G6PD deficiency and hemolysis.
Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzyme disorder that leaves red blood cells less able to handle oxidative stress. Several drugs — most prominently dapsone, with smaller risks from sulfasalazine and certain sulfa antibiotics — can precipitate hemolytic anemia in affected patients. The deficiency is more common in some Mediterranean, African, and South/Southeast Asian populations.
- Pattern
- X-linked recessive; most affected are males. Carrier females may be variably affected.
- Higher prevalence
- Mediterranean, African, Middle Eastern, and South/Southeast Asian populations.
- Sulfa drugs of note
Dapsone(highest risk), sulfasalazine, some sulfa antibiotics at higher doses.- Other triggers
- Primaquine, nitrofurantoin, rasburicase, fava beans, some other drugs.
What G6PD does
Glucose-6-phosphate dehydrogenase catalyses the first step of the pentose phosphate pathway, generating NADPH. Red blood cells need NADPH to keep glutathione in its reduced form, and reduced glutathione is the cell's main defence against oxidative damage to hemoglobin and the cell membrane. Other cells have alternative ways of generating reducing power; the red cell, lacking a nucleus and most organelles, relies heavily on G6PD.
In G6PD deficiency, the enzyme works less efficiently, and the red cell's antioxidant capacity is reduced. Under normal conditions this is often clinically silent. Under oxidative stress — certain drugs, certain infections, fava beans, naphthalene exposure — hemoglobin is damaged, denatured proteins (Heinz bodies) form, and the affected cells are removed from the circulation, sometimes catastrophically.
Population prevalence
G6PD deficiency is one of the most common enzyme disorders in humans. Carrier rates are high in regions with historical malaria endemicity — partial protection against malaria has been the proposed evolutionary explanation. Estimates of population prevalence vary widely by region but are notably higher in Mediterranean (around the basin), Sub-Saharan African, Middle Eastern, and South/Southeast Asian populations than in Northern European populations. The variant phenotypes also differ: African variants tend to be milder than Mediterranean variants.
Because the gene is on the X chromosome, the disorder is more common in males. Carrier females may be partially affected because of X-inactivation, with a wide range of clinical expression.
Sulfa drugs and G6PD
Different sulfa-family drugs carry different levels of risk:
Dapsone is the highest-risk sulfa-family drug. Hemolysis on dapsone occurs in G6PD-deficient patients reliably enough that pre-prescription G6PD testing is standard in many settings, particularly when dapsone is used long-term (leprosy, dermatitis herpetiformis, PCP prophylaxis). Even mild G6PD variants may show hemolysis on dapsone. Dapsone-induced methemoglobinemia is a separate concern.
Sulfasalazine can cause hemolysis in G6PD deficiency, mostly attributed to the sulfapyridine moiety. Risk is lower than dapsone but real, and pre-treatment G6PD testing is sometimes done in patients from higher-prevalence populations.
Sulfa antibiotics (sulfamethoxazole, sulfadiazine) can cause hemolysis in G6PD deficiency, more so at higher doses and prolonged courses. Routine short-course use of TMP-SMX in known G6PD-deficient patients is approached with caution; whether it is safe to use depends on the variant, the indication, and the prescriber's judgement.
Other drugs sometimes used as alternatives to sulfa antibiotics also carry G6PD-related risks: nitrofurantoin (for UTI) and primaquine (for malaria) are notable.
What hemolysis looks like
Drug-induced hemolysis in G6PD deficiency typically begins one to three days after starting the drug. Symptoms can include: pallor, fatigue, jaundice (yellow eyes and skin), dark urine (sometimes very dark — like cola), back or abdominal pain, breathing difficulty in severe cases. Laboratory findings include anemia, elevated indirect bilirubin, low haptoglobin, raised reticulocytes, and sometimes hemoglobinuria.
Severity varies widely. Mild cases self-limit when the drug is stopped. Severe cases may require transfusion. In neonates, hemolysis can contribute to severe jaundice with risk of kernicterus.
What to do
If G6PD deficiency is known: avoid dapsone where possible; for other drugs, the prescriber considers indication, alternatives, and the specific G6PD variant. Pre-prescription G6PD testing is appropriate in some settings, including before dapsone in many guidelines and before rasburicase (a non-sulfa drug used in tumour lysis syndrome).
If hemolysis is suspected on a drug — symptoms or laboratory findings consistent — the offending drug is stopped, and supportive care is given. Severe cases may need transfusion. The diagnosis is often reviewed and confirmed once the patient has recovered, because measuring G6PD activity during an acute hemolytic episode can give falsely normal results (the deficient older cells have already been destroyed; younger cells have higher activity).
Pediatric and family considerations
G6PD deficiency is heritable. Family screening may be appropriate after a new diagnosis, particularly for boys and for relatives planning pregnancy. Newborn screening for G6PD deficiency is performed in some countries, particularly those where it is common.
Other triggers — fava beans (favism), naphthalene exposure (mothballs), some food preservatives — are unrelated to drug therapy but worth being aware of for affected patients. Sulfa and G6PD deficiency covers the special-population considerations more fully.