2- MACROCYTIC ANEMIA

• Megaloblastic anemia


  Vitamin B12 or Folate deficiency → defective DNA synthesis → megaloblasts in bone marrow, hypersegmented neutrophils in blood film, +/- thrombocytopenia
• Vitamin B12

  • Only found in meat & dairy products
  • In the stomach, Vitamin B12 is released from animal protein by acid & pepsin and binds to the R-binder (aka Transcobalamin) which comes from the saliva
  • In the duodenum, pancreatic enzymes release Vitamin B12 from the R-binder, and it binds to the Intrinsic Factor (produced from gastric parietal cells)
  • Vitamin B12 & IF complex is absorbed in terminal ileum, and Vitamin B12 is transported by Transcobalamin II then stored in the liver
• Causes of vitamin B12 deficiency


  • Poor diet (vegan)
  • Malabsorption (ex: celiac, tropical sprue), ileal resection, gastrectomy, tapeworm
  • Pernicious anemia
• Pernicious anemia

  • Autoimmune disease; autoantibodies against parietal cells and/or intrinsic factor
  • Atrophic gastritis, loss of parietal cells, achlorhydria → loss of IF production → Vitamin B12 malabsorption
  • May be associated with other autoimmune disease (thyroid, Addison, vitiligo)
  • Increased risk of gastric carcinoma
  • Common in elderly, more in women
• Neurological features of B12 deficiency

  • The MOST CHARACTERISTIC neuron lesion is SCDC, but the MOST COMMON is peripheral polyneuropathy (→ absent reflexes)
  • Subacute combined degeneration of spinal cord: Degeneration of the posterior & lateral columns, UMNL signs: weakness, ataxia, hyperreflexia, spastic paraplegia, Loss of vibration + proprioception
  • Patients have both UMN signs & LMN signs (mixed picture; ex: absent ankle reflexes with exaggerated knee reflexes)
  • Dementia, optic atrophy → visual disturbances
• Folate


  Found in green vegetables and offal (liver, kidney), absorbed in the duodenum
• Causes of folate deficiency

  • Poor intake (most common cause)
  • Excess utilization (pregnancy, ICU)
  • Malabsorption (celiac, tropical sprue)
  • Drugs (methotrexate, phenytoin, trimethoprim, sulfasalazine)
• No neurological symptoms in folate deficiency
• Investigations for megaloblastic anemia


  • CBC: ↓Hb, ↓Retics, macrocytic (↑MCV)
  • Blood film: hypersegmented neutrophils
  • Bone marrow: hypercellular with megaloblastic changes
• Vitamin B12 studies

  • ↓ Serum Vitamin B12 <50 ng/L (N>160)
  • Red cell folate may be ↓ (Vitamin B12 is needed for folate conversion)
  • If Pernicious anemia: anti-parietal cell antibodies, anti-IF antibodies
  • ↑ homocysteine AND ↑ methylmalonic acid (MMA)
• Folate studies


  • ↓ Red cell folate (N is 160-640)
  • ↑ homocysteine
• Serum bilirubin may be increased (excess breakdown of Hb; due to ineffective erythropoiesis in BM)
• Look for celiac/Crohn's/tropical sprue if necessary
• Vitamin B12 treatment

  IM hydroxocobalamin or oral B12 2mg/day
• Folate treatment


  Treat underlying cause; oral folic acid 5mg/day for 4 months
• Complication of B12 and folate replacement

  Hypokalemia (rapid cell production)
• Folate deficiency may mask B12 deficiency

  After replacement of folate, hematological symptoms improve but neurological symptoms deteriorate
• Macrocytosis without hypersegmented neutrophils


  • Physiological (pregnancy, newborn)
  • Alcohol excess
  • Liver disease
  • MDS, sideroblastic, aplastic
  • Hydroxyurea, azathioprine
  • Cold agglutins
  • Hemolysis
  • ↑ retics (hemorrhage, hemolysis)