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Macrocytic Anaemia ( Megaloblastic and Non -Megaloblastic)

In macrocytic anaem ia the red cells are abnormally large (mean corpuscular volume, MC V
>100 fL).
— There are several caus es of marocytosis but they can be broadly subdivided into
meg aloblastic and non megaloblastic based on the appearance of developing erythroblasts in
the bone marrow and red cells morphology in the peripheral blood
Causes of macrocytosis (MCV> 100 Fimto liter )
Non megaloblastic
Not related to B12/folate deficiency
Megaloblastic :
Impaired D NA formation due to lack of, B12 or folic
acid
Physiological : Pregnancy and Infants
Pathological : Alcohol , Liver disease ,
MDS , Myxodema
Reticulocytosis (Acute haemolytic anaemia)
Neonates
Round red cells shape
Normal bone marrow
Vitamin B12 deficiency, Folale deficiency
Defective Vitamin B12 or folate metabolism
Transcobalamin II deficiency
Defects of DNA synthesis
Ovale red cells shape
Megaloblastic maturation of bone marrow
hemopoietic precursors

Megaloblastic anaemias (MGBA)

Are anaem ia with large RBC (ovalocytes,MCV> 100 fl) in the p eripheral , and large
erythroid cells (megaloblast) in the bone marrow. Usually associated with leukopenia
with hyper segmented neutrophils and thrombocytopenia
Megaloblastic anemias result from conditions in which nucleic a cid synthesis is
abnormal, due to vitamin B 12 and Folate deficiency result in failure or delayed of
mitotic division
Biochemichal basis of megaloblastic anaemia:
Vitamin B 12 and Folic acid play role as cofactors in the conv ersion of deoxy — uridine
monophosphate (dUMP) to deoxy — thymidine (dTMP) , an essential step in the synthesis of
DNA
Folate is required in one of its coenzyme forms, 5,IO -methylene tetrahydrofolate (THF)
polyglutamate, in the synthesis of thymidine monophosphate from its precursor
deoxyuridine monophosphate.
Vitamin BI2 is needed to convert methyl THF, which enters the cells from plasma, to THF,
from which polyglutamate forms of folate are synthesized.
Dietary folates are all converted to methyl THF (a monoglutamate) by the small intestine.

Dietary folates (In the small intestine ) → MTHF in the plasma → in the cells cytoplasm reduced to THF by B12 as Co —enzyme

THF →5, 10 -methylene THF →dUMP →DTMP →DTDP →DTTP →DNA Synthesis

When DNA synthesis is delayed causing delayed nuclear maturation and decrease number of
mitotic division result in decrease of red cells production , and erythropoies is changes from
normoblastic to megaloblastic .
Also M egaloblast late erythroid precursors cells undergo intramedullary (in the bone
marrow) death or hemolysis and this will aggravate the anaemia and producing mild
elevation in serum indirect bilirubin (jaundice) and lactate dehydrogenase.

Causes of folate deficiency.  Causes of vitamin B12

deficiency
A. Nutrit ional: old age, poverty, goat's milk
B. Malabsorption: gluten -induced enteropathy
extensive jejunal resection or Crolm's disease
C. Excess utilization
1,Physio logical: Pregnancy and lactation.
2. Patilological
Haematological diseases: chronic haemolytic
anaemias, Leukaemia.
Inflammatory diseases , psoriasis, exfoliative
dermatitis,
Drugs, Anticonvulsants,
alco holism,
Nutritional (vegans)
Malabsorption
A. Gastric causes
1.Pernicious anaemia
2,Total or partial gash'ectomy
B. Intestinal causes
diverticulosis, blind -loop,
Ileal resection and Crohn's
disease
Congenital selective
malabsorption with proteinuria
Fish tapeworm


B12 and fo lic Acid nutritional aspects

Folic acid B12
200 -250 µg/day
liver, greens and yeast
Easily destroyed
100 -150 µg/day
10 -12 mg (sufficient for 4 months)

Duodenum and jejlUlum

Conversion to methyltetrahydrofolate
7-30µg/day
Vegetable diet , Animal
Little effect
1-2 µg/day
2-3 mg (sufficient for 2 -4
years)
Ileum
Intrinsic factor

Normal daily dietary intake

Main foods
Effect of Cooking
Minimal daily requirement
Body stores

Absorption Site

Mechanism

Laboratory feature of megaloblastic anaemia:

A. Hematologial:
1; low Hct, low Hb, Low red cells count, High MCV> 100
low WBC (neutrophils), low platelets
2. Peripheral blood show: . Macrocytes with ovale shape red cells, hype rsegmented
neutrophils (> 5lobes) , low platelets count
Low reticulocytes count which is a lso seen in IRON deficiency anaemia, aplastic
anaemia , anaemia of chronic disorders and pernicious anaemia .
3. Bone marrow hypercellular with hemopoietic precursors show:
a. Erythroid precursors macroerythroblast show open stipp led chromatin and mature
hemoglobin in the cytoplasm. (nuclear cytoplasmic as ynchrony) .
b. Myeloid precursors show giant meatamyelocytes and band cells,
c. megakaryocytes show hypepolyploidy (increase number of nuclear lobes >16 lobe )

B. Biochemichal investigations

1. increase indirect bilirubin and LDH (lactate dehydrogenase)
2. Increase homocystein in blood and urine
3. Assay of serum B12 /folate , and red cells folate
a. In B 12 deficiency result low serum B 12 and normal serum folate,
low red cells folate
b. In folate deficiency result normal serum B 12 and low serum folate ,
low red cells folate

Investigation of B 12 and folic acid

In Folate deficiency In B12 deficiency Test
Normal
Low
Low
Low
Normal or raised
low
Serum vitamin BI2
Serum folate
Red cell folate

Pernicious anemia : failure of B12 binding from diet or failure of it absorption

This is caused by autoimmune antibodies attack the gastric mucosa leading to a trophy of the stomach. The
wall of the stomach becomes thin, with chronic inflammatory cells infiltration, a plasma cell and lymphocytes
There is achlorhydria and absent secr etion of IF (B12 —binding factor)
More females than males are affected (1.6 : 1), with a peak occurrence at 60 years, and there may be
associated other autoimmune disease including the autoimmune polyendocrine syndrome (Table 4.4).
The disease is common in northern Europeans and tends to occur in families
Antibodies (investigated in the serum of the patient)
1. 95% of patients show parietal cell antibody however it is not specific o nly for Pernicious .anemia
2. 50% type I or blocking antibody to IF which inhibits IF binding to B12 – ( it is the most specific for
pernicious anaemia)
3. 35% show a second (type II or precipitating) antibody to IF receptors which inhibits its ileal binding site.
Diagnosis of pernicious anemia :
1. Megaloblastic anemia on peripheral blood and bone marrow with positive biochemical investigations
2. Investigation of Antibody in the serum of the patients
3. Gastric endoscopy and biopsy show chronic atrophic gastritis
4. history of chronic dyspepsia and indigestion


رفعت المحاضرة من قبل: Ahmed monther Aljial
المشاهدات: لقد قام 3 أعضاء و 125 زائراً بقراءة هذه المحاضرة






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