Megaloblastic Anaemia

Characterized by the presence in the bone marrow of erythroblasts with delayed nuclear maturation because of defective DNA synthesis (megaloblasts)

Aetiology

B12 deficiency

• Low dietary intake e.g. veganism

• Pernicious anaemia: autoimmune condition with resulting destruction of gastric parital cells → results in intrinsic factor deficiency with B12 malabsorption and deficiency
• Often associated with atrophic gastritis and personal or family history of other autoimmune disorders

• Other causes include gastrectomy and congenital deficiency of intrinsic factor

Folate deficiency

• Inadequete intake (found in leafy green vegetables)

• Malabsorption

• Excess utilisation - haemolysis, exfoliating dermatitis, pregnancy, malignancy

• Drugs - anticonvulsants

Others

• Drugs

• Rare inherited abnormalities

Pathophysiology

• Megaloblast: an abnormally large nucleated red cell precursor with an immature nucleus

• Megaloblastic anaemias are characterised by a lack of red cells due to predominant defects in DNA synthesis in developing recursor cells (megaloblasts) in the marrow

• In maturing megaloblasts, division is reduced and apoptosis increases

• Cytoplasmic development and haemoglobin accumulation occur normally, and so the precursor cell is bigger with an immature nucleus, i.e. a megaloblast

• Once haemoglobin level in the cell is optimal, the nucleus is extruded, leaving behind a bigger-than-normal red cell, i.e. a macrocyte

• But overall, there are fewer macrocytes → anaemia

Importance of B12 and folate

• B12 and folate are essential co-factors in linked biochemical reactions, regulating:
• DNA synthesis and nuclear maturation (e.g. blood cell effect)
• DNA modification and gene activity (e.g. nervous system)

• Vitamin B12 is liberated from protein complexes in food by gastric enzymes and then binds to a vitamin B12-binding protein (‘R’ binder)

• Vitamin B12 is released from the ‘R’ binder by pancreatic enzymes and then becomes bound to intrinsic factor

• Intrinsic factor is a glycoprotein secreted by gastric parietal cells; it combines with vitamin B12 and carries it to a specific receptor on the mucosa of the ileum

• Vitamin B12 enters the ileal cells and intrinsic factor remains in the lumen and is excreted

• Vitamin B12 is transported from the enterocytes to the bone marrow and other tissues by the glycoprotein transcobalamin II

• Dietary folates converted to monoglutamate

• Absorbed in jejunum

• Stores are lower than for B12

Clinical presentation

Clinical features of B12/folate deficiency

• Signs + symptoms of anaemia

• Weight loss, diarrhoea, infertility

• Sore tongue, jaundice

• Development problems

• Patients with macrocytic anaemia may appear midly jaundiced
• Due to ineffective erythropoiesis caused by intramedullary haemolysis, meaning a breakdown of cells within the bone marrow

• B12 deficiency can also present with neurological problems - posterior/dorsal column abnormalities, neuropathy, dementia, psychiatric manifestations

Investigations

• FBC - macrocytic anaemia, pancytopenia in some patients (nuclear maturation defects can affect multiple lineages)

• Blood film - macrovalocytes and ‘hypersegmented’ neutrophils (normally 3-5 nuclear segments)

• Assay B12 and folate levels in serum (low levels may not always indicate deficiency and normal levels may not always indicate normalcy)

• Check for auto-antibodies
• Anti gastric-parietal cell (sensitive not specific)
• Anti intrinsic factor (specific, not sensitive)

Management

• Treat the cause where possible

• Vitamine B12 injections for life in pernicious anaemia

• Folic acid tablets 5mg/day PO

• Red cell transfusion - only in potentially life-threatening anaemia