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megaloblastic anemia
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Megaloblastic anemias
Megaloblastic anemia
Megaloblastic anemias constitute a diverse group of entities with-
1. Impaired DNA synthesis
2. Megaloblastic changes in blood & BM due to nuclear : cytoplasmic asynchrony
Etiologies : Vit B12 def. including Pernicious anemia, Folate def.
PATHOGENETIC CLASSIFICATION OF NON MEGALOBLASTIC MACROCYTIC ANEMIA
Associated with accelerated erythropoiesis Hemolytic anemia
Post haemorrhagic anemia
Alcoholism
Liver disease
MDS
Myelophthistic anemia
Acquired sideroblastic anemia
Hypothyroidism
CDA(TYPES I &III)
DIAMOND BLACKFAN SYNDROME
Intracellular substances: Folate and Cobalamin
Folate Pteridine ring, glutamate side chain Enzymatically active form is tetra-hydrofolate (THF) Intermediate in transfer of one carbon units Involved in purine, pyrimidine metabolism, and s-
adenosyl methione (S-Adomet) generation
Cobalamin Cobalt-tetrapyrrole ring Cobalamin forms
Methylcobalamin Adenosylcobalamin Cyanocobalamin
Cobalamin deficiency traps folate
Folic acid THF
Methyl-THF
Homocystiene Methionine
M
Methyl-cobalamin
Methylene-THF
Serine
Glycine
P Pyridoxal-5-phosphate
Cobalamin deficiency Inhibits Methionine synthesis It also traps Methyl-THF, and activates more methylene THF to be converted to Meth-THF Internal THF deficiency ensues,yield of less polyglutamated forms. Excess homocysteine is converted to Cysteine, which is toxic to cells
Cystiene
DHF
dUMP dTMP
mthfr
Folate and cobalamin help amino-acid synthesis
THF Methyl-THF
Homocystiene Methionine
M
M Methyl-cobalamin
S-AdoMet S-Ado- homocyctiene
Methyl-acceptor Methylated product
Folic acid
S-Ado-Meth is regulator of folate metabolism,inhibits mthfr
S-Ado-met is also a methyl donor and hence has a role in amino-acid synthesis
Folate and Cobalamin deficiency inhibit amino-acid synthesis
Metabolic effects of B12 & folic acid
Methyl malonyl CoA Succinyl malonyl CoA
accumulates
Abnormal fatty acids myelin breakdown & neurologic complications
Histidine FIGLU glutamate + formimino FH4
B12 MMCoA mutase
FH4
Folate absorption Dietary sources - Food folate - Folic acid
Intestinal transporter
Folic acid THF
Meth-THF
Meth-THF
Mu
cosal cell
Blo
od
vessel
Proximal jejunum Saturable absorption
Terminal ileum Non-saturable absorption
Tissues
Folate receptor
Rapid absorption
Intestinal transporter
Folic acid THF
Meth-THF
Meth-THF
Folate stores
In liver and red cells
Polyglutamate form
Total content:5-20 mg,exhausted in 4 mths
Normal loss through sweat,saliva.urine.faecus
Cobalamin absorption Dietary sources - Animal produce
Meth-THF
Blo
od
vessel
Gastric mucosa
Cubulin receptor
TC-II
Proteases
IF
Ileal mucosa
TC-II-R Tissu
e
R-B12 complex
Duodenum
Pancreas
Cobalamin stores
Liver is the principle site
Also present in kidney,heart and brain
Storage form is adenosyl-cobalamin
Major routes of loss through biliary excretion and desquamation of intestinal epithelial cells
Folate vs Cobalamin
Folate
RDA 400ug adults; 600ug pregnant women
Fresh vegetables, fruits, dairy, meats.
Absorption in proximal and distal small intestine
Does not involve specific binding proteins for absorption and transport
Storage form is limited, RDA essential. Development of deficiency rapid.
Cobalamin
RDA 2.5ug in adults
Present in animal sources Milk cheese eggs
Absorption in distal small intestine
Requires specific binding proteins (IF, TC-II)
Stored in body, excretion is limited. Development of deficiency is slow.
Folate vs Cobalamin
Folate
Deficiency due to Poor dietary intake
Increased requirement
Alcoholism
Anti-folate drugs
Extensive intestinal resection
Cobalamin
Deficiency due to Poor intake (vegans)
IF deficiency (pernicious anemia)
Inflammatory bowel disease
Ileum resection
Gastrectomy
Fish tapeworm
Combined deficiency Tropical sprue Gluten sensitive enteropathy
Pernicious anemia
Autoimmune des. of gastric mucosa leading to chronic atrophic gastritis parietal cell loss decreased IF release B12 def
I Ab blocks binding of B12 to IF
II Ab blocks binding of IF-B12 to ileal R
III Ab not specific
Auto-reactive T cell mediated injury
Pernicious anemia
Similar blood and bone-marrow findings
Atrophy of fundic glands
Intestinal metaplasia
Atrophic glossitis
CNS lesions (SACD of dorso-lateral tracts)
Consequences of folate and cobalamin deficiency
Manifest deficiency Megaloblastic anemia
Altered DNA synthesis
Nuclear cytoplasmic asynchrony
Neurological dysfunction Altered myelin synthesis
Subacute combined degeneration
Mucosal abnormalities (Glossitis)
Subclinical deficiency Hyper-homocystienemia
Atherosclerosis
Hematological findings
Affects all three series of cells
Anemia, Dyserythropoiesis
Leukopenia
Thrombocytopenia
Affects cellular maturation
Megaloblasts in marrow
Macrocytes in peripheral smear
Hypersegmented neutrophils
Peripheral smear
Hypersegmented neutrophils
Macrocytes
Vit B12 def.
S.Vit B12 (N 160-900ng/l)
Homocysteine,S. methyl malonic acid
IF antibodies
Folic acid def
S. folic acid
FIGLU in urine (intermediate product in conversion of histidine to glutamate)
Biochemical findings
Tests for diagnosis
Test Cobalamin def Folate def Discriminating capacity
S.cobalamin N or Fair to good
S.folate N or
Very good
Red cell folate or n
poor
S.Methylmalonyl acid
N Very good
De-oxyuridine suppression test
abnormal abnormal Very good
Schillings test
Stage I Oral dose radiolabelled, 1ug Parenteral dose 1000 microg 24 hr urine N >10%, PA
Stage II : repeat with IF supplements
Schillings test : radioactive B12 is used to assess status of IF and VitB12 ; to distinguish PA from other causes of B12 def.
Megaloblastic anemia: Bone Marrow
BM : hypercellular, may completely replace the fatty marrow
M:E is reversed Megaloblasts larger in
size, open seive-like chromatin and well hemoglobinized cytoplasm
Giant metamyelocytes and band forms
Megakaryocytes large and bizarre multilobate nuclei
Reversal of symptoms
New reticulocytes: 2-3 days
LDH and s.bilirubin decline
Neutrophil hypersegmentation persists for 2 wks or more
WBC and platelets: 1 wk
Peak retic:10 days (hb increases)
Fully normal:8 weeks,neurological manifestations first few wks