Makindo Medical Notes

Related Subjects: |Iron deficiency Anaemia |Haemolytic anaemia |Macrocytic anaemia |Megaloblastic anaemia |Microcytic anaemia |Myelodysplasia |Myelofibrosis

📖 About

• Macrocytic anaemia is most often due to Folate or Vitamin B12 (cobalamin) deficiency.
• This impairs normal DNA synthesis, leading to ineffective cell division.
• Results in ineffective erythropoiesis with destruction of immature precursors in bone marrow.

🧬 Aetiology / Pathophysiology

• Failure of Homocysteine → Methionine conversion (needs Folate + B12 as cofactors).
• B12 also required for Methylmalonyl-CoA → Succinyl-CoA; hence ↑ methylmalonic acid is specific for B12 deficiency.
• Arrested nuclear maturation → large cells (macrocytosis) with open chromatin.
• Pancytopenia may occur: red cells, white cells, and platelets all reduced.

⚠️ Causes

• B12 deficiency: Pernicious anaemia (anti-IF Ab), gastrectomy, ileal disease (Crohn’s, ileal resection), vegan diet, nitrous oxide abuse.
• Folate deficiency: Poor diet, alcoholism, increased demand (pregnancy, haemolysis), malabsorption (coeliac disease).
• Drugs: Methotrexate, Azathioprine, Hydroxyurea, phenytoin, antiretrovirals, chemotherapy.
• Bone marrow disorders: Myelodysplastic syndrome.

🩺 Clinical Features

• General: Fatigue, pallor, exertional breathlessness.
• Mucocutaneous: Angular stomatitis, glossitis (“beefy tongue”).
• Skin: Premature greying, vitiligo.
• Neurology (B12 deficiency): Peripheral neuropathy, impaired vibration/position sense, ataxia, subacute combined degeneration (posterior + lateral columns). ⚡ These may precede anaemia.

🔎 Investigations

• FBC: Low Hb, raised MCV, ± low platelets/WCC.
• Blood film: Hypersegmented neutrophils (≥6 lobes), oval macrocytes.
• Haemolysis markers: ↑ LDH, ↑ bilirubin.
• Reticulocytes: Low (underproduction).
• Confirmatory tests: Serum B12 & Folate; methylmalonic acid ↑ in B12 deficiency only.
• Pernicious anaemia screen: Anti-intrinsic factor antibodies (NICE).

💊 Management

• Replace both B12 and Folate if unsure (folate alone in B12 deficiency can worsen neurological injury).
• B12 replacement: Hydroxocobalamin 1 mg IM:
  • No neurological signs → 3× weekly for 2 weeks, then every 3 months lifelong if cause persists.
  • With neurological signs → alternate days until no further improvement, then every 2 months.
• Folate replacement: Folic acid 5 mg PO daily for ≥4 months, but only after B12 repletion confirmed.
• Address cause: dietary advice, treat malabsorption, stop causative drugs, manage MDS if present.

📚 References

• NICE CKS – Anaemia, B12 and Folate Deficiency
• UpToDate – Megaloblastic Anaemias

Cases — Megaloblastic Anaemia

• Case 1 — Pernicious Anaemia (Vitamin B12 Deficiency): A 68-year-old woman presents with fatigue, glossitis, and paraesthesia in her feet. FBC: Hb 8.6 g/dL, MCV 115 fL. Blood film: macro-ovalocytes and hypersegmented neutrophils. Serum B12 low, intrinsic factor antibodies positive. Diagnosis: Megaloblastic anaemia due to pernicious anaemia.
• Case 2 — Folate Deficiency in Pregnancy: A 26-year-old woman at 20 weeks gestation complains of tiredness and shortness of breath. Hb 9.2 g/dL, MCV 112 fL, serum folate low, B12 normal. She has not been taking antenatal supplements. Diagnosis: Folate-deficient megaloblastic anaemia in pregnancy.
• Case 3 — Drug-Induced (Methotrexate): A 54-year-old man with psoriasis on methotrexate develops anaemia. FBC: Hb 9.0 g/dL, MCV 110 fL. Blood film: macrocytosis with hypersegmented neutrophils. Folate level low. Diagnosis: Megaloblastic anaemia secondary to folate antagonism from methotrexate.

Teaching Commentary 📘

Megaloblastic anaemia arises from defective DNA synthesis in erythroid precursors, usually due to vitamin B12 or folate deficiency. Classic blood film findings: macro-ovalocytes and hypersegmented neutrophils. - B12 deficiency often causes neurological features (peripheral neuropathy, subacute combined degeneration). Common causes: pernicious anaemia, gastrectomy, vegan diet, malabsorption (Crohn’s). - Folate deficiency is common in pregnancy, alcoholism, poor diet, and with drugs (methotrexate, phenytoin). Always measure both B12 and folate; correcting folate alone in B12 deficiency risks worsening neuro symptoms. Treatment: parenteral B12 (hydroxocobalamin IM in UK) or oral folate depending on deficiency.