MEGALOBLASTIC ANAEMIADR AKOR A.E

OUTLINE

INTRODUCTION/DEFINITION AETIOLOGY AETIOPATHOGENESIS OVERVIEW OF VIT B₁₂/FOLATE METABOLISM

VITAMIN B₁₂ DEFICIENCY

FOLATE DEFICIENCY

OTHER CAUSES

CLINICAL FEATURES

HEAMATOLOGICAL FINDINGS/OTHER INVESTIGATIONS

TREATMENT

PROGNOSIS/CONCLUSION

REFERENCES.

Overview morphological classification of Anaemia

DEFINITION

GROUP OF ANAEMIAS CAUSED BY IMPAIRED DNA SYNTHESIS AND CHARACTERISED BY THE PRESENCE OF MEGALOBLASTIC ERYTHROPOIESIS IN THE BONE MARROW WHICH IS THE HALLMARK OF THIS GROUPS OF ANAEMIAS.

AETIOLOGY FOLATE DEFICIENCY OR DEFECTIVE METABOLISM VITAMIN B₁₂ DEFICIENCY OR DEFECTIVE METABOLISM OTHERS:

•DRUGS

•PERNICIOUS ANAEMIA(AUTOIMMUNE)

•ALCOHOL EXCESS

• SURGERIES

•NITROUS OXIDE

VITAMIN B₁₂ METABOLISM

COMPRISES OF 3 MAJOR STRUCTURES;1. A CORRIN NUCLEUS2. NUCLEOTIDE(5,6 DIMETHYL BENZAMIDOLE)3. PHOSPHORYLATED SUGAR (RIBOSE-3-PHOSPHATE)

CONT.

METABOLICALLY ACTIVE FORMS1. 5-DEOXYADENOSYL COBALAMIN-LIVER2. METHYLCOBALAMIN-PLASMA3. HYDROXOCOBALAMIN-CONTAINS COBALT ION IN ITS OXIDISED

FORM(Co III)-MAIN DIETARY FORM4. CYANOCOBALAMIN-STABLE SYNTHETIC FORM

Vitamin B12 Metabolism

Forms :1. Ado (2-deoxyadenosyl) form; found in

mitochondria; Cofactor for Methyl Malonyl CoA Mutase.

2. Methyl cobalamin; found in plasma,cytoplasm; Cofactor for Methionine synthase.

3. Hydroxocobalamin

Absorption

Active

Passive1%

• Intrinsic factor

• buccal• duodenal• ileal

Absorption

Proteins involved in active absorption are, Intrinsic factor { a glycoprotein }. Haptocorrins(also cobalophilin,R-

factor,formerly Transcobalamin I -protects B12) produced by salivery glands and granulocytes

Cubilin- Endothelial B12 receptor that binds amnionless to induce endocytosis

Transcobalamin(formerly-Transcobalamin II).

TC I – cobalamin analogues.

IFs are destroyed in illeal cells Cobalamin enters portal blood after 6 hrs of oral

ingestion.

Amount recirculated in bile 0.5 - 5µg. Body stores 2-3mg. Sufficient for 2-4 years without dietary

intake of cobalamin. Daily requirement: 1-3µg. Only traces are excreted in urine; in

pharmacological doses large part is excreted in urine.

Causes of cobalamin defiency Nutritional –Vegans (legumes) Abnormalities – TC I & II deficiency;

Congenital absence of IF Malabsorption

Gastrectomy (total / partial)Tropical sprueIntestinal stagnant loop syndromeSelective malabsorptionIleal resectionCrohn’s diseasePernicious anemia

OVERVIEW OF FOLATE METABOLISM FOLIC ACID(PTEROYGLUTAMIC ACID) IS THE

ACTIVE FORM OF FOLATE CONSIST OF 3 PARTS; 1.PTERIDINE DOUBLE RING 2.P-AMINOBENZOIC ACID 3.L-GLUTAMIC FOLIC ACID EXIST AS PTEROYLPOLYGLUTAMATE IN

THE BODY UNSATURATED FORM IS

TETRAHYDROFOLATE(THF) FOLIC ACID IS REDUCED BY DIHYDROFOLATE

REDUCTASE TO THF

Folate Exist as polyglutamate in vegetables which is poorly

absorbed Converted to monoglutamate by folate conjugases

found in pancreatic juice,bile & jejunal cells secretion Destroyed easily by cooking especially in large

amounts of water. Storage in liver (sufficient for 3-4 months) Total body folate around 10-12mg. Daily requirements: 100-150µg(Pregnancy: 400-800µg).

Absorption – • Upper small intestine(duodenum and jejenum). 50-80% of dietry content

Transport –• Plasma protein bound 1/3.• Considerable enterohepatic circulation occurs• Alcohol interferes with the release of methyl-THFA by

hepatocytes• only traces are excreted; but in pharmacological

doses 50-90% are excreted.

Epithelial surfaces: macrocytosis Infertility in both men and women CVD – Ischaemic HD. Malignancy : Acute Lymphoblastic Leukemia

of childhood. Neurologic : bilateral peripheral neuropathy

and degeneration; Alzhiemer’s disease Maternal: prematurity; abortion; neural tube

defects Children: poor brain development ; impaired

intellectual development.

Haematological findings

Oval macrocytes Anisocytosis (varied sizes ) Poikilocytosis ( abnormal shaped ) Hypersegmanted neutrophils Howell – jolly bodies Raised Unconjugated bilirubin Haptoglobins Urine – urobilinogen, hemosiderin.

Howell jolly bodies are

the basophilic

nuclear remnants in

the circulating erythrocyte

s

Deoxyuridine (dU) Suppression Test This test is based on the finding that unlabelled dU can suppress

the uptake of thymidine into the DNA of cultured lymphocytes or marrow cells.

It measures the degree to which prior incubation of BM cells in vitro will suppress the uptake of radioactive thymidine into the DNA of the cells.

Normal response is a suppression of thymidine uptake. Normal Response is reduced or absent in B12 or folate deficiency

ie no suppression. It is corrected on adding the deficient vitamin. The Addition of folinic acid corrects for both. A normal response in the presence of MA shows cause is not B12 or folate

Schilling’s test

There are 3 parts to the schilling’s test: Part I: A large parenteral dose of unlabelled B12 is administered

in order to saturate the levels of TC I and II i.e. about 1000g of radioactive B12 IM.

Oral dose of about 1g of radioactive B12 is given orally (test dose).

Because TC has already been saturated, any labeled B12 absorbed by the intestines is carried unbound and is excreted in the urine.

Urine is collected for 24 hours > 10% of test dose in the urine is normal

In PA or malabsorption it is <5%. Also low in renal disease but normal in vegans.

Schilling’s test

Part II: if less than 9% of labeled B12 is excreted in the 24 hr urine, IF is administered orally with a second dose of labeled B12 and the test is repeated. B12 malabsorption of gastric origin is corrected whereas malabsorption of ileal origin is not.

Part III: oral antibiotics are administered for 1 week, and part II is then repeated to determine if bacterial overgrowth in the intestine is responsible for the malabsorption. In the presence of ileal disease, the result remains negative.

ELISA findings

Serum cobalamin normal:160-1000 ng/Lsevere anemia <100ng/L Serum folate normal: 2µg/L-15µg/L Red cell folate normal: 160 - 640µg/L.

TREATMENT

COBALAMIN: Hydroxocobalamin is preferred because it is

more highly protein-bound and therefore remains longer in the circulation.

Initial therapy should consist of 1000 mcg of vitamin B12 intramuscularly daily or every other day for 1-2 weeks to replenish body stores.

Maintenance therapy consists of 1000 mcg intramuscularly once every three months for life.

If neurologic abnormalities are present, maintenance therapy injections should be given every 1–2 weeks for 6 months before switching to 3monthly injections.

Oral doses of 1000 mcg of vitamin B12 daily are usually sufficient to treat patients with pernicious anemia who refuse or cannot tolerate the injections.

After pernicious anemia is in remission following parenteral vitamin B12 therapy, the vitamin can be administered intranasally as a spray or gel.

Folate:

5-15mg; for 4 months Parenteral administration of folic acid is

rarely necessary, since oral folic acid is well absorbed even in patients with malabsorption syndromes.

Therapy should be continued until the underlying cause of the deficiency is removed or corrected.

Therapy may be required indefinitely for patients with malabsorption or dietary inadequacy.

Folic acid supplementation to prevent folic acid deficiency should be considered in high-risk patients, including pregnant women, patients with alcohol dependence, hemolytic anemia, liver disease, or certain skin diseases, and patients on renal dialysis.

Prophylactic folic acid foods – bread, wheat, rice.

Potasssium supplements if needed. Antiplatelets if needed.

THERAPEUTIC RESPONSE TO VIT B₁₂ OR FOLIC ACID

Non megaloblastic but macrocytic anemias

RBC’s are round not oval There are no hypersegmented neutrophils and howell – jolly

bodies

Macrocytosis without megaloblastosis

PROGNOSIS

EARLY RECOGNITION AND TREATMENT PROVIDES A NORMAL AND USUALLY UNCOMPLICATED LIFE SPAN.DELAYED TREATMENT PERMITS PROGRESSION OF THE ANAEMIA AND NEUROLOGICAL COMPLICATIONS.

THE MENTAL AND NEUROLOGICAL DAMAGE CAN BECOME IRREVERSIBLE WITHOUT THERAPY.

CONCLUSION

AS EASY AS MEGALOBLASTIC ANAEMIA MAY SEEM CARE MUST BE TAKEN IN ITS MANAGEMENT AS IT CAN LEAD TO IRREVESIBLE DAMAGES IF INPROPERLY MANAGED

CAUTION: PATIENTS WITH MEGALOBLASTIC ANAEMIA SHOULD NEVER RECEIVE

EMPIRICAL TREATMENT WITH FOLIC ACID ALONE. IF THEY LACK VIT.B₁₂,FOLIC ACID IS POTENTIALLY CAPABLE OF PRECIPITATING SUBACUTE

COMBINE DEGENERATION OF THE CORD.

REFERENCES

POST GRADUATE HAEMATOLOGY(5th ED)-VICTOR HOFFBRAND, et al. e-MEDICINE(2004)-ARTICLE ON PERNICIOUS ANAEMIA-MARCEL E

CONRAD,MD. MEDICAL STUDENTS NOTES(NPGMC)-2015 JATAU E.D OXFORD HAND BOOK OF CLINICAL HAEMATOLOGY(2nd ED)-DREW

PROVAN, et al. HAEMATOLOGY IN CLINICAL PRACTICE-ROBERT SHILMAN et al.

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