Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency is a genetic disorder that affects the health and stability of red blood cells. To understand the condition, it is essential to first understand the challenging job of a red blood cell. As these cells travel through the body delivering oxygen, they are constantly exposed to damaging molecules called “oxidants” or “free radicals.” These oxidants are byproducts of normal metabolism and can also be introduced by infections, certain medications, and some foods.

A helpful analogy is to think of each of your red blood cells as a delicate bubble.

• As these bubbles float through your system, they are constantly bumping into “sharp objects” (oxidative stressors) that can cause nicks and damage.
• Healthy red blood cells have a powerful, built-in “repair kit” that protects them from this damage. This repair kit is an antioxidant system powered by a substance called NADPH.
• The G6PD enzyme is the essential tool that continuously recharges this system, ensuring the repair kit is always ready to defend the bubble.
• In a person with G6PD deficiency, this specific G6PD “tool” is missing or broken. The red blood cell’s repair kit cannot be recharged.
• Under normal conditions, this may not be a problem. But when the person is exposed to a major oxidative stress like a specific drug or a severe infection, it is like throwing a handful of nails at the fragile bubbles.
• Without their protective repair kit, the red blood cells cannot withstand the assault. They pop and burst by the millions in a process called hemolysis.

This massive, sudden destruction of red blood cells is known as an acute hemolytic crisis, and it is the hallmark of symptomatic G6PD deficiency. The debris from these destroyed cells, particularly bilirubin, floods the system, causing the characteristic signs of the crisis.

In my experience, many patients learn they have G6PD deficiency only after a sudden episode of jaundice or dark-colored urine following an infection or new medication.

The sole cause of G6PD deficiency is a mutation in the G6PD gene. This gene contains the precise set of instructions for making the G6PD enzyme. The G6PD gene is on the X chromosome.

A mutation in this gene results in the production of a G6PD enzyme that is unstable and does not last as long as it should. Newly made red blood cells may have enough of the enzyme, but as the red blood cells get older (they normally live for about 120 days), the faulty G6PD enzyme degrades prematurely. This leaves the older red blood cells unprotected and highly vulnerable to destruction when they encounter an oxidative stressor. There are hundreds of different mutations in the G6PD gene, which can cause varying degrees of enzyme deficiency and clinical severity.

In my experience, patients often ask if they “caught” it, so I clarify it’s an inherited condition, and symptoms only appear under specific triggers.

G6PD deficiency is an inherited genetic disorder. It is not contagious. It is passed down from parents to their children through an X-linked recessive inheritance pattern. This has several important implications:

• The G6PD gene is on the X chromosome, one of the two sex chromosomes. Females have two X chromosomes (XX), while males have one X and one Y chromosome (XY).
• Because males only have one X chromosome, if they inherit an X chromosome with the faulty G6PD gene, they will have the deficiency.
• Females, on the other hand, have a second X chromosome, which in most cases carries a normal copy of the gene. This normal gene usually produces enough of the G6PD enzyme to protect them from symptoms, making them unaffected carriers.
• The condition is most often passed from a carrier mother to her son. For each son born to a carrier mother, there is a 50% chance that he will inherit the faulty gene and have G6PD deficiency.

Clinically, G6PD deficiency results from inherited mutations in the G6PD gene, typically passed in an X-linked recessive pattern, affecting mostly males.

Global Prevalence and the Malaria Hypothesis

G6PD deficiency is extremely common worldwide, affecting an estimated 400 million people. It is most prevalent in populations from parts of the world where malaria is or was endemic, particularly in individuals of African, Mediterranean, Middle Eastern, and South and Southeast Asian descent. This is because being a carrier of G6PD deficiency is believed to confer a protective advantage against severe malaria, an example of natural selection in humans.

The most important feature of G6PD deficiency is that most people who have it are completely asymptomatic and feel perfectly healthy most of the time. The condition only becomes apparent when an individual is exposed to a specific trigger that causes a sudden episode of hemolysis.

The signs and symptoms of this acute hemolytic crisis typically develop rapidly, usually 24 to 72 hours after exposure to a trigger. They are all related to the massive, sudden destruction of red blood cells.

• Jaundice: This is a classic sign. White eyes and skin turn yellow. This is caused by the buildup of bilirubin, a yellow pigment created from hemoglobin breakdown from destroyed red blood cells.
• Dark, Tea-Colored Urine: As large amounts of hemoglobin are released from the destroyed red cells, it is filtered by the kidneys and passes into the urine, making it appear very dark red, brown, or cola-colored.
• Symptoms of Anemia: The rapid drop in the number of red blood cells leads to symptoms of anemia, including:
  • Profound fatigue, weakness, and lethargy.
  • Shortness of breath.
  • A rapid heartbeat (tachycardia).
  • Dizziness.
• Other Symptoms: Back pain or abdominal pain can also occur.

In newborns, G6PD deficiency can be a major cause of neonatal jaundice that appears in the first few days of life. If this jaundice is severe and not treated properly, it can lead to kernicterus, a form of brain damage.

In my experience, most individuals are born with it and remain asymptomatic until exposed to oxidative stress, such as certain drugs, infections, or fava beans.

A diagnosis of G6PD deficiency may be suspected in a child or adult who develops a sudden hemolytic crisis, or in a newborn with severe jaundice.

• Newborn Screening: In many countries, G6PD deficiency is included in the routine newborn screening panel. A small blood sample from a heel prick is tested, allowing for diagnosis before any symptoms occur.
• Blood Tests during a Crisis: If a person presents with a hemolytic crisis, initial blood tests (like a complete blood count and a peripheral blood smear) will show signs of anemia and red blood cell destruction. A bilirubin level will be very high.
• G6PD Enzyme Assay: The definitive diagnosis is made with a blood test that directly measures the activity level of the G6PD enzyme in the red blood cells. Low enzyme activity confirms diagnosis of G6PD deficiency.
• Important Diagnostic Note: This test can sometimes be falsely normal if it is performed during or immediately after a hemolytic crisis. This is because all the old, deficient red cells have been destroyed, and the newly released, young red cells from the bone marrow still have adequate enzyme levels. If G6PD deficiency is strongly suspected but the initial test is normal, it must be repeated several weeks after the person has recovered.
• Genetic Testing: DNA testing can also be performed to identify the specific mutation in the G6PD gene.

In my experience, I also monitor blood counts, bilirubin levels, and reticulocyte counts during symptomatic episodes to assess the severity of hemolysis.

There is no cure for the underlying genetic enzyme deficiency. The entire focus of lifelong management is on preventing hemolytic crises by avoiding known oxidative triggers. Knowledge and prevention are key to living a healthy life with this condition.

1. Avoidance of Triggers

This is the cornerstone of management. Individuals with G6PD deficiency and their families must be educated on the specific substances to avoid.

• Fava Beans: For individuals with the more severe Mediterranean variant, eating fava beans (also known as broad beans) can trigger a severe hemolytic crisis known as favism. These must be strictly avoided.
• Certain Medications: This is a critical area of education. Many common drugs are known to be unsafe for people with G6PD deficiency. These include:
  • Certain antibiotics, especially sulfa drugs (like trimethoprim-sulfamethoxazole).
  • Certain antimalarial drugs, particularly primaquine.
  • High doses of aspirin.
  • Rasburicase, a drug used for tumor lysis syndrome.
  • It is essential for a person with G6PD deficiency to inform all their doctors and pharmacists about their condition before taking any new medication.
• Certain Chemicals: Exposure to the chemical naphthalene, which is found in some types of mothballs, can also trigger a crisis.

2. Treatment of an Acute Hemolytic Crisis

If a hemolytic crisis does occur, treatment is supportive and is managed in a hospital.

• Stop the Trigger: The first and most important step is to identify and discontinue the offending drug or substance.
• Supportive Care: This may include intravenous (IV) fluids to protect the kidneys from damage.
• Blood Transfusion: For patients with very severe anemia, a red blood cell transfusion may be necessary to restore oxygen-carrying capacity.
• Dialysis: In very rare cases of severe hemolysis leading to acute kidney injury, temporary dialysis may be required.

Most hemolytic episodes are self-limiting, and with the removal of the trigger, the body’s bone marrow will produce new, healthy red blood cells and the person will recover.

3. Patient Education

• Individuals diagnosed with G6PD deficiency should be given a clear list of medications and foods to avoid.
• Wearing a medical alert bracelet or necklace that identifies their condition is strongly recommended.

I focus on avoiding triggers, patients must be educated on which drugs and foods to avoid, as prevention is the mainstay of management.

Glucose-6-Phosphate Dehydrogenase deficiency is one of the most common genetic conditions in the world, affecting hundreds of millions of people. It is crucial to understand that it is not a constant state of illness, but rather an underlying vulnerability. Individuals with G6PD deficiency are healthy and asymptomatic until their vulnerable red blood cells are exposed to a powerful oxidative stressor. The key to living with this condition is empowerment through knowledge. By understanding the nature of the deficiency and diligently avoiding the known triggers specifically fava beans and a list of unsafe medications, individuals can completely prevent the dangerous episodes of hemolysis. In my experience, once patients are aware of their condition and potential triggers, they can live full, healthy lives with very few complications.

National Institutes of Health, MedlinePlus. (2023). G6PD Deficiency. Retrieved from https://medlineplus.gov/genetics/condition/glucose-6-phosphate-dehydrogenase-deficiency/

National Organization for Rare Disorders (NORD). (2022). Glucose-6-Phosphate Dehydrogenase Deficiency. Retrieved from https://rarediseases.org/rare-diseases/glucose-6-phosphate-dehydrogenase-deficiency/

World Health Organization (WHO). (1989). Glucose-6-phosphate dehydrogenase deficiency. Retrieved from https://apps.who.int/iris/handle/10665/39733