Notes · Pathology · 8 November 2026

G6PD deficiency – hemolytic anemia

Definition

• Glucose‑6‑phosphate dehydrogenase (G6PD) deficiency is an X‑linked enzymatic disorder causing reduced activity of the G6PD enzyme, which is essential for the pentose‑phosphate pathway that generates nicotinamide adenine dinucleotide phosphate (NADPH) in red blood cells (RBCs).
• The deficiency predisposes RBCs to oxidative damage, leading to episodic hemolytic anemia when exposed to oxidative stressors.

Epidemiology

• G6PD deficiency is the most common enzymopathy worldwide, affecting an estimated 400 million people.
• Prevalence is highest in malaria‑endemic regions: 10‑20 % in sub‑Saharan Africa, the Mediterranean basin, the Middle East, and parts of South‑East Asia.
• Because the gene is X‑linked, males are usually hemizygous and fully express the deficiency, while females can be heterozygous carriers with variable enzyme activity due to lyonization (random X‑inactivation).

Aetiology (Causes)

• Genetic mutations: Over 200 different G6PD gene mutations have been identified; the most clinically relevant are classified by the World Health Organization (WHO) into Class I (severe chronic hemolysis) to Class V (increased activity).
• Oxidative triggers:
  • Drugs: antimalarials (primaquine, chloroquine), sulfonamides, nitrofurantoin, dapsone, certain antibiotics (e.g., ciprofloxacin), and high‑dose vitamin C.
  • Infections: bacterial sepsis, viral hepatitis, and malaria itself generate reactive oxygen species.
  • Foods: fava beans (favism) contain vicine and convicine, potent oxidants.
  • Chemicals: naphthalene (mothballs) and certain industrial solvents.

Pathophysiology

• Normal role of G6PD: The enzyme catalyzes the conversion of glucose‑6‑phosphate to 6‑phosphogluconolactone, producing NADPH. NADPH maintains reduced glutathione (GSH) in RBCs, which detoxifies hydrogen peroxide and other reactive oxygen species (ROS).
• Deficiency effect: Insufficient NADPH leads to depletion of GSH, allowing ROS to oxidize hemoglobin (forming methemoglobin) and membrane lipids. Oxidized hemoglobin precipitates as Heinz bodies, which are removed by splenic macrophages, causing membrane fragility and premature RBC destruction (extravascular hemolysis).
• Intravascular hemolysis can also occur when oxidative damage is severe, releasing free hemoglobin into plasma, consuming nitric oxide, and causing renal tubular injury.
• Lyonization in females: Random X‑inactivation creates a mosaic of normal and deficient RBCs; the proportion of deficient cells determines clinical severity.

Clinical Features

• Baseline: Most individuals are asymptomatic; routine screening may reveal low G6PD activity.
• Acute hemolytic episode:
  • Sudden onset of fatigue, pallor, jaundice (yellow sclerae), dark urine (cola‑colored) due to hemoglobinuria.
  • Abdominal or back pain from gallstones (pigment stones) may develop chronically.
  • Splenomegaly is uncommon in acute episodes but may be present in chronic hemolysis (Class I).
• Neonatal jaundice: Severe deficiency can cause early‑onset hyperbilirubinemia within the first 24 hours, increasing risk of kernicterus if untreated.
• Triggers: Symptoms typically appear 24‑72 hours after exposure to an oxidative stressor.

Investigations

• Complete blood count (CBC):
  • Hemoglobin ↓, hematocrit ↓, reticulocyte count ↑ (reflecting marrow response).
  • Mean corpuscular volume (MCV) usually normal (normocytic anemia).
• Peripheral smear:
  • Bite cells (RBCs with peripheral “bites” where Heinz bodies were removed) and Heinz bodies (visible with supravital staining).
• Biochemical markers:
  • Serum bilirubin ↑ (predominantly indirect), lactate dehydrogenase (LDH) ↑, haptoglobin ↓ (consumed during hemolysis).
• Urinalysis: Positive for hemoglobin or hemosiderin without red cells (hemoglobinuria).
• G6PD enzyme assay: Quantitative spectrophotometric measurement of enzyme activity expressed as units per gram of hemoglobin (U/g Hb). Values <10 % of normal confirm deficiency; testing should be performed at least 2‑3 weeks after an acute hemolytic episode to avoid false‑normal results due to reticulocytosis (reticulocytes have higher G6PD activity).
• Molecular testing: PCR‑based detection of common mutations (e.g., Mediterranean, African A−) is useful for carrier screening and prenatal diagnosis.

Management (Current Guidelines – 2023 WHO & 2022 AAP)

• Acute hemolysis:
  • Immediate discontinuation of the offending drug or removal of the trigger (e.g., stop primaquine, avoid fava beans).
  • Supportive care with intravenous fluids (e.g., 0.9 % saline at 20‑30 mL/kg over the first hour, then maintenance) to maintain renal perfusion and prevent acute tubular necrosis.
  • Transfusion of packed RBCs if hemoglobin falls below 7 g/dL or if there are symptomatic signs of tissue hypoxia.
  • Folate supplementation (1 mg oral daily) to support erythropoiesis during increased reticulocyte production.
• Neonatal jaundice:
  • Phototherapy according to AAP 2022 bilirubin nomograms; exchange transfusion is reserved for bilirubin levels >25 mg/dL or signs of acute bilirubin encephalopathy.
• Chronic management:
  • Patient education on avoidance of known oxidant drugs and foods; provide a “G6PD deficiency card” listing contraindicated substances.
  • Routine vaccination (including pneumococcal and influenza) to reduce infection‑related oxidative stress.
  • Annual screening for gallstones with abdominal ultrasound in patients with recurrent hemolysis.
• Pregnancy:
  • Continue folate supplementation; avoid primaquine and other contraindicated drugs; monitor maternal hemoglobin and bilirubin each trimester.
• Counselling & genetic testing: Offer carrier testing to female relatives and genetic counseling for families planning future pregnancies.

Complications

• Severe hyperbilirubinemia: Risk of kernicterus (irreversible brain damage) in neonates if bilirubin is not promptly lowered.
• Acute kidney injury (AKI): Hemoglobinuria can cause tubular obstruction and oxidative injury; monitor serum creatinine and urine output during hemolytic crises.
• Pigment gallstones: Chronic hemolysis leads to bilirubin supersaturation in bile, forming black pigment stones that may cause cholecystitis or biliary colic.
• Anemia‑related complications: Fatigue, reduced exercise tolerance, and in severe cases, high‑output cardiac failure.
• Infection susceptibility: Splenic sequestration is rare but can predispose to bacterial infections; ensure up‑to‑date immunizations.

High‑Yield Exam Points

• X‑linked inheritance: Males are usually affected; females can be carriers with variable expression.
• Favism: Classic trigger; remember that fava beans contain vicine and convicine, which generate ROS.
• Drug list: Memorize the common offending agents—primaquine, sulfonamides, nitrofurantoin, dapsone, and high‑dose vitamin C.
• Heinz bodies & bite cells: Pathognomonic smear findings; Heinz bodies are intracellular precipitates of denatured hemoglobin, removed by splenic macrophages leaving bite cells.
• Enzyme assay timing: Test at least 2‑3 weeks after hemolysis to avoid false‑normal results due to reticulocyte surge.
• Neonatal management: Phototherapy thresholds per AAP 2022; exchange transfusion only for bilirubin >25 mg/dL or neurologic signs.
• WHO classification: Class I = severe chronic hemolysis; Class II = severe deficiency (<10 % activity) with intermittent hemolysis; Class III = moderate deficiency (10‑60 % activity) with hemolysis under stress; Class IV = mild or no deficiency; Class V = increased activity.
• Preventive strategy: Provide patients with a “G6PD card” listing prohibited drugs and foods; this is a common OSCE station.

Practice questions

1. A 28‑year‑old man from Greece presents with sudden jaundice and dark urine 48 hours after taking a sulfonamide antibiotic. Which of the following peripheral smear findings is most characteristic of his condition?
A. Spherocytes
B. Schistocytes
C. Bite cells
D. Target cells

Answer: C — bite cells are typical of G6PD‑deficiency hemolysis due to removal of Heinz bodies.

2. In a newborn screened positive for G6PD deficiency, the total serum bilirubin rises to 22 mg/dL at 24 hours of life without signs of encephalopathy. According to the 2022 AAP guidelines, the next best step is:
A. Immediate exchange transfusion
B. Initiate phototherapy
C. Observe without intervention
D. Administer intravenous immunoglobulin

Answer: B — phototherapy is indicated for bilirubin levels this high in a term infant without neurologic signs.

3. Which of the following statements about the G6PD enzyme assay is correct?
A. It can be reliably performed during an acute hemolytic crisis.
B. Results are expressed as mL/kg/h.
C. Enzyme activity <10 % of normal confirms severe deficiency.
D. Female heterozygotes always show normal activity.

Answer: C — activity less than 10 % of normal defines severe (Class II) deficiency.

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