Glucose-6-phosphate Dehydrogenase Deficiency – G6PD

What is Glucose-6-phosphate Dehydrogenase Deficiency?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an inherited metabolic disorder in which the enzyme G6PD is either insufficiently active or present in too low a quantity within red blood cells (erythrocytes). This enzyme plays a critical role in protecting red blood cells from oxidative stress. When it is absent or dysfunctional, erythrocytes become vulnerable to damage under certain conditions, leading to their premature destruction – a process known as hemolysis.

G6PD deficiency affects an estimated 400 to 500 million people worldwide, making it one of the most prevalent genetic conditions in humans. It is particularly common in tropical and subtropical regions, including parts of Africa, the Middle East, the Mediterranean, and Southeast Asia.

Causes and Inheritance

G6PD deficiency is inherited in an X-linked recessive pattern, meaning the defective gene is located on the X chromosome. Since males have only one X chromosome, a single defective copy of the gene is sufficient to cause the condition. Females, having two X chromosomes, are typically only fully affected if both copies carry the mutation; however, they can be carriers and pass the trait to their children.

More than 400 different genetic variants (mutations) of the G6PD gene have been identified, each causing varying degrees of enzyme deficiency. The WHO classifies these variants into five classes based on the severity of the enzyme defect and its associated clinical manifestations.

Mechanism of Action

G6PD is a key enzyme in the pentose phosphate pathway, a metabolic route that is especially important in red blood cells. It catalyzes the first step of this pathway, generating NADPH – a molecule essential for protecting cells against reactive oxygen species (oxidative stress). NADPH maintains glutathione in its active, reduced form, which in turn safeguards the cell membrane and hemoglobin of erythrocytes.

Without adequate G6PD activity, this protective mechanism is compromised. When certain triggers – such as infections, specific medications, or foods – generate oxidative stress, the unprotected red blood cells are damaged and destroyed, resulting in hemolytic anemia.

Symptoms

Many individuals with G6PD deficiency remain asymptomatic throughout their lives and only discover their condition during an acute hemolytic episode. Common symptoms include:

• Jaundice (icterus): yellowing of the skin and eyes due to elevated bilirubin levels
• Pale skin and general weakness caused by anemia
• Dark urine (hemoglobinuria) resulting from red blood cell breakdown
• Fatigue and exhaustion
• Rapid heartbeat and shortness of breath in severe anemia
• Enlarged spleen (splenomegaly) in some cases

In newborns, G6PD deficiency can cause prolonged neonatal jaundice (persistent jaundice after birth), which, if left untreated, may in severe cases lead to brain damage (kernicterus).

Triggers of a Hemolytic Crisis

Acute episodes of hemolysis are frequently triggered by external factors that induce oxidative stress:

• Infections (the most common trigger, e.g., bacterial or viral infections)
• Medications: certain antimalarials (primaquine, chloroquine), sulfonamides, nitrofurantoin, high-dose aspirin, dapsone
• Fava beans: consumption can trigger severe hemolysis in affected individuals, a condition known as favism
• Certain chemicals, such as naphthalene (found in some mothballs)
• Metabolic acidosis

Diagnosis

G6PD deficiency is typically diagnosed through laboratory tests:

• G6PD enzyme activity assay: Direct measurement of enzyme activity in the blood – the gold standard for diagnosis
• Fluorescent spot test: A rapid screening test to assess enzyme activity
• Genetic testing: Identifies the specific gene mutation, particularly useful for female carriers
• Complete blood count and reticulocyte count: Indicators of active hemolysis
• Bilirubin and haptoglobin levels: Additional markers of hemolysis

Important note: During an acute hemolytic episode, enzyme activity levels may appear falsely normal, as the oldest and most affected red blood cells have already been destroyed. Diagnostic confirmation should therefore be performed several weeks after the acute episode has resolved.

Treatment

There is currently no cure for G6PD deficiency. Management focuses on:

• Avoidance of triggers: Patients receive a detailed list of medications and foods to avoid
• Management of acute hemolytic crises: Withdrawal of the causative agent, adequate fluid intake, and blood transfusions in severe cases
• Treatment of neonatal jaundice: Phototherapy (light therapy) or, in severe cases, exchange transfusion
• Folic acid supplementation may be beneficial in cases of chronic hemolysis to support red blood cell production

With consistent avoidance of known triggers, the majority of affected individuals lead normal, symptom-free lives.

References

1. WHO Working Group: Glucose-6-phosphate dehydrogenase deficiency. Bulletin of the World Health Organization, 67(6):601-611, 1989.
2. Luzzatto L, Ally M, Notaro R: Glucose-6-phosphate dehydrogenase deficiency. Haematologica, 105(10):2291-2294, 2020. PubMed PMID: 32855328.
3. Cappellini MD, Fiorelli G: Glucose-6-phosphate dehydrogenase deficiency. The Lancet, 371(9606):64-74, 2008.