1. No category

Megaloblastic Anemia
Teoman SOYSAL Prof.MD
Megaloblastic Anemia

A subclass of macrocytic anemia
(under morphologic classification)
Or
 A subclass of anemias due to defective
DNA synthesis
(pathogenetic classification)
Megaloblastic Anemia

Main causes of “Megaloblastic Anemia”
– Vit.B12 deficiency
– Folic acid deficiency
– Others
Megaloblastic Anemia

30-50 % of all macrocytic anemias are
caused by folic acid and/or Vit.B12
deficiency.
Vit B12

Metabolic active cobalamins in the body
are;
– Methyl cobalamin and adenosyl cobalamin


Hydroxocobalamin can be reversed to the
above cobalamins.
Pharmacy:
– Most stable cobalamin: cyanocobalamin
Vit B12

Natural forms
– Produced by microorganisms
(bacteria/fungi)
– Plants do not produce or contain Vit B12
(except contamination)
– Colonic bacterial production occurs but
their location is distal to the site of
absorbtion
Vit.B12

Food sources rich in Vit.B12
– Liver
– Kidney
– Muscle
– Egg
– Milk ,Cheese and other diary products
– Seafood
Plants are not sources of
Vit.B12
Vit.B12
Daily requirements
Age
0-1
1 – 10
Adults
Pregnancy
2nd Trimestr
3rd Trimestr
Lactation
Amount/day
0.3 – 0.5 g,
0.7 – 1.5 g
2g .
(2g + )
0.5g
1g
2.5 – 3 g
Vit.B12





Average diet contains 5 – 30 g Vit. B12
daily
The amount of Vit. B12 in the body is about
2 – 5 mg.
Most of it is in the liver.
The store is sufficient for 3-6 years in case
of impaired absorbtion.
The storage form is mainly
adenosylcobalamin.
B12 in diet
Parietal cell
IF
R - B12
stomach
Pancreas enzymes
Enterohepatic
circulation
B12
R- B12
B12
B12
Ileum cells
TC II
IF - B12
B12
Duodenum
and jejunum
IF
İleum
Vit.B12





Circulates with TCII and TCI in plasma.
Generally in the form of methylcobalamin.
Although most of the B12 is bound to TCI ,
TCII is the functional carrier, rapidly
cleared from plasma.
TCII deficiency is a cause of megaloblastic
anemia.
Vit .B12
Plazma level of Vit. B12

200 - 900 ng/ L
Functions of Vit.B12
1)
Methylmalonyl co - A mutase
Methylmalonyl co - A
succinyl co - A
5-deoxyadenosyl B12
Functions of Vit.B12
2Methyl FH4
FH4
Homocystein
Methionin
B12
Methionin synthase
SAM
Folic Acid
Pteroyl glutamic acid and similar compounds are
termed as folic acid .
Polyglutamate is the natural form.
Dihydro or tetrahydro folate are metabolic active forms.
Folic acid
Sources :


Produced by plants and some
microorganisms
Folate rich foods;
– vegetables (Green leaf),
– Liver and kidney (parenchymal organs)
– Molds.
Folic acid
Daily requirements
Age

0 - 10
> 10
Pregnants
Lactation

Diet contains 100 - 500 g folate/day.



3.6g /kg
3g /kg
500 g
+100 g
Folate absorbtion

Mainly jejunum.

In the form of monoglutamate .

Methyltetrahydrofolate monoglutamate is
the form it is found in serum .
Folate levels:
Normal ranges


Serum:
Red cell:
6 – 21 g/L (RBC volume)
160 – 640 g/L (RBC volume)
Folate deficiency


Serum folate :
Red cell folate:
<4g /L
<140g /L
Folate stores

Total body folate:
5 – 20 mg

Storage place :
Liver

Storage form:
Methyl-FH4 polyglutamate
Functions of folic acid:
Transfer of methyl or formyl groups to other
compounds.
eg-During the production of thymidylate for the synthesis of
DNA (methylation of deoxyuridylate)
Source of the 1-carbon moieties;
1-serine
Serine + THF
glycine + N-methylene THF
2-Formiminoglutamic acid
Formiminoglutamate+FH4
glutamate+N-formimino THF
Deoxyuridilate
Thymidylate synthase
Methylene
Thymidilate
DNAthymine
Dihydrofolate
THFA
THFA
Dihydrofolate
reductase
serine
Methyonine
glycine
B12
Homocystein
Methyl THFA
Megaloblastic Hematopoiesis
Anemia +/- leukopenia +/thrombocytopenia.
Causes of cytopenias :
1-DNA synthesis is deranged
2-Ineffective hematopoiesis
3-Shortened RBC survival

Causes of Megaloblastic
Anemia



Vit. B12 deficiency
Folate deficiency
Other causes
Causes of VitB12 deficiency
I-Decreased intake
( complete vegetarianism)
II-Impaired absorbtion
 Gastric causes
( Pernicious anemia, gastrectomy , caustic injury, Zollinger-Ellison )

Intestinal causes
( Ileal resection or disease,eg:sprue,blind loop syndr,Diph.Latum, )



Pancreatic disease-(insufficiency)
Familial selective Vit B12 absorbtion defect (Imerslund –
Grasbeck)
Drugs
( PAS, colchicin, neomycine, omeprazol,potasyum chloride,ethanol )
III-Other causes
Causes of folate deficiency



Decreased intake
Increased demands
Drug related folate insufficiency
Causes of Folate deficiency
A) Decreased intake
1-Dietary causes
Senility,
Alcoholism
Hyperalimentation
Hemodialysis
Prematurity
Synthetic diet feeding
Goat’s milk feeding
2- Malabsorbtion
Nontropical sprue
Tropical sprue
Intestinal resection
Other intestinal diseases
Causes of Folate Deficiency
B) Increased demands
Pregnancy
Chronic hemolytic diseases
Myeloproliferative diseases
Dermatitis(expholiat.)
Hyperthyroidism
C) Drugs
Oral contraseptive drugs
Some anticonvulsant drugs
Triamterene
Cholestyramine
Other causes of megaloblastic anemia (1)
I- Combined deficiency of Folate and Vit B12 :


Tropical sprue
Gluten enteropathy
II- Acute megaloblastic anemia:

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Nitrous oxide anesthesia
Dialysis
Severe disease + antifolate drug (eg:trimethoprim)
Total parenteral feeding
Other causes of megaloblastic anemia (2)
III- Megaloblastic anemia due to drugs
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Dihydrofolate reductase inhibitors (eg:MTX,trimethoprim)
Purine antagonists (eg: 6 MP, azathioprin)
Pyrimidine antagonists ( eg: ARA-C)
Alkylators (eg: cyclophosphamide )
Zidovudine
Other causes of megaloblastic anemia (3)
IV- Inherited metabolic diseases:
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Orotic asiduria
Lesch-Nyhan syndrome
Thiamine responsive megaloblastic anemia
Transcobalamin II deficiency
Homocystinuria , methyl malonic asiduria
Deficiency of enzymes of folate metabolism
Methyl tetrahydrofolate transferase
Formimino transferase
Dihydrofolate reductase
V- Other:

Erythroleukemia (?)-not an anemia- alike only
morphologically
Clinical features of megaloblastic
anemia
Folic acid deficiency
Anemia Atrophic glossitis Neurologic changes
Vit B12 Deficiency
Tissues or organs other than
bone marrow are also affected


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Skin,GIS, female genital system mucosal
epithelium
Congenital abn.(neural tube defects)
Neurologic changes(Vit.B12 deficiency)
– Peripheral neuropathy
– Subacute combined degeneration of spinal cord
– Cerebral -Mental changes

Hyperhomocysteinemia
Clinical findings(1)

Anemia:
Symptoms of anemia + palor+slight
icterus

Glossitis :
Sore tongue, poor taste sensation, pain
Papill. atrophy-beefy tongue
Clinical findings(2)
Neurologic changes-Vit B12 deficiency
(may occur without anemia)
Paresthesias
Loss of position sense, ataxia
Decreased deep tendon reflexes
Muscle weakness
Loss of vibration sense ( post column )
Spasticity, reflex changes, Babinsky
(lateral column )
Romberg
Mental changes:Memory loss, confusion, dementia,

hallutination etc
Clinical findings(3)

Other signs:
Vitiligo
Hyperpigmentation
Premature graying of hair
Weight loss
Fever
Diarhea
Constipation
Meteorismus
Splenomegaly
Peripheral blood
CBC:
Anemia 
Leukopenia 
Thrombocytopenia
RBC Indexes:

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MCV
MCH
RDW
Peripheral smear(1) :
RBC’s
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Macroovalocytosis ,
Anisocytosis, poikilocytosis ,
Bazophilic stippling ,
Howell-Jolly bodies and Cabot ring,
Nucleated red cells
Peripheral smear(2) :
Neutrophyls

Neutrophyl hypersegmentation
(an early sign of megaloblastic hematopoiesis)
Bone marrow findings in
megaloblastic anemia
Bone marrow
Hypercellular with erythroid hyperplasia.
Erythroid series

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Giant erythroblasts called megaloblasts
Increased numbers of early erythroblasts
Nuclear cytoplasmic asynchronism
Increased mytosis
Bone marrow

Giant metamyelocytes and bands
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Giant megakaryocytes
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Increased bone marrow iron stores
Biochemical findings
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LDH
( LDH -1> LDH - 2)
Bilirubin(indirect)
Ferritin and serum iron
Haptoglobin
Special Lab tests
1- VitB12deficiency
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Serum Vit B12
Methylmalonic acid
excretion***
Formiminoglutamate
(FIGlu) excr.(50% cases )
Radioactive VitB12
absorbtipon test
Deoxyuridine supression
test
Hyperhomocysteinemia
2-Folate deficiency

Serum folate
(misleads in case of recent folate intake)

RBC folate
(Misleads in cases of Vit B12 deficiency)


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Formiminoglutamate (FIGlu)
excretion
Deoxyuridine supression test
Hyperhomocysteinemia
Treatment


Treat underlying disease
Replacement treatment
1- Vit B12 deficiency
cobalamine replacement
For 2 weeks: 1000 g / day İM
Followed by:
1000 g / week until Hb returns to normal
1000 g /mo:life long if necessary(eg:pern.anemia)
Do not administer folic acid alone to patients with B12 deficiency.
Cobalamine replacement
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Neurologic response is unpredictable
BM: Megaloblastic changes are lost in 1 - 3
days.
Reticulocytosis : max:5 – 8 days
Hypesegmentation: lost in 1-2 weeks.
Hb:Normalises in 5 – 6 weeks.
MCV :Normalises in 10 weeks.
Hypokalemia.
Treatment
2- Folate deficiency
 Treat underlying condition
 Folic acid replacement:
Dose :

Start with 1 mg / day ( 2 - 3 weeks )

Continue with 0.25 - 0.50 mg / day

Pregnants: 1 mg / day
Pernicious Anemia
( Addison - Biermer )
Deficiency of intrinsic factor and
 Megaloblastic anemia
 Athrophic glossitis
 Neurologic changes
Types of PA:



Adult: Med: 60 years
Juvenile : 10 - 20 years
Congenital : < 2 years
P.A.
Pathogenesis:
Adult type
Atrophic gastritis:
•Gastric (body)Corpus involved
•All gastric secretions are decresed
•Chief cells and parietal cells are lost and
•intestinal metaplasia may occur.
Congenital type
Selective IF deficiency ( Autosomal res )
Pathogenesis of Gastritis in P.A.
Heredity:


P.A can be found in the relatives of the patients.
Related to certain HLA antigens ;
HLA-B7, DW2, DW5, DR2
Autoimmunity:

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Anti –parietal cell antibodies : 85 %
Anti-IF antibodies
: 55 - 70 %
Anti-thyroid antibodies
Other autoimmune diseases and cellular immunity
P.A.
Lab
In addition to typical blood findings of
megaloblastic anemia;
 Serum anti-IF antbd***
 Serum anti-PC antbd
 Achilia , serum gastrin level increase
 Gastroscopy and biopsy: atrophic gastitis***

Schilling’s test
P.A.
Treatment

Life long
 Cobalamine
replacement.
Complication

Gastric Ca: 2 times normal population