g6pd deficiency

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"glucose-6-phosphate dehydrogenase deficiency"[MeSH Terms]

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Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Overview

G6PD deficiency is the most common disease-producing enzyme abnormality in humans, affecting more than 400 million people worldwide. It is inherited as an X-linked recessive trait, so it primarily affects males (hemizygous). Females can be carriers (heterozygous) and, depending on the degree of X-inactivation (lyonization), may have variable enzyme activity ranging from normal to severely reduced.

Highest prevalence occurs in people with ancestry from sub-Saharan Africa, the Mediterranean, Middle East, and Southeast Asia. This geographic overlap with malaria-endemic regions is not coincidental - G6PD-deficient erythrocytes offer partial protection against Plasmodium falciparum because the oxidant stress induced by the parasite lyses the RBC before the parasite can complete its lifecycle.

Pathophysiology

The core mechanism is a failure of oxidant defense in red blood cells.

Metabolic pathway in erythrocyte showing G6PD role in NADPH production and glutathione cycle

Figure 13.10 - Lippincott Biochemistry 8e: Pathways of glucose 6-phosphate metabolism in the erythrocyte. When G6PD is deficient, NADPH production fails, reduced glutathione (G-SH) is depleted, and H₂O₂ accumulates.

Why RBCs are uniquely vulnerable:

The pentose phosphate pathway (PPP) is the only source of NADPH in red blood cells (other tissues can use the malic enzyme pathway).
NADPH is required to regenerate reduced glutathione (G-SH) via glutathione reductase.
G-SH neutralizes hydrogen peroxide (H₂O₂) via glutathione peroxidase.
Without G6PD, NADPH fails, G-SH is depleted, H₂O₂ accumulates.
Oxidized hemoglobin denatures into insoluble masses = Heinz bodies, which attach to the RBC membrane.
Membrane rigidity increases, and the spleen removes these cells - producing hemolysis.
RBCs also have no nucleus/ribosomes, so they cannot synthesize new G6PD enzyme. Older cells (with naturally declining enzyme) are most vulnerable.

Heinz bodies - denatured hemoglobin inclusions in G6PD-deficient erythrocytes

Figure 13.11 - Lippincott Biochemistry 8e: Heinz bodies in erythrocytes of a G6PD-deficient patient. These denatured protein masses cause membrane rigidity and splenic clearance.

Genetics and Variants

The G6PD gene is located at Xq28. More than 400 variants have been identified; over 100 mutations described, mostly missense point mutations affecting enzyme kinetics, stability, or NADP+/G6P binding.
Active G6PD is a homodimer or tetramer; mutations at subunit interfaces impair stability.

Key clinical variants:

Variant	Population	Enzyme Activity	Half-life	Clinical Effect
GdB (normal)	99% White Americans	Normal	~60 days	None
GdA+	20% African Americans	Normal	Normal	None
GdA-	10% African Americans	Mildly reduced	~13 days	Intermittent hemolysis
GdMed	Mediterranean, India, SE Asia	Markedly reduced	Short	More severe hemolysis
GdCanton	Asian	Reduced	-	Similar to GdA-

The GdA- variant has a shortened enzyme half-life (13 days vs. 60), so young RBCs have near-normal activity while older cells are severely deficient. This means after an acute hemolytic episode, as older cells are destroyed and replaced by young reticulocytes, the measured G6PD level may appear falsely normal - a diagnostic pitfall.

WHO Classification (5 Classes)

Class	Enzyme Activity	Clinical Syndrome
I	Severely deficient	Congenital nonspherocytic hemolytic anemia (CNSHA) - spontaneous, no precipitant needed
II	Severely deficient (<10%)	Intermittent hemolysis (e.g., GdMed)
III	Mildly deficient (10-60%)	Hemolysis only after oxidant stress (e.g., GdA-)
IV	Normal (60-150%)	Asymptomatic
V	Elevated activity	Asymptomatic

Classes II and III together account for >90% of G6PD variants.

Precipitating Factors (Triggers)

Affected individuals remain asymptomatic unless exposed to oxidant stress:

1. Drugs (the "A" categories):

Antimalarials: Primaquine, pamaquine, chloroquine
Sulfonamides/Sulfones: Dapsone, sulfamethoxazole-TMP, sulfanilamide
Antibiotics: Nitrofurantoin, chloramphenicol, nalidixic acid
Analgesics: Phenacetin (aspirin in moderate doses is generally acceptable; paracetamol is safe)
Miscellaneous: Naphthalene (moth balls), methylene blue, vitamin K analogues, rasburicase

2. Favism - ingestion of fava (broad) beans, especially in the Mediterranean variant. Not all G6PD-deficient individuals develop favism, but all patients with favism have G6PD deficiency.

3. Infection - the most common precipitant. Macrophage-generated free radicals during the inflammatory response diffuse into RBCs and cause oxidative damage.

Clinical Manifestations

1. Acute Hemolytic Anemia (AHA)

Most dramatic presentation. Onset within 24-48 hours of oxidant exposure.

Symptoms: Irritability, fever, nausea, abdominal pain, diarrhea
Signs: Jaundice, hemoglobinuria (dark/"cola-colored" urine), pallor, hepatosplenomegaly
Labs: Normochromic normocytic anemia, reticulocytosis, anisocytosis, poikilocytes, bite cells (splenic pitting of Heinz bodies), raised bilirubin, raised LDH, reduced haptoglobin
Severe anemia may precipitate heart failure; acute renal failure may occur

2. Neonatal Jaundice (NNJ)

Seldom present at birth; peak onset days 2-3 of life
Severity variable; can be severe enough to cause kernicterus or death
Anemia is rarely severe (unlike AHA)
Risk increased in infants who also carry UGT1A1 polymorphism (Gilbert syndrome)
Management same as NNJ from other causes - usually phototherapy

3. Chronic Nonspherocytic Hemolytic Anemia (CNSHA) - Class I

Rare; caused by uncommon variants with severely impaired basal NADPH production
Lifelong hemolysis without any external precipitant
Severity varies - some compensated, others require intermittent or regular transfusions

Diagnosis

Screening:

Fluorescence spot test: G6PD converts NADP+ → NADPH, which fluoresces under long-wave UV light. Rapid, inexpensive, high sensitivity. Semiquantitative only. Unreliable after acute hemolysis (young reticulocytes have normal activity) and may miss female heterozygotes.

Confirmatory:

Spectrophotometric assay: Direct measurement of NADPH production. More sensitive but still requires ~20-30% G6PD-deficient cells for an abnormal result.
DNA/molecular testing: Best for female heterozygotes and when hemolytic episode has just occurred.
Timing matters: Test at least 2-3 months after an acute episode to avoid false-negative results.

Management

Acute Hemolytic Anemia:

Remove the trigger - stop offending drug, treat underlying infection
Most cases require no specific treatment beyond supportive care and hydration
Severe anemia: blood transfusion (can be a medical emergency in children)
Acute renal failure: hemodialysis if needed; recovery is the rule without pre-existing kidney disease

Chronic CNSHA:

Regular folic acid supplementation
Avoid hemolytic drugs and oxidant exposures
Blood transfusions during exacerbations (usually triggered by intercurrent infection)
Iron chelation if regular transfusions are required
Splenectomy: no evidence of selective splenic destruction unlike hereditary spherocytosis, but has shown benefit in severe cases in practice

Neonatal jaundice: Standard management - phototherapy; exchange transfusion for severe hyperbilirubinemia

Prevention:

Screening programs in high-prevalence populations
Patient education: avoid triggers, carry a drug list
Test before prescribing primaquine, dapsone, or other high-risk drugs

Sources:

Lippincott Illustrated Reviews: Biochemistry, 8e, pp. 445-448 (G6PD Deficiency and Precipitating Factors)
Goldman-Cecil Medicine, Ch. 147 (G6PD Clinical Manifestations, Diagnosis, Drug Table)
Harrison's Principles of Internal Medicine, 22e (Management of AHA and CNSHA)

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