Megaloblastic anaemia
Definition
Megaloblastic anaemia is a type of macrocytic anaemia characterised by defective DNA synthesis in the bone marrow, resulting in the production of large, immature, and dysfunctional red blood cells (megaloblasts). On bone marrow examination, erythroblasts exhibit delayed nuclear maturation with a lacy, open chromatin pattern.Pathophysiology
The fundamental defect in megaloblastic anaemia is impaired DNA synthesis, typically due to deficiencies in vitamin B12 (cobalamin) or folate. Impaired DNA replication prevents cells from entering mitosis, causing continued cytoplasmic growth without nuclear division. This results in macrocytosis and ineffective erythropoiesis. Other rapidly dividing cells, such as neutrophils and gastrointestinal epithelial cells, may also be affected.Role of vitamin B12 and folate
Vitamin B12
- Found in animal-derived foods.
- Binds to R protein in the stomach and then to intrinsic factor (IF) secreted by gastric parietal cells.
- The IF-B12 complex is absorbed in the terminal ileum via specific receptors.
- In circulation, B12 binds to transcobalamin II for tissue delivery.
- Stored in the liver with a 2–4 year reserve.
- Deficiency causes defective myelin synthesis which leads to neurological complications.
Folate
- Present in green vegetables, liver, and yeast.
- Absorbed mainly in the duodenum and jejunum.
- Limited body stores (~4 months); deficiency may appear quickly in malnourishment.
- Essential for thymidine synthesis; deficiency leads to DNA fragmentation.
Causes of B12 deficiency
- Inadequate intake e.g. strict vegan diet
- Gastric causes: pernicious anaemia, gastrectomy, atrophic gastritis, congenital IF deficiency, H. pylori infection
- Intestinal causes: ileal resection, Crohn's disease, coeliac disease, fish tapeworm infestation, bacterial overgrowth
Causes of folate deficiency
- Poor intake: alcoholism, elderly, institutionalised individuals
- Increased demand: pregnancy, haemolysis, malignancy, inflammation
- Malabsorption: coeliac disease, Crohn’s, tropical sprue
- Drugs: methotrexate, phenytoin, sulfasalazine
- Liver disease and alcohol misuse
Clinical features
General:
- fatigue
- pallor
- shortness of breath
- glossitis
- angular cheilitis
- Lemon-yellow skin tint (pallor + mild jaundice from ineffective erythropoiesis)
- Neurological symptoms: symmetrical peripheral neuropathy, loss of proprioception, spasticity, ataxia
- Subacute combined degeneration of the spinal cord (posterior columns and corticospinal tracts)
- Cognitive changes or mood disturbance
- Associated with neural tube defects in pregnancy
Investigations
- Full Blood Count (FBC): Raised MCV, low haemoglobin, low reticulocyte count
- Blood film: Oval macrocytes, hypersegmented neutrophils
- Serum B12 and folate
- Raised LDH and indirect bilirubin (due to intramedullary haemolysis)
- Bone marrow biopsy (if unclear): hypercellular marrow with megaloblastic changes, giant metamyelocytes
- Homocysteine and methylmalonic acid: Both elevated in B12 deficiency, only homocysteine elevated in folate deficiency
Important note
Replacing folate before vitamin B12 in patients with combined deficiency can worsen or unmask neurological symptoms by accelerating haematological improvement while leaving B12-related neurotoxicity untreated.
Replacing folate before vitamin B12 in patients with combined deficiency can worsen or unmask neurological symptoms by accelerating haematological improvement while leaving B12-related neurotoxicity untreated.