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G6PD Deficiency - 5 Mark Question (MBBS Medicine)

Definition

Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is the most common inherited enzyme deficiency in humans, affecting over 400 million people worldwide. It is an X-linked recessive disorder where deficiency of the G6PD enzyme renders red blood cells (RBCs) unable to withstand oxidative stress, leading to hemolytic anemia.
(Harrison's Principles, 22E; Lippincott Biochemistry, 8E)

Pathophysiology

G6PD is the rate-limiting enzyme of the Pentose Phosphate Pathway (PPP). In RBCs, the PPP is the only source of NADPH.
Pathways of glucose 6-phosphate metabolism in the erythrocyte showing how G6PD deficiency impairs NADPH production and leads to hemolysis
The chain of events:
  1. G6PD converts Glucose-6-phosphate → 6-Phosphogluconolactone + NADPH
  2. NADPH keeps glutathione in its reduced active form (G-SH)
  3. Reduced glutathione neutralizes H₂O₂ via glutathione peroxidase
  4. When G6PD is deficient → less NADPH → glutathione becomes oxidized (G-S-S-G) → H₂O₂ accumulates → oxidation of hemoglobin → Heinz body formation → membrane damage → hemolysis
RBCs are especially vulnerable because they have no mitochondria or nucleus - they cannot regenerate the enzyme or use alternative NADPH-generating pathways.
(Lippincott Biochemistry, 8E; Goldman-Cecil Medicine)

Genetics

  • X-linked recessive - gene locus at Xq28
  • Predominantly affects males (hemizygous); females are mostly carriers
  • Over 400 variants described; most are missense point mutations
  • Common variants:
    • G6PD A- (Africa) - Class III, enzyme activity 10-23%
    • G6PD Mediterranean (Middle East, South Asia) - Class II, activity <5%, more severe
    • G6PD Canton (Asia) - Class II, similar to Mediterranean
(Goldman-Cecil Medicine, Harrison's 22E)

WHO Classification (5 Classes)

ClassClinical SeverityResidual Enzyme Activity
ICongenital nonspherocytic hemolytic anemia (CNSHA)<10%
IISevere - acute hemolytic anemia (e.g., G6PD Mediterranean)<10%
IIIModerate - hemolysis only after oxidant stress (e.g., G6PD A-)10-60%
IVNo clinical symptoms (e.g., G6PD B normal)>60%
VOverproduction of G6PD (asymptomatic)>100%
Classes II and III together represent >90% of G6PD variants.

Precipitating Factors (Triggers)

  1. Drugs (the most important "4 A's" - Antibiotics, Antimalarials, Analgesics, Antipyretics):
    • Antimalarials: Primaquine, Pamaquine, Chloroquine
    • Sulfonamides / Sulfones: Dapsone, Sulfamethoxazole-TMP (Co-trimoxazole), Sulfanilamide
    • Other antibiotics: Nitrofurantoin, Chloramphenicol, Nalidixic acid
    • Analgesics: Aspirin (high dose), Phenacetin
    • Miscellaneous: Rasburicase, Methylene blue
  2. Fava beans (Favism) - especially G6PD Mediterranean variant
  3. Infections - most common trigger; inflammatory response generates free radicals in macrophages that diffuse into RBCs
  4. Neonatal period - neonatal jaundice

Clinical Features

1. Acute Hemolytic Anemia (AHA)

  • Onset 24-72 hours after oxidant exposure
  • Symptoms: fever, malaise, nausea, abdominal pain, back pain
  • Dark urine (hemoglobinuria), jaundice
  • Pallor, tachycardia
  • Hepatosplenomegaly may be present
  • Severe cases: acute renal failure, congestive heart failure

2. Neonatal Jaundice (NNJ)

  • Appears 1-4 days after birth
  • May be severe, requiring phototherapy or exchange transfusion
  • Risk of kernicterus if untreated

3. Congenital Nonspherocytic Hemolytic Anemia (CNSHA)

  • Rare, Class I variants only
  • Chronic hemolysis even without oxidant trigger
  • Pallor, splenomegaly, gallstones (pigment)

Laboratory Findings

  • CBC: Normochromic, normocytic anemia; reticulocytosis
  • Peripheral blood smear: Bite cells (blister cells), poikilocytes, Heinz bodies (on supravital staining with crystal violet) - represent precipitated, denatured hemoglobin
  • Elevated bilirubin (indirect), raised LDH, reduced haptoglobin
  • Hemoglobinuria (dark urine)
  • G6PD assay: Quantitative spectrophotometric assay (definitive test) - measure enzyme activity. Note: May be falsely normal during acute hemolysis due to preferential lysis of older enzyme-depleted cells; repeat after 3 months.
  • Fluorescent spot test: Screening test (NADPH fluoresces under UV light)

Management

  1. Preventive (most important):
    • Avoid known triggering drugs and foods (fava beans)
    • Screen before prescribing oxidant drugs (esp. primaquine, dapsone)
  2. Acute hemolytic episode:
    • Remove the offending agent / treat underlying infection
    • Supportive care: IV fluids, maintain urine output to prevent renal failure
    • Blood transfusion if anemia is severe (Hb <7 g/dL or symptomatic)
    • Hemodialysis if acute renal failure develops
    • Phototherapy or exchange transfusion for neonatal jaundice
  3. CNSHA (Class I):
    • Folic acid supplements
    • Regular hematologic surveillance
    • Avoid hemolytic drugs
    • Splenectomy in severe cases

Why G6PD Deficiency Persists in Populations (Evolutionary Advantage)

G6PD-deficient RBCs infected by Plasmodium falciparum undergo increased oxidative stress → premature lysis → protective against severe malaria. This explains the high prevalence in malaria-endemic regions (Africa, Mediterranean, South/Southeast Asia).
Sources: Goldman-Cecil Medicine; Harrison's Principles of Internal Medicine, 22E; Lippincott Illustrated Reviews: Biochemistry, 8E
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