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Glucose-6-Phosphate Dehydrogenase Deficiency (G6PDD)

Glucose-6-Phosphate Dehydrogenase Deficiency (G6PDD) 

- G6PD is a metabolic enzyme required in the pentose phosphate pathway and is particularly important in red blood cell metabolism. 

The function of G6PD: 

• Regenerates NADPH, allowing regeneration of Glutathione. 

• Protects against oxidative stress. 

• Deficiency of G6PD leads to hemolysis during oxidative stress- infection, medication, fava beans. 

• Oxidative stress causes the formation of Heinz bodies and extravascular hemolysis. 

- It is the most common red cell enzyme disease related to hemolysis. 

- Large no. of abnormal genes code for the G6PD. 

- X-linked disease, lead to G6PD Deficiency (RBCs enzyme deficiency) asymptomatic unless Oxidative stress causes the RBC’s to break apart. 

- Inherited –, Recessive. 

- The gene of G6PD is present on the X chromosome. 

- Therefore, the deficiency state is a sex-linked trait 

- Affected males inherit the abnormal gene from their mother, who is usually a carrier (heterozygous). 

G6PD variants: 

• There are more than 400 variants of G6PD enzyme: 

• G6PD A and G6PD B are well-known variants. 

G6PD B: The normal G6PD enzyme. 

- G6PD A: Found to have normal enzyme activity, but the difference from B is a single amino acid substitution, Lead to different electrophoretic mobility

• G6PD A: the common one associated with hemolysis, electrophoretically identical to A but has only 5- 15% of the normal enzymatic activity.
• Mediterranean G6PD: Same as B in electrophoresis, but its activity is usually 1% lower than normal. 

World Health Organization classifies for G6PD genetic variants: 

• Class I: Severe deficiency (<10% activity) with chronic (nonspherocytic) hemolytic anemia. 

• Class II: Severe deficiency (<10% activity), with intermittent hemolysis. 

• Class III: Mild deficiency (10-60% activity), hemolysis with stressors only. 

• Class IV: Non-deficient variant, no clinical sequelae. 

• Class V: Increased enzyme activity, no clinical sequelae. 

What happens in G6PD deficiency? 

Cause of G6PD deficiency: 

• Individuals who have inherited one of the many G6PD mutations do not show clinical manifestation. 

• Some of the patients with G6PD develop hemolytic anemia if they are exposed or ingest any of the followings oxidizing agents: 

1-Oxidant drugs: 

- Antibiotics: e.g. co-trimoxazole, sulfanilamide, dapsone, Salazopyrin, nitrofurans, chloramphenicol. 

- Antimalarials (e.g. primaquine, pamaquine, Fansidar, chloroquine, Maloprim) 

- Antipyretics: e.g. aspirin.
- Antihelminths: (e.g. β-naphthol, stibophen. 

- Miscellaneous: e.g. vitamin K analogs, naphthalene, probenecid. 

2- Favism: 

The hemolytic effect of ingesting fava beans is not observed in all individuals with G6PD deficiency but all patients with favism have G6PD deficiency. 


• Oxidative denaturation of hemoglobin is the major cause of H.A in G6PD deficiency. 

• It is important in the conversion of glucose-6- P to phosphogluconate. 

• For subsequent production of NADPH & reduced glutathione (GSH). 

• GSH protects enzymes & hemoglobin against oxidation by reducing H2O2 & free radicals. 

• H2O2 is generated normally in small amounts during normal red cell metabolism. 

• Larger amounts produced when an oxidant drug interacts with oxyhemoglobin. 

• Normal red cells have sufficient G6PD activity to maintain adequate GSH levels. 

• When deficient, red cells fail to produce sufficient G6PD to detoxify peroxide. 

• Hb is then oxidized to Hi, heme is liberated from globin & globin denatures producing Heinz bodies. 

• Heinz bodies attach to membrane sulfhydryl groups inducing cell rigidity. 

• At this point red cells can no longer traverse the splenic microcirculation. 

• Hence lysis occurs. 


- Patients with this condition do not display any signs of the disease until their red blood cells are exposed to certain chemicals in food or medicine, or to stress. 

- Symptoms are more common in men and may include: 

• Dark urine 

• Enlarged spleen 

• Fatigue 

• Pallor 

• Rapid heart rate 

• Shortness of breath 

• Jaundice 

Diagnosis of G6PD Deficiency Hemolytic Anemia: 

1-CBC: Bite cells, blister cells, irregular small cells, Heinz bodies, polychromasia. 

2-Screening: Qualitative assessment of G6PD enzymatic activity. 

3-Confirmatory test: Quantitative measurement of G6PD enzymatic activity. 

Because of the higher enzyme level in young red cells, a red cell enzyme assay may give a 'false' normal level in the phase of acute hemolysis with a reticulocyte response. 

4-Molecular test: Detection of G6PD gene mutation. 

5. Special test: Methemoglobin Reduction Test:
- Sodium nitrite converts Hb (hemoglobin) to Hi (methemoglobin). 

- Adding methylene blue should stimulate the pentose phosphate pathway, reducing methemoglobin. 

- In G6PD deficiency, methemoglobin persists. 

• Normal blood → clear red color 

• Deficient blood → brown color 

Care of G6PD patients: 

• The most important measure is prevention – avoidance of the drugs and foods that cause hemolysis. 

• Vaccination against some common pathogens (e.g. hepatitis A and hepatitis B) may prevent infection-induced attacks. 

• In the acute phase of hemolysis, blood transfusions might be necessary, or even dialysis in acute renal failure. 

• Blood transfusion is an important symptomatic measure, as the transfused red cells are generally not G6PD deficient and will live a normal lifespan in the recipient's circulation. 

• Some patients may benefit from splenectomy as this is an important site of red cell destruction. 

• Folic acid should be used in any disorder featuring a high red cell turnover. 

• Although vitamin E and selenium have antioxidant properties, their use does not decrease the severity of G6PD deficiency.