Glucose-6-phosphate dehydrogenase deficiency (G6PD) is intravascular hemolytic anemia. It is inherited in an X-linked recessive manner. Patients have episodic hemolysis due to an identified oxidative stressor that causes damage to red blood cells (RBCs) which lack sufficient NADPH.

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Image: “Blood test” by torange.biz. License: CC BY 4.0


Epidemiology and Etiology

Epidemiology

  • Found in Malarial Endemic regions; Mediterranean, African, Middle Eastern descent
  • Present exclusively in males as it is X-linked Recessive
  • Females can be silent carriers

Etiology

  • Mutation in the Glucose-6-phosphate dehydrogenase(G6PD) enzyme 
  • A single-base change that results in a single amino-acid substitution 
  • Mutation lowers the half-life of the enzyme 
  • G6PD deficiency results in a defect of the Pentose Phosphate Shunt during glycolysis
  • Inheritance is X-linked Recessive (band Xq28)

Image: “G6PD” G6PD deficiency is an X-linked disorder found on Band Xq28. By Lecturio.

Video Gallery

G6PD Deficiency: Etiology by Carlo Raj, MD
G6PD Deficiency: Biochemistry of G6pd by Carlo Raj, MD
Pediatric G6PD Deficiency by Brian Alverson, MD

Pathophysiology

  • G6PD is the rate-limiting enzyme in the Pentose Phosphate Pathway
  • G6PD enzyme is responsible for 
    • Oxidation of glucose-6-phosphate 
    • Reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to NADPH 
  • NADPH maintains glutathione in its reduced form
  • Reduced glutathione is needed to neutralize oxidative metabolites
  • In RBCs, this is the ONLY pathway that produces NADPH.
  • Thus, a lack of G6PD results in a deficiency in NADPH and increased oxidative damage.
  • Oxidative stressors can denature hemoglobin and cause intravascular hemolysis.
  • Extravascular hemolysis would be due to splenic clearance of the deformed RBCs.
metabolic-pathways

Image: Metabolic pathways. By Lecturio.

Common oxidative stressors

Drugs Foods Other
  • Sulfas (TMP-SMX)
  • Quinolones
  • Nitrofurantoin
  • Aspirin/NSAIDs
  • Methylene blue
  • Fava beans
  • Blue food coloring
  • Any infection (most common)
  • Naphthalene (mothballs)
  • Diabetic ketoacidosis

Clinical manifestations

  • History of a trigger for the oxidative stress
  • Episodic Symptoms of Anemia
    • Pallor
    • Shortness of Breath
    • Fatigue
    • Tachycardia
  • Flow murmur (best heard at upper sternal borders)

    Image: “Hematuria” by Byomicsonline.org. License: CC BY 4.0

  • Intravascular Hemolysis
    • Jaundice
    • Hemoglobinuria (cola-colored urine) – Hematuria
  • Neonate (Males)

Video Gallery

G6PD Deficiency: Clinical Pathology by Carlo Raj, MD

Diagnostics

Suspected in cases of episodic hemolytic symptoms.

  • CBC
    • ↓ Hb
    • ↑ Retics
    • ↑ LDH
    • ↓ Haptoglobin
    • ↑ Bilirubin
  • Peripheral Blood Smear
    • Heinz Bodies
    • Bite Cells
  • Beutler test 
    • Done 2–3 weeks after an acute episode
    • quantifies NADPH/G6PD levels

Treatment

  • Prevention
    • Avoid oxidative stressors: infections, drugs, fava beans in the diet
  • During Hemolysis
    • If Hb < 9 with hemolysis – Blood Transfusion
    • Neonatal Jaundice – Phototherapy or exchange transfusion
  • Splenectomy considered in rare cases of chronic hemolytic anemia

Differential Diagnoses

  • Hemolytic Anemia: Hemolytic Anemias encompasses anemia due to a shortened half-life of the RBC. The causes include extravascular ( extrinsic/intrinsic) or intravascular. G6PD is an extravascular, intrinsic type.
  • Sideroblastic Anemia: It is microcytic anemia in which the bone marrow produces sideroblasts (ring-shaped blood cells) due to the inability of the body to place iron properly into hemoglobin. It presents with abnormal iron studies as well as splenomegaly.
  • Sickle Cell Disease: A hereditary hemoglobinopathy resulting in hypoxia and anemia. They share demographics however, sickle cell disease is a chronic hemolytic disorder whereas G6PD deficiency is episodic and less severe.
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