*

CAUSES & CLINICAL FEATURES OF

MEGALOBLASTIC ANEMIA

By – Moushmi Biswas

* The Megaloblastic anemias are group of disorders characterised by presence of distinctive morphological appearances of developing red cells in bone marrow.* The marrow : Hyper cellular & Anemia is based on ineffective erythropoesis.* The cause is usually deficiency of Cobalamin ( VIT B12) and/or Folate.* Folate is an important substrate and Vit B12 a cofactor for generation of essential amino acids methionine from homocystiene. This reaction produces Tetrahydrofolate which is then converted to Thymidine monophosphate for DNA synthesis.* So deficiency leads to impairement of DNA synthesis and accumulation of homocysteine which predominantly are cause of its clinical manifestations.

* What is Megaloblastic Anemia

Vit B12 * Sources: Meat, Fish, Egg , Milk[ absent in foods of non animal origin ]

* Requirement : 1micro gram/ day* Absorption :

FOLATESources : Liver, Yeast, Spinach, GLV, NutsRequirement : 100 micro gram/ dayAbsorption : Is rapidly absorbed from small intestine.

*Vitamin B12 and Folate

(1) Vit B12 ( cobalamin) deficiency

(2) Folate deficiency

(3) Therapy with antifolate drugs (Mtx)

(4) Idependent of deficiency * AML, Myelodysplasis * Therapy with drugs interfering with synthesis of DNA ( 6-Merccaptopurine, Azidothymidine etc )

*Causes

* Causes of vit B12 deficiencyNUTRITIONAL VegansMALABSORTION Pernicious anemiaGASTRIC FACTORS • Cong. Absence of IF

• Total/partial gastrectomy• Gastric bypass surgery• Atrophic gastritis• Use of PPI

INTESTINAL FACTORS • Obstruction• Ileal resection• Tropical sprue• Transcobalamin II

deficiency• Severe pancreatitis• Gluten induced

enteropathy• HIV

DRUGS • Colchicine, anticonvulsants, cytotoxic drugs

Alcohol

*Causes of Folate deficiency

DIETARY • Old age & infancy• Poverty , alcoholism

MALABSORPTION * Tropical sprue, GIE* Jejunal resection, Crohn’s ds, systemic bact. Infection

EXCESSIVE UTILISATION OR LOSS

* Physiological : Pregnancy &lactation• Pathological : - CML, sickle cell ds - Carcinoma, lymphomas - TB, psoriasis, malaria

ANTIFOLATE DRUGS Anticonvulsants, Sulfasalazine, Tetracyclins

MIXED Liver ds, Alcoholism, ICUs

*Clinical featureSYMPTOMS (1) Malaise -90%(2) Paraesthesia – 80%(3) Breathlessness -50%(4) Sore mouth -20%(5) Weight loss(6) Altered skin pigmentation(7) Grey hair(8)Impotence(9) Poor memory(10) Depression(11) Personality change(12) Hallucinations(13) Visual disturbances

SIGNS

(1) Smooth tongue

(2) Angular cheilosis

(3)Vitiligo

(4) Skin pigmentation

(5) Heart failure

(6) pyrexia

NEUROLOGICAL FINDINGS D/T VIT B12 DEFICIENCY(a)Peripheral nerves * GLOVE AND STOCKING paraesthesia * Loss of ankle reflexes(b) Spinal cord * Posterior columns – diminished vibration sensation and proprioception. * Corticospinal tracts – upper motor neuron signs.(c) Cerebrum * Dementia * Optic atrophy(d) Autonomic neuropathy

Haemolytic findings

*PERIPHERAL BLOOD*Oval macrocytes,usually with considerable

anisocytosis and poikilocytosis.*MCV>100fL unless there is a cause of

microcytosis (E.g. Iron deficiency or Thalassaemia trait) is present.*Some neutrophils are hypersegmented.*Leukopenia due to a reduction in granulocytes &

lymphocytes,but this is usually >1.5x10^9/L

*Platelet count moderately reduced,rarely<40x10^9/L*In a non anaemic patient,the presence of a few

macrocytes & hypersegmented neutrophils in the peripheral blood may be the only indication of the underlying disorder.

*BONE MARROW*In a severely anaemic patient,the marrow is

hypercellular with an accumulation of primitive cells due to selective death by apoptosis of mature forms.*The erythroblast nucleus maintains a primitive

appearance despite maturation and haemoglobinization of the cytoplasm.*The cells are larger than normoblasts,and an

increased number of cells with eccentric lobulated nuclei as nuclear fragments

*may be present.*Giant and abnormally shaped metamyelocytes

and enlarged hyperpolyploid megakaryocytes are characteristic.*In severe cases,the accumulation of primitive

cells can mimic acute myeloid leukaemia,when in less anaemic patients,the changes in the marrow may be difficult to recognize.*In megablastoid cells with both immature

appearing nuclei and defective haemoglbinization and is usually seen in myelodysplasia.

CHROMOSOMES*Bone marrow cells,transformed

lymphocytes,and other proliferating cells in the body show a variety of changes,including random breaks,reduced contraction,spreading of the centromere,and an exaggeration of secondary chromosomal constrictions and overprominent satellites.*Drugs- Antimetabolite drugs (e.g. Cytosine

arabinoside,Hydroxyurea and Methotrexate) same megaloblastic appearances.

*Ineffective haematopoiesis*There is an accumulation of unconjugated bilirubin in plasma due to the death of nucleated red cells in the marrow ( Ineffective erythropoiesis)*Raised Urine Urobilinogen*Reduced Haptoglobins*Positive urine hemosiderin*A raised serum Lactate Dehydrogenase.*False diagnosis of Autoimmune hemolytic

anaemia- A weakly positive direct antiglobulin test (cause- due to complement)

*TREATMENT*Severe megaloblastic anaemia- Vit B 12 + Folic

Acid ( before Vit B12 & Red Cell folate results are available ) .*Use of folic acid alone in the presence of Vit B12

deficiency may result in worsening of neurological deficits.*In severe angina/heart failure- Transfusion*If cardiovascular system is adapted to chronic

anaemia- Exchange transfusion or slow administration of 1 U of red cells with diuretic cover may be given cautiously.

*Vit B12 deficiency*Hydroxycobalamin 1000 microgram IM for 6

doses 2 or 3 days apart, followed by maintenance therapy 1000 microgram every 3 months for life.*The reticulocyte count will peak by 5th-10th day

of replacement therapy .*The Haemoglobin will rise by 10g/L every week

until normalized.*The response of the marrow is associated with a

fall in plasma potassium levels & rapid depletion of iron stores. If an initial response

*is not maintained and the blood film is dimorphic, the patient may need additional iron therapy.*A sensory neuropathy may take 6-12 months to

connect, long standing neurological damage may not improve.

*FOLATE DEFICIENCY*Oral folic acid 5 mg daily for 3 weeks will treat acute deficiency and 5 mg once weekly is adequate maintenance therapy.*Prophylactic Folic Acid in pregnancy prevents

megaloblastosis in women at risk, and reduces risk of fetal neural tube defects.*Prophylactic supplementation is also given in

chronic haematological disease associated with reduced red cell lifespan.*Supraphysiological supplementation (400

microgram/day) can reduce the risk of

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