Makindo Medical Notes

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

Carriers of a G6PD mutation may be partially protected against malaria. 🧪 Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency is an X-linked recessive enzymopathy that leaves red cells vulnerable to oxidative stress. 🌍 It affects ~400 million people worldwide and offers partial protection against Plasmodium falciparum malaria in carriers.

📊 Epidemiology

• Most common in Africa, the Mediterranean, the Middle East, and parts of Asia.
• One of the most frequent enzyme deficiencies globally (~400 million affected).

🔬 Aetiology & Pathophysiology

• Defect in the hexose monophosphate (HMP) shunt → ↓ NADPH production.
• NADPH is needed to regenerate reduced glutathione (GSH), which protects RBCs from oxidative damage.
• Without this protection:
  • Iron in haemoglobin oxidises → methaemoglobin formation.
  • Membrane lipids undergo peroxidation → haemolysis.

🧬 Genetics

• Mutations in the G6PD gene (X chromosome);>400 variants described.
• Hemizygous males are fully affected; heterozygous females usually carriers, but lyonisation can unmask disease.
• Some alleles confer survival advantage by reducing malaria severity.

⚛️ Atomic-Level Mechanism: How NADPH Works

• NADPH donates a hydride ion (H⁻) to glutathione reductase.
• This reduces oxidised glutathione (GSSG) back to 2 molecules of reduced glutathione (GSH).
• GSH then neutralises ROS such as H₂O₂, regenerating water and preventing oxidative cell injury.
• Continuous NADPH supply is therefore essential for red cell survival under oxidative stress.

🚨 Precipitants of Haemolysis

• Drugs: Primaquine, sulfonamides, ciprofloxacin, nitrofurantoin, quinidine, dapsone, probenecid.
• Foods: 🍃 Broad beans (favism).
• Other Stressors: Severe infection, DKA, metabolic stress.

⚠️ Complications

• Severe haemolysis → jaundice, haemoglobinuria, and risk of acute kidney injury (AKI).
• Neonatal jaundice → risk of kernicterus if untreated.

🩺 Clinical Features

• Onset usually 2–4 days after exposure to trigger.
• Acute haemolysis: Pallor, jaundice, dark urine, tachycardia, fatigue, shortness of breath.
• Drug- or infection-induced haemolysis: May occur unpredictably.
• Rare: chronic haemolysis in severe variants.

🔎 Investigations

• FBC: Anaemia with ↑ reticulocytes.
• Biochemistry: ↑ unconjugated bilirubin, ↑ LDH, ↓ haptoglobin.
• Blood film: “Bite cells” and “blister cells” due to splenic pitting; Heinz bodies (denatured Hb) visible with supravital stains.
• Urine: Haemoglobinuria, ↑ urobilinogen.
• Schumm’s Test: Positive (detects methaemalbumin).
• G6PD enzyme assay: Confirmatory test (beware false negatives if tested during acute haemolysis).
• DAT/Coombs test: Negative, distinguishing from autoimmune haemolysis.

🧾 Differential Diagnosis

• Malaria (in endemic regions).
• Sickle cell disease.
• Autoimmune haemolytic anaemia.

💊 Management

• Avoid Triggers: Stop causative drugs, avoid fava beans.
• Treat Infection: Prompt antibiotics and supportive care.
• Monitor: Hb, reticulocytes, urine output, U&E daily.
• Renal Protection: Hydration and monitoring for AKI.
• Transfusion: Reserved for severe or life-threatening anaemia.
• Education: Lifelong avoidance of oxidative drugs/foods; genetic counselling in affected families.