1. health and fitness
2. disease
3. thyroid disease

Course title :Hematology (1)
Course code:MLHE-201
Supervisor :Prof Dr.Magda Sultan
Date : 12/12/2013
Outcome:
The student will be able to know :
-Definitions of megaloblastic and nonmegaloblastic anaemias.
-How to diagnose these anaemias ?.
- What are their causes ?
Megaloblastic anaemia
• Macrocytic anemias are characterized by large RBCs
with a normal hemoglobin content.
• Macrocytic anemias are classified as either
megaloblastic or non-megaloblastic
– Megaloblastic anemias are associated with
defective DNA synthesis and therefore, abnormal
RBC maturation in the bone marrow (a nuclear
maturation defect).
– In megaloblastic anemias, the granulocytic and
megakaryocytic maturation are also affected and
this leads to pancytopenia
 The
biochemical basis for this is as follows:
Megaloblastic dyspoiesis (abnormal synthesis)
occurs when the DNA synthesis in the
hematopoietic system is disrupted or slowed down.
 Other rapidly proliferating cells in the body are also
affected.
 Administration of drugs that interfere with DNA
metabolism can be the cause of a megaloblastic
anemia.
 On rare occasions there is an inherited disorder that
affects DNA synthesis


However, the primary defect in DNA replication is
usually due to depletion of thymidine triphosphate
which leads to retarded mitosis, and therefore
retarded nuclear maturation.
 Vitamin B12 deficiency is usually due to a
deficiency of a factor necessary for B12 absorption
while a folic acid deficiency is usually due to an
inadequate dietary intake.
 The depletion of thymidine triphosphate is usually
due to a deficiency of vitamin B12 or folic acid.
Absorption and metabolism of vitamin B12
and folic acid:
Vitamin B12 (cyanocobalamine):
- Is found in meats, eggs, dairy products, and liver.
- Is absorbed via a binding protein called intrinsic
factor (IF)



Vitamin B12 and IF bind to mucosal cells in the ileum and
B12 enters.
When B12 is released from the mucosal cell, it binds to
transport proteins in the blood stream (transcobalamine
IIII). Type II is the primary transport protein. Therefore a
congenital deficiency in type II can lead to a megaloblastic
anemia.
B12 is transported to the bone marrow for use or to the liver
for storage.
VITAMIN B12 ABSORPTION
HOW IS B12 INVOLVED IN DNA
SYNTHESIS?
MEGALOBLASTIC ANEMIAS
Decreased vitamin B12 therefore results in no
conversion of N5-methyl THF to THF. Thus,
the net result is that dTMP for DNA synthesis
is not made.
 Humans need 3-5 ug of vitamin B12 per day.
Since 70% of dietary B12 is absorbed, the diet
needs to contain 5-7 ug/day.

MEGALOBLASTIC ANEMIAS

Folic acid (pteroyl glutamic acid)
Is found in most foods, including eggs, milk,
yeast, and liver.
 Is abundant in green, leafy vegetables and is
synthesized by many microorganisms.
 Is destroyed by heat
 Absorption occurs in the small intestine

HOW IS FOLIC ACID INVOLVED IN DNA
SYNTHESIS?
MEGALOBLASTIC ANEMIAS
» Therefore, with decreased folic acid, the net result is the
same as that for decreased vitamin B12 – there is
decreased conversion of dUMP to dTMP, and thus, dTTP
which is required for DNA synthesis.
» Defective DNA synthesis may occur when dUTP gets
used in place of dTTP because there is a great increase
in erroneous DNA copying where dUTP is put in place of
dTTP.
» Humans need to get about 50 ug/day of folic acid from
the diet
Causes of megaloblastic anemia
-Vitamin B12 deficiency
» 85% is due to lack of intrinsic factor (IF) secondary to
gastric atrophy – this is called pernicious anemia (PA) and
it occurs most often in older adults (over 40), most
commonly in individuals of Northern European descent,
and more commonly in women. Antibodies against the
parietal cells in the G.I. tract and against IF are commonly
found in these individuals.
» After gastrectomy
» Malabsorption syndrome
» Inadequate dietary intake (rare)
» Defective or absent transport proteins (transcobalamine)
MEGALOBLASTIC ANEMIAS

Folic acid deficiency





Inadequate diet is the major cause and this occurs most
often in the poor, elderly, and alcoholics.
When there is increased requirement such as in
pregnancy, hemolytic anemia, leukemia, etc.
Malabsorption – may be due to diseases of the upper
small intestine such as ileitis, tropical sprue, and
gluten sensitive enteropathy.
When there is increased loss such as in patients
undergoing hemodialysis
Drug inhibition – examples are oral contraceptives,
anticoagulant drugs, alcohol, and isoniazid
MEGALOBLASTIC ANEMIAS
• Clinical manifestations occur in two categories – those
found in folic acid or vitamin B12 deficiency, and those
mainly found in B12 deficiency
– In both types of deficiency the symptoms include
pallor, weakness, a smooth, sore tongue, and
diarrhea alternating with constipation
– In vitamin B12 deficiency, and occasionally folic acid
deficiency, there are neurological disturbances
including numbness and tingling of extremities, gait
abnormalities, and mental disturbances.
MEGALOBLASTIC ANEMIAS


Lab findings
Macrocytic, normochromic anemia
(MCV=100-140, MCHC is normal))
MCH is increased (due to increased cell
size)
Hemoglobin and RBC counts are decreased
 WBC and platelet counts are decreased
 On a peripheral smear, a triad of things is
commonly seen: oval macrocytes, Howell Jolly
bodies (nuclear DNA fragments), and
hypersegmented neutrophils (5 or more lobes).
MEGALOBLASTIC ANEMIAS

In addition:
 Anisocytosis is usually moderate
 Poikilocytosis is striking with nucleated
RBCs, polychromatophilia, and cabot rings
(spindle remnants).
 RBC dimorphism is seen with concomitant
IDA.
 The absolute reticulocyte count is decreased
because of ineffective erythropoiesis.
PERIPHERAL SMEAR OF
MEGALOBLASTIC ANEMIA
• Oval Macrocyte
• Howell Jolly Body
• Cabot ring
PERIPHERAL SMEAR OF
MEGALOBLASTIC ANEMIA
Hypersegmented
neutrophil
MEGALOBLASTIC ANEMIAS
The bone marrow will show hypercellularity,and
megaloblastic erythroid series , yet there are decreased
numbers of all cell types in the peripheral blood because
ineffective hematopoiesis is occurring and many cells are
dying prematurely in the bone marrow.
 In folic acid deficiency – there will be decreased serum
and RBC folate
 In B12 deficiency – there will be decreased serum vitamin
B12
 Specific tests for PA
 Gastric analysis – if there is no free HCl after
histamine stimulation, this may indicate PA since the
same cells that secrete HCl, also secrete intrinsic factor
(IF)
 Test for antibodies to IF

NON-MEGALOBLASTIC MACROCYTIC
ANEMIA
NON-MEGALOBLASTIC MACROCYTIC
ANEMIA
Note that the macrocytic RBCs are not oval, but are
round.
 There are no hypersegmented neutrophils or HowellJolly bodies

DIFFERENTIAL DIAGNOSIS WITH
INCREASED MCV
LAB RESULTS OF MEGALOBLASTIC VS
NON-MEGALOBLASTIC MACROCYTOSIS
Assignement :
• Student name : ‫تغريد محمود ابراهيم‬
Title: Laboratory diagnosis of macrocytic
anaemias
Student name : ‫حماده محمد عشري‬
Title : Types of macrocytic anaemias .
Student name : ‫باخوم سدراك نظير‬
Title : Peripheral blood findings in megaloblastic
anaemias .
• Training questions :
What are the peripheral blood findings in megaloblastic
anaemias ?
Mention the causes of megaloblastic anaemia.
-Reference Book : - Essential hematology
- Dacie .