MEGALOBLASTIC ANAEMIA This results from a deficiency of : 1-vitamin B folic acid, or from disturbances in folic acid metabolism. 3-or both

VITAMIN B 12 AND FOLIC ACID- PHYSIOLOGIC CONSIDERATIONS Vitamin B 12 Folic acid Sources meat, fish green vegetables, yeast Daily requirement 2-5 ug ug Body stores 3-5 mg (liver) 10-12mg (liver) Places of absorption ileum duodenum and proximal segment of small intestine 2

 Folate is an important substrate of, and vitamin B 12 a co-factor for DNA synthesis which is the constituent of the nucleus.  The end result of their deficiency is cells with arrested nuclear maturation but normal cytoplasmic development

 All proliferating cells will exhibit megaloblastosis; hence changes are evident in the buccal mucosa, tongue, small intestine, cervix, vagina &most evident in the bone marrow.  Cells become arrested in development and die within the marrow; this ineffective erythropoiesis results in an expanded hypercellular marrow.

Peripheral Blood Film Shows The mature red cells are large and oval, and sometimes contain nuclear remnants. The mature neutrophils show hypersegmentation of their nuclei, with cells having six or more nuclear lobes. If severe, a pancytopenia may be present in the peripheral blood.

Folate metabolism. Folate is essential for the de novo synthesis of purines, deoxythymidylate monophosphate (dTMP), and methionine For methionine synthesis, a cobalamin- requiring reaction is needed,

(cobalamine

Dietery Sources&Storage FOLIC ACID Folates are produced by plants and bacteria; hence dietary leafy vegetables (spinach, broccoli, lettuce), fruits (bananas, melons) and animal protein (liver, kidney) are a rich source excess cooking for longer than 15 minutes destroys folates. Total body stores of folate are small and deficiency can occur in a matter of weeks. Vitamin B 12 The average daily diet contains 5-30 μg of vitamin B 12, mainly in meat, fish, eggs and milk- well in excess of the 1 μg daily requirement The liver stores enough vitamin B 12 for 3 years and this, together with the enterohepatic circulation, means that vitamin B 12 deficiency takes years to become manifest even if all dietary intake is stopped

FOLIC ACID It is synthesized by many different plants and bacteria. Fruits and vegetables constitute the primary dietary source of the vitamin The minimum daily requirement is normally about 50 microgm, but this may be increased several fold during periods of enhanced metabolic demand such as pregnancy

CAUSES OF FOLATE DEFICIENCY Diet Poor intake of vegetables Malabsorption e.g. Coeliac disease Increased demand Pregnancy Cell proliferation, e.g. haemolysis Drugs Certain anticonvulsants (e.g. phenytoin) Contraceptive pill Certain cytotoxic drugs (e.g. methotrexate

MEGALOBLASTIC ANEMIAS- Causes of Folic acid deficiency 1. Inadequate intake - diet lacking fresh, slightly cook food; chronic alcoholism, total parenteral nutrition, 2. Malabsorption - small bowel disease (sprue, celiac disease,) - alcoholism 3. Increased requirements: - pregnancy and lactation - infancy - chronic hemolysis - malignancy - hemodialysis 4. Defective utilisation Drugs:folate antagonists(methotrexate, trimethoprim, triamteren), purine analogs (azathioprine), primidine analogs (zidovudine), RNA reductase inhibitor (hydroxyurea), miscellaneous (phenytoin, N 2 ) 14

Causes of vitamin B 12 deficiency 1-Dietary deficiency( This only occurs in strict vegetarians 2-Gastric factors( Hypochlorhydria, gastric surgery, 3-Pernicious anaemia (autoimmune disorder in which the gastric mucosa is atrophic with loss of parietal cells causing intrinsic factor deficiency,average age of onset of 60 years, 4-Small bowel factors (fish tapeworm, bacterial overgrowth, Terminal ileum disease (sprue, celiac disease, ilea resection, Crohn disease,

CLINICAL FEATURES OF MEGALOBLASTIC ANAEMIA Symptoms Malaise (90%) Breathlessness (50%) Paraesthesiae (80%) Sore mouth (20%) Weight loss Altered skin pigmentation Grey hair Impotence Poor memory Depression Personality change Hallucinations Visual disturbance Signs Smooth tongue Angular cheilosis Vitiligo Skin pigmentation Heart failure Pyrexia

DIAGNOSTIC FEATURES OF MEGALOBLASTIC ANAEMIA Investigation Result Haemoglobin Often reduced, may be very low MCV Usually raised, commonly > 120 fl Erythrocyte count Low for degree of anaemia Blood film Oval macrocytosis, poikilocytosis, red cell fragmentation, neutrophil hypersegmentation Reticulocyte count Low for degree of anaemia Leucocyte count Low or normal Platelet count Low or normal Bone marrow Increased cellularity, megaloblastic changes in erythroid series, giant metamyelocytes, dysplastic megakaryocytes, increased iron in stores, pathological non-ring sideroblasts Serum ferritin Elevated Plasma LDH Elevated, often markedly

NEUROLOGICAL FINDINGS IN B 12 DEFICIENCY Vitamin B 12 deficiency but not folate deficiency is associated with neurological disease in up to 40% of cases Peripheral nerves Glove and stocking paraesthesiae Spinal cord 1-Subacute combined degeneration 2- Posterior columns-diminished vibration and proprioception 3- Corticospinal tracts-upper motor neuron signs Cerebrum 1- Dementia 2-Optic atrophy Autonomic neuropathy

MANAGEMENT OF MEGALOBLASTIC ANAEMIA Where a patient with a severe megaloblastic anaemia is very ill and treatment must be started before vitamin B 12 and red cell folate results are available, Always treat with both folic acid and vitamin B 12. The use of folic acid alone in the presence of vitamin B 12 deficiency may result in worsening of neurological defects.

MANAGEMENT OF MEGALOBLASTIC ANAEMIA(contd.) Vitamin B 12 deficiency Vitamin B 12 deficiency is treated with hydroxycobalamin 1000 μg i.m. in five doses 2 or 3 days apart followed by maintenance therapy of 1000 μg every 3 months for life 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 will prevent megaloblastosis in women at risk

ANAEMIA OF CHRONIC DISEASE It is characterized by : It occurs in the setting of chronic infections, chronic inflammation or neoplasia Normal MCV (normocytic, normochromic) The serum iron is low but iron stores are normal or increased, as indicated by the ferritin or stainable marrow iron.

INVESTIGATIONS TO DIFFERENTIATE ANAEMIA OF CHRONIC DISEASE FROM IRON DEFICIENCY ANAEMIA FerritinIronTIBC Transferrin saturation Soluble transferrin receptor Iron deficiency anaemia↓↓↑↓↑ Anaemia of chronic disease↑/Normal↓↓↓↓/Normal

ANAEMIA IN OLD AGE Mean haemoglobin: falls with age in both sexes, but remains well within the normal range. When a low haemoglobin does occur, it is generally due to disease. Anemia can never be considered 'normal' in old age.

ANAEMIA IN OLD AGE(contd.) Symptoms: may be subtle and insidious. Cardiovascular features such as dyspnoea and oedema, and cerebral features such as dizziness and apathy, tend to predominate. Ferritin: if less than 45 μg/l in older people is highly predictive of iron deficiency Serum iron and transferrin: fall with age because of the prevalence of other disorders, and are not reliable indicators of deficiency.

ANAEMIA IN OLD AGE(contd.) Most common cause of iron deficiency: gastrointestinal blood loss. Most common cause of vitamin B 12 deficiency: pernicious anaemia, as the prevalence of chronic atrophic gastritis rises in old age. Neuropsychiatric symptoms associated with vitamin B 12 deficiency: well established but a causal relationship has not been clearly shown. Dementia associated with vitamin B 12 deficiency in the absence of haematological abnormalities is rare. Anaemia of chronic disease: frequent in old age because of the rising prevalence of diseases that reduce erythropoiesis.