Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency

A 24 year old man of Mediterranean descent presents to the emergency department with fatigue, jaundice, and dark urine 2 days after taking trimethoprim-sulfamethoxazole for a urinary tract infection. He reports similar episodes in the past after eating fava beans. Physical examination reveals mild scleral icterus and splenomegaly. Laboratory studies show anemia, elevated LDH, elevated indirect bilirubin, decreased haptoglobin, and reticulocytosis. Peripheral blood smear demonstrates bite cells, and supravital staining reveals Heinz bodies. Diagnosis?

Diagnosis is Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency.

1. Definition

Glucose-6-phosphate dehydrogenase (G-6-PD) deficiency is an X-linked recessive enzymatic disorder causing impaired protection of red blood cells against oxidative stress, leading to episodic hemolytic anemia.

2. Epidemiology

1. X-linked recessive disorder
2. Most common enzymatic disorder of RBCs worldwide
3. Common in:
• African descent
• Mediterranean descent
• Middle Eastern populations
• Malaria-endemic regions
4. Provides partial protection against malaria

3. Etiology and Pathogenesis

1. Deficiency or instability of the G6PD enzyme leads to decreased NADPH production
2. Reduced NADPH causes inability to maintain reduced glutathione
3. RBCs become highly susceptible to oxidative stress
4. Oxidative stress causes hemoglobin denaturation and hemolysis
5. Hemolysis is predominantly extravascular, with some intravascular hemolysis

4. Variants

4.1 African Variant

1. Mildly reduced G6PD activity
2. Causes mild intermittent hemolysis with oxidative stress

4.2 Mediterranean Variant

1. Markedly reduced G6PD activity
2. Causes severe hemolysis with oxidative stress

5. Triggers of Hemolysis

5.1 Drugs

• Sulfonamides
• Dapsone
• Nitrofurantoin
• Primaquine
• Doxorubicin

5.2 Infections

• Bacterial or viral infections

5.3 Metabolic Stress

• Diabetic ketoacidosis (DKA)

5.4 Foods

• Fava beans

6. Pathophysiology

1. Oxidative stress causes oxidation and denaturation of hemoglobin
2. Denatured hemoglobin precipitates within RBCs forming Heinz bodies
3. Heinz bodies are best visualized with supravital staining
4. Splenic macrophages remove Heinz bodies resulting in bite cells
5. Progressive RBC membrane damage causes hemolysis

7. Clinical Features

7.1 Hemolytic Episodes

1. Episodic hemolytic anemia precipitated by oxidative stress
2. Sudden onset fatigue and weakness
3. Pallor

7.2 Associated Findings

1. Dark urine
2. Jaundice
3. Splenomegaly

7.3 Neonatal Presentation

1. Neonatal jaundice may occur in severe cases
2. Severe hyperbilirubinemia may rarely cause kernicterus

8. Diagnosis

8.1 Peripheral Blood Smear

1. Heinz bodies
• Denatured hemoglobin precipitates within RBCs
2. Bite cells
• Caused by splenic macrophage removal of Heinz bodies

8.2 Laboratory Findings

1. Decreased hemoglobin
2. Increased reticulocyte count
3. Increased indirect bilirubin
4. Increased LDH
5. Decreased haptoglobin

8.3 G6PD Enzyme Assay

1. Decreased G6PD levels confirm diagnosis
2. Levels may be falsely normal immediately after acute hemolysis because:
• Older deficient RBCs have already lysed
• Younger reticulocytes retain relatively higher G6PD activity
3. Testing should therefore be repeated several weeks after recovery

9. Management

9.1 Remove Trigger

1. Stop precipitating drugs or avoid oxidative stressors

9.2 Supportive Care

1. Maintain adequate hydration
2. Blood transfusion if severe hemolysis occurs

9.3 Long-Term Management

1. Avoid known oxidative triggers
2. Folic acid supplementation may support erythropoiesis
3. Iron supplementation only if iron deficiency is present

10. Key Clinical Insight

Acute episodic hemolytic anemia triggered by oxidative stress with Heinz bodies and bite cells strongly suggests G-6-PD deficiency

11. Exam Level Pearls

1. G-6-PD deficiency is an X-linked recessive disorder
2. Oxidative stress precipitates hemolysis
3. Heinz bodies and bite cells are classic findings
4. Heinz bodies require supravital staining for visualization
5. Fava beans and sulfonamides commonly trigger attacks
6. G6PD assay may be falsely normal during acute hemolysis
7. Most patients are asymptomatic between episodes
8. Mediterranean variant causes more severe hemolysis than African variant
9. Hemolysis is usually self-limited because reticulocytes contain higher G6PD activity
10. Neonatal jaundice is a high-yield presentation of G-6-PD deficiency