G6PD deficiency

Summary

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme defect in humans. It is an X-linked recessive disorder that mainly affects males.

G6PD is the rate-limiting enzyme of the HMP shunt, producing NADPH needed to keep glutathione in its reduced form. Without NADPH, red blood cells cannot neutralize reactive oxygen species (ROS), so hemoglobin is oxidized and precipitates as Heinz bodies.

Patients are usually asymptomatic until exposed to an oxidative trigger — fava beans, infection, or drugs (sulfa, dapsone, primaquine, nitrofurantoin). They then develop acute episodic hemolytic anemia: pallor, jaundice, back pain, and dark (cola-colored) urine.

Smear shows bite cells and blister cells; Heinz bodies need a supravital stain. Coombs test is negative. Diagnosis is confirmed by a G6PD enzyme assay performed weeks after the acute episode (false negatives are common during hemolysis).

Management is largely supportive: stop the trigger, hydrate, transfuse if needed, and counsel on lifelong avoidance of oxidant drugs and fava beans.

Definition & Genetics

• Definition: Inherited deficiency of the G6PD enzyme, the first and rate-limiting enzyme of the pentose phosphate pathway (HMP shunt).
• Function of G6PD: Produces NADPH, which:
  • Reduces glutathione (GSH) → neutralizes H₂O₂ and other ROS.
  • Supports respiratory burst in neutrophils (NADPH oxidase).
• Inheritance: X-linked recessive.
  • Affects mainly males; female carriers usually asymptomatic but may rarely hemolyze due to lyonization.
• Common variants:
  • Mediterranean variant: severe; very low enzyme activity; affects both young and old RBCs → can cause severe hemolysis.
  • African (A−) variant: mild; enzyme is unstable but produced normally — only older RBCs are deficient → self-limited hemolysis.

Epidemiology

• Most common enzyme deficiency in humans — affects > 400 million people worldwide.
• Highest prevalence in regions where malaria is/was endemic:
  • Mediterranean (including Jordan and surrounding region — high yield locally).
  • Middle East, Africa, Southeast Asia.
• Why? The deficiency confers partial protection against Plasmodium falciparum (the parasite cannot survive in oxidatively stressed RBCs) → positive selection (similar to sickle cell and thalassemia).
• Predominantly affects males (X-linked); heterozygous females are usually asymptomatic carriers.

Pathophysiology

RBCs lack mitochondria, so the HMP shunt is their only source of NADPH. When G6PD is deficient, oxidative stress overwhelms the cell:

1. Oxidative trigger (drug, infection, fava bean) → generates ROS (mainly H₂O₂).
2. ↓ NADPH → ↓ reduced glutathione (GSH).
3. ROS oxidize hemoglobin → denatured Hb precipitates inside the RBC as Heinz bodies.
4. Splenic macrophages remove Heinz bodies → leaves bite cells and blister cells.
5. Damaged RBCs are destroyed:
   • Mostly extravascular hemolysis (spleen) → unconjugated hyperbilirubinemia, jaundice.
   • Severe attacks add intravascular hemolysis → hemoglobinemia, hemoglobinuria (dark urine), ↓ haptoglobin.

View the HMP shunt diagram · normal vs deficient pathway.

Triggers

Patients are asymptomatic at baseline. Hemolysis occurs only after exposure to an oxidative trigger:

Open full reference table of medications that trigger hemolysis.

Clinical features

Symptoms appear 24–72 hours after exposure to a trigger and last 1–2 weeks.

• Acute hemolytic anemia: sudden pallor, fatigue, dyspnea, tachycardia.
• Jaundice / scleral icterus (unconjugated hyperbilirubinemia).
• Dark / cola-colored urine → hemoglobinuria (intravascular hemolysis).
• Back or abdominal pain (from intravascular hemolysis).
• Splenomegaly in chronic / repeated attacks.

Special presentations:

• Neonatal jaundice: unconjugated hyperbilirubinemia in the first 24–72 hours of life — may require phototherapy or exchange transfusion. Risk of kernicterus if untreated.
• Favism: severe hemolysis after fava bean ingestion — almost exclusively in the Mediterranean variant.
• Chronic non-spherocytic hemolytic anemia (rare): severe enzyme variants → ongoing hemolysis even without triggers.

Diagnosis

Step 1 — Recognize hemolysis (general labs):

• ↓ Hemoglobin/hematocrit; normocytic, normochromic anemia.
• ↑ Reticulocyte count (marrow response).
• ↑ LDH, ↑ indirect (unconjugated) bilirubin.
• ↓ Haptoglobin (especially with intravascular hemolysis).
• Hemoglobinuria → dipstick positive for blood, no RBCs on microscopy.
• Direct Coombs test: NEGATIVE (rules out autoimmune hemolysis).

Step 2 — Peripheral blood smear (high yield):

• Bite cells (degmacytes) — RBCs with a "bite" taken out by splenic macrophages.
• Blister cells — submembranous vacuole of oxidized hemoglobin.
• Heinz bodies — denatured hemoglobin inclusions; NOT visible on routine Wright-Giemsa stain → need supravital stain (crystal violet or new methylene blue).

View bite and blister cells on smear · Heinz bodies on supravital stain.

Step 3 — Confirm with G6PD enzyme assay:

• Quantitative measurement of G6PD activity in RBCs.
• ⚠️ False negative if performed during an acute attack — old (deficient) RBCs are already lysed; remaining young RBCs (reticulocytes) have higher enzyme activity.
• Wait 2–3 months after the acute episode to confirm.

Differential diagnosis

Compare G6PD deficiency with the other common normocytic hemolytic anemias tested on the exam:

Two quick discriminators:

• Coombs positive → autoimmune hemolytic anemia (warm or cold), NOT G6PD.
• Spherocytes on smear → hereditary spherocytosis or autoimmune hemolysis; bite cells → G6PD.

Open the hereditary spherocytosis reference table · intravascular vs extravascular hemolysis.

Management

There is no specific cure. Treatment is supportive and centers on trigger avoidance.

Acute hemolytic episode:

1. Identify and stop the trigger (drug, infection treatment, no more fava beans).
2. IV fluids / hydration → prevent acute kidney injury from hemoglobinuria.
3. Blood transfusion only if symptomatic anemia or Hb < 7 g/dL.
4. Monitor for renal failure and electrolyte disturbances.
5. Most episodes are self-limited in the African (A−) variant because young reticulocytes have higher enzyme activity.

Neonatal jaundice:

• Phototherapy for moderate hyperbilirubinemia.
• Exchange transfusion for severe cases (to prevent kernicterus).

Long-term / prevention:

• Patient education — give a written list of drugs and foods to avoid (the single most important intervention).
• Screen newborns in high-prevalence regions (Jordan, Mediterranean).
• Genetic counseling for affected families.
• Vaccinations (especially hepatitis A/B) to reduce infectious triggers.

Complications

• Acute kidney injury — pigment (hemoglobin) nephropathy from intravascular hemolysis.
• Severe anemia / shock — particularly in the Mediterranean variant.
• Neonatal kernicterus — if hyperbilirubinemia is not treated.
• Cholelithiasis (pigment gallstones) — chronic ↑ bilirubin in recurrent hemolysis.
• Chronic hemolytic anemia in rare severe enzyme variants.
• Iatrogenic hemolysis — exposure to oxidant drugs in unscreened patients (avoidable).

Mnemonics

Key Points for Exams – نقاط مهمة للامتحانات

• Most common enzyme deficiency in the world · X-linked recessive · mainly affects males.
• High prevalence in the Mediterranean (including Jordan), Middle East, and Africa — protective against falciparum malaria.
• G6PD makes NADPH → reduces glutathione → protects RBCs from oxidative stress (H₂O₂).
• Triggers: infection (most common), fava beans, drugs (sulfa, dapsone, primaquine, nitrofurantoin, rasburicase, methylene blue).
• Presentation: acute hemolysis 1–3 days after trigger → pallor, jaundice, back pain, cola-colored urine.
• Smear: bite cells + blister cells; Heinz bodies only on supravital (crystal violet) stain.
• Labs: ↑ retics, ↑ LDH, ↑ indirect bilirubin, ↓ haptoglobin, Coombs NEGATIVE.
• Diagnosis confirmed by G6PD enzyme assay 2–3 months after the acute episode (false negative during hemolysis).
• Treatment is supportive: stop trigger, hydration, transfuse if severe. No specific therapy.
• Rasburicase contraindicated → use allopurinol for tumor lysis syndrome.
• Neonatal jaundice in G6PD → phototherapy / exchange transfusion to prevent kernicterus.
• Mediterranean variant = severe (favism); African A− variant = mild, self-limited.