most pts with B12
deficiency have serum B12 levels < 100 pg/ml.

 Serum LDH: High

 Serum unconjugated bilirubin: Increased

 Vit B12 absorption test:

 Schilling test is the traditional test to document decreased oral absorption of B12
that is characteristics of pernicious anemia.
 Diagnostic features of pernicious
anemia
 Diagnostic findings
 Very low serum Vit B12, often < 100pg/l
 Anti-intrinsic factor antibodies in serum (present in 50%)

 Corroborative findings
 Macrocytic dysplastic blood picture
 Megaloblastic marrow
 Abnormal Vit B12 absorption test corrected by addition of intrinsic factor (schilling test).
Diagnostic features of Megaloblastic
anemia
 Hemoglobin: Often reduced, may be very low
 MCV: usually raised, commonly > 120 fl.
 Erythrocyte count: Low for degree of anemia
 Blood film: Oval macrocytosis, poikilocytosis, red cell fragmentation,
neutrophil hypersegmentation.
 Reticulocyte count: Low for degree of anemia
 Platelet count: normal or reduced.
 Bone marrow: Increased cellularity, megaloblastic changes in erythroid
series, giant metamyelocytes, dysplastic megakaryocytes, increased iron in
stores, pathological non-ring sideroblasts.
 Serum iron: high
 Serum Ferritin: high
 Plasma LDH: high
Megaloblastic anemia due to Folic acid
(Folate) deficiency
 Folic acid is present in vegetable and animal foodstuffs. Its deficiency results in
megaloblastic anemia. The most common cause of folic acid deficiency is
inadequate dietary intake; malabsorption of folic acid is rare B/C it is absorbed
from the entire GIT.

 Causes of folic acid deficiency:

1. Nutritional

Poor intake

 Old age

 Starvation

 Alcohol excess
Poor intake due to anorexia

 GI diseases such as Celiac disease, Crohn’s disease

 Cancer

2. Excess utilization
Physiological

 Pregnancy

 lactation

Pathological

 Hemolysis

 Inflammatory disease
 Clinical Features
 Features of anemia and underlying cause

 Glossitis may occur

 Unlike with B12 deficiency there is no neuropathy.

 Diagnostic features of Folic acid deficiency

Diagnostic findings
 Low serum folate levels

 Red cell folate levels low (but may be normal if folate deficiency is of very
recent onset).

Corroborative findings
 Macrocytic dysplastic blood picture

 Megaloblastic marrow
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