Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency
Favism

Article written and reviewed by Dr Luca Moretti

glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common red-cell enzymopathy worldwide and is caused by a genetic defect of the G6PD enzyme, which is essential for protecting red blood cells against oxidative stress. This X-linked recessive condition typically presents with hemolytic anemia of variable severity, often triggered by oxidant exposures such as infections, drugs or foods, particularly fava beans, hence the term “favism.”

Although most affected individuals are asymptomatic in everyday life, G6PD deficiency can cause potentially severe episodes of acute hemolysis and has major public-health relevance, particularly in high-prevalence regions. The global distribution follows a characteristic malaria-associated pattern, with high prevalence in Africa, the Mediterranean, the Middle East and Southeast Asia. In some populations, up to 30% of males may be hemizygous for a deficient variant.

Detailed knowledge of the genetics, pathophysiology, risk factors and possible clinical manifestations of G6PD deficiency is essential for optimal patient management and for appropriate prevention, diagnosis and treatment. The following sections examine all the main characteristics of this hematologic condition in detail, with particular attention to epidemiologic and diagnostic aspects, complications and the most recent therapeutic perspectives.

Structure, Function and Physiologic Role of G6PD

glucose-6-phosphate dehydrogenase is a key enzyme of the pentose phosphate pathway, also called the hexose monophosphate shunt, and is fundamental to red-cell metabolism. It catalyzes conversion of glucose-6-phosphate to 6-phosphoglucono-δ-lactone, generating NADPH, the principal source of reducing power in human cells. Because mature red blood cells have no other NADPH-producing system, G6PD is their only source of NADPH needed to maintain reduced glutathione and antioxidant defense.

The NADPH generated by the G6PD-catalyzed reaction is required to maintain glutathione in its reduced form (GSH), which neutralizes free radicals and reactive oxygen species (ROS). Under physiologic conditions, this system protects the red-cell membrane and hemoglobin from oxidation, ensuring red blood cell survival and function throughout its average lifespan of approximately 120 days.

G6PD deficiency reduces NADPH production and makes red blood cells vulnerable to oxidants. In the most common variants, disease becomes clinically evident mainly during acute oxidative stress, whereas class A variants may cause chronic nonspherocytic hemolytic anemia even without a recognizable trigger.

Etiology, Genetics and Molecular Variants

The etiology of G6PD deficiency is exclusively genetic and related to pathogenic variants of the G6PD gene on the long arm of the X chromosome (Xq28). Inheritance follows an X-linked recessive pattern: males, with a single X chromosome, are hemizygous and clinically affected by one pathogenic copy; females may be heterozygous or, more rarely, biallelic. In heterozygous females, lyonization produces a red-cell mosaic and G6PD activity may range from normal to markedly reduced, with possible clinical expression; biallelic forms are rare.

More than 200 molecular G6PD variants have been described, differing in residual enzyme activity and protein stability. The most common include:

• Mediterranean G6PD (c.563C>T, p.Ser188Phe): common in the Mediterranean region, the Middle East and parts of Asia, this deficient variant is associated with acute oxidative hemolysis. Residual enzyme activity is markedly reduced but varies among individuals and assay methods and should not be described by a universal value below 5%.
• G6PD A− (c.202G>A on the c.376A>G background): common in African and African-descended populations, this deficient variant is associated with acute oxidative hemolysis; residual activity is variable and should not be fixed universally at 10–15%.
• Other regional variants, including G6PD Canton, G6PD Mahidol and G6PD Kaiping, with variable enzyme activity and clinical expression.

Most mutations are missense, causing substitution of one or more amino acids and altering enzyme stability or catalytic function. The WHO classification of variants is based on residual enzyme activity and clinical severity:

• Class A: variants with median enzyme activity below 20% associated with chronic nonspherocytic hemolytic anemia.
• Class B: variants with median activity below 45% associated with acute hemolysis triggered by oxidants.
• Class C: variants with median activity above 60%, without an association with hemolysis.
• Class U: variants of uncertain clinical significance because data are insufficient.

Clinical expression depends on the specific variant, the proportion of red blood cells containing deficient enzyme, and concomitant environmental factors.

Risk Factors and Prevention

The risk factors for hemolytic crises in people with G6PD deficiency should not be confused with the genetic cause of the disease; they are conditions or substances that increase oxidative stress in red blood cells. The most important include:

• Drug exposure: risk must be assigned to the individual drug and dose. Rasburicase, pegloticase, methylene blue, dapsone and tafenoquine are examples of high-risk agents. For primaquine the risk is dose-dependent: standard anti-relapse regimens of 0.25–0.5 mg/kg/day for 14 days are high risk, whereas lower-dose regimens may fall into intermediate- or low-risk categories. Nitrofurantoin is classified as intermediate risk, while other drugs historically included in generic lists may carry low or absent risk at standard doses.
• Acute infections: an important trigger of hemolysis, including in children; their relative frequency compared with fava beans and drugs varies with the epidemiologic and clinical setting. Infection-associated inflammatory and oxidative stress can precipitate hemolysis.
• Ingestion of fava beans: fava beans contain compounds such as vicine and convicine that can generate powerful oxidative stress and precipitate favism with rapid-onset hemolysis.
• Exposure to chemicals: naphthalene, found in mothballs, aniline dyes and aromatic derivatives.

Prevention of clinical manifestations is based mainly on:

• Health education for patients and families;
• Identification of triggers and consultation of an up-to-date risk classification for individual drugs;
• Genetic counseling in high-prevalence populations and newborn screening where implemented;
• Active clinical monitoring during high-risk periods such as infections, surgery and pregnancy;
• Informing healthcare professionals to prevent accidental exposure to hazardous drugs or substances.

In high-prevalence countries, primary-prevention programs including screening and public education have significantly reduced severe favism and iatrogenic acute hemolysis.

Pathogenesis and Pathophysiology

The pathogenesis of glucose-6-phosphate dehydrogenase (G6PD) deficiency is closely related to the central role of this enzyme in red-cell metabolism. G6PD catalyzes the first and most important step of the pentose phosphate pathway, the only source of NADPH production in mature human red blood cells. NADPH maintains glutathione in its reduced form (GSH), which is central to neutralizing reactive oxygen species (ROS) and preventing oxidative damage to red-cell proteins, lipids and membrane structures.

Under physiologic conditions, continuous GSH regeneration protects hemoglobin and membrane proteins from oxidative processes occurring during normal cellular metabolism and, more intensely, during exposure to exogenous oxidants such as drugs, infections or fava beans. In G6PD deficiency, the ability to regenerate reduced glutathione falls sharply, so even modest oxidative stress can cause irreversible damage to proteins and membrane lipids.

Oxidative damage to hemoglobin causes formation of Heinz bodies , aggregates of denatured hemoglobin that attach to the inner red-cell membrane. Together with structural membrane abnormalities, these aggregates make the cell rigid and fragile and lead to rapid recognition by the reticuloendothelial system, especially the spleen. This causes premature removal of damaged red blood cells through predominantly extravascular, splenic hemolysis; with massive injury, substantial intravascular hemolysis may also occur, releasing free hemoglobin directly into plasma and urine.

The level of residual G6PD activity influences red-cell protection. In many variants, young red blood cells and reticulocytes retain greater activity than older cells; in severe variants such as Mediterranean G6PD, even young cells may be markedly deficient. This contributes to spontaneous limitation of crises in many variants, especially G6PD A−; in severe variants in which reticulocytes and young red cells remain markedly deficient, hemolysis may continue while oxidative stress persists.

Exposure to an oxidative trigger such as drugs, infection or fava beans therefore causes:

• Rapid onset of oxidative stress that cannot be adequately buffered;
• Oxidation of hemoglobin and membrane proteins with formation of Heinz bodies;
• Loss of red-cell deformability and characteristic morphological findings such as bite cells, blister cells and Heinz bodies;
• Activation of the reticuloendothelial system and massive removal of red blood cells from the circulation;
• In severe cases, direct membrane lysis and release of free hemoglobin, with risk of hemoglobinuria and acute kidney injury.

Pathophysiologically, an acute hemolytic crisis is characterized by a rapid fall in hemoglobin, increased hemoglobin breakdown products such as indirect bilirubin and LDH, reticulocytosis and, with massive intravascular hemolysis, hemoglobinuria. In newborns and infants, limited ability to handle oxidative injury can rapidly lead to severe hyperbilirubinemia with a risk of bilirubin encephalopathy or kernicterus if not treated promptly.

The chronic nonspherocytic form , which is rare and associated with particularly unstable molecular variants, features persistent low-grade oxidative stress that shortens red-cell survival even in the absence of triggers. The clinical picture is dominated by chronic anemia, mild jaundice, splenomegaly and occasionally nonspecific symptoms such as fatigue and reduced exercise tolerance. New oxidative insults can precipitate acute hemolytic crises in these patients as well.

Overall, many G6PD-deficiency variants remain clinically silent until oxidative stress occurs, but variants associated with chronic hemolytic anemia and neonatal hyperbilirubinemia may manifest even without a recognizable exogenous trigger.

Clinical Manifestations

The clinical manifestations of G6PD deficiency reflect the interaction among genetic background, residual enzyme activity, patient age and intensity of the oxidative insult. Most carriers, especially heterozygous women, remain asymptomatic throughout life. However, the spectrum ranges from potentially fatal acute hemolytic crises to unrecognized chronic forms and episodes of neonatal jaundice.

The acute hemolytic crisis is the most typical and concerning presentation. After exposure to a trigger such as fava beans, oxidant drugs or infection, hemolysis develops rapidly, from a few hours to about three days depending on the trigger, with progressive marked pallor, jaundice, acute malaise, tachycardia, dyspnea, dark urine that may become frankly hemoglobinuric, with a “cola” color. Children may present with lethargy, poor appetite and, in severe cases, signs of hypoperfusion and shock.Ingestion of fava beans or favism causes some of the most explosive presentations and may require urgent transfusion, particularly in young patients and carriers of the Mediterranean variant.

Clinical manifestations are dominated by a rapid fall in hemoglobin, sometimes exceeding 3–5 g/dL within 24–48 hours, accompanied by jaundice from increased indirect bilirubin, hemoglobinuria with massive lysis, reticulocytosis and splenomegaly. Severity ranges from minimally symptomatic disease to severe hemodynamic compromise, especially when treatment is delayed or a crisis occurs in vulnerable patients such as newborns, older adults, or people with comorbidities.

Neonatal jaundice is one of the most concerning complications in newborns with G6PD deficiency, especially with other predisposing conditions such as prematurity, polycythemia, or inadequate feeding. Hyperbilirubinemia may begin early, within the first 24–48 hours, be refractory to phototherapy, and rapidly reach neurotoxic levels with a risk of kernicterus. In many high-prevalence areas, lack of timely diagnosis and treatment remains a cause of mortality and permanent neurologic morbidity.

The chronic nonspherocytic forms, which are extremely rare, present with chronic anemia of variable severity, often associated with mild jaundice, splenomegaly, and reduced exercise tolerance. Acute hemolytic crises can still occur, abruptly worsening the hematologic picture.

In summary, G6PD deficiency ranges from complete absence of symptoms to fulminant hemolytic crisis, with unrecognized chronic forms and dangerous neonatal complications in between. The risk and severity of manifestations depend on the individual molecular profile and the clinical and healthcare context.

Diagnostic Evaluation

The diagnosis of G6PD deficiency integrates clinical suspicion with quantitative measurement of enzyme activity. Molecular analysis is useful in complex or discordant cases, in female carriers and when genetic definition is needed, but is not required in every case to confirm the diagnosis.

Diagnostic suspicion arises in the presence of:

• An acute hemolytic crisis after known or suspected exposure to drugs, fava beans or acute infection, especially in males or children of Mediterranean, African or Asian ancestry.
• Early, severe neonatal jaundice resistant to phototherapy without another identified cause, after exclusion of ABO/Rh incompatibility and autoimmune hemolytic disease.
• Chronic nonspherocytic anemia of unknown origin, particularly when associated with mild jaundice and splenomegaly.

The laboratory evaluation is based on hematologic and biochemical tests:

• Complete blood count: generally normocytic anemia with marked reticulocytosis during an acute crisis.
• Peripheral blood smear: bite cells, blister cells, polychromasia and red cells containing Heinz bodies, which are demonstrated with a supravital stain such as brilliant cresyl blue.
• Hemolysis markers: increased indirect bilirubin, elevated lactate dehydrogenase (LDH), and reduced serum haptoglobin.
• Direct antiglobulin test: usually negative during G6PD-related hemolytic crises; a positive result requires consideration of a concomitant immune cause.
• Hemoglobinuria: present in more severe crises, with dark urine.

The G6PD enzyme activity assay is the decisive diagnostic test. It should preferably be performed away from the acute crisis because reticulocytosis can mask a partial deficiency. If testing is negative during the acute phase, it should be repeated after 2–3 months.

Molecular identification of the genetic variant is useful in complex cases, for genetic counseling and in newborn-screening programs. DNA analysis can distinguish among variants, identify heterozygous carriers, assess family risk and guide prevention strategies.

Differential diagnosis includes all other causes of acute hemolytic anemia, including autoimmune, microangiopathic, hereditary and toxic causes, and in newborns other causes of hyperbilirubinemia such as ABO/Rh incompatibility, other enzymatic defects and congenital liver disease.

A typical diagnostic algorithm for G6PD deficiency includes:

• Clinical suspicion and detailed history, including family history, oxidant exposure and geographic ancestry;
• Hematologic and biochemical tests during the acute phase and convalescence;
• G6PD activity measurement in whole blood, avoiding interpretive errors caused by reticulocytosis;
• Molecular testing and genetic counseling when indicated.

Prompt recognition of G6PD deficiency is essential to prevent severe complications, guide treatment and provide appropriate health education.

Treatment and Prognosis

Management of G6PD deficiency requires an integrated approach that accounts for clinical variability, the need to prevent hemolytic crises, and the characteristics of different molecular phenotypes. No causal therapy currently restores enzyme activity; prevention of crises and prompt treatment of complications are therefore the cornerstones of care.

In asymptomatic individuals or people with low-risk variants, the fundamental strategy is health education: patients and families should know to avoid fava beans, naphthalene and high-risk drugs, consult updated sources for other medications, and inform healthcare professionals and pharmacists of the condition.

Management of an acute hemolytic crisis is based on three pillars:

• Immediate removal of the trigger , including stopping the causative drug or fava-bean exposure and treating an active infection;
• Transfusion support for severe symptomatic anemia, especially in children and vulnerable patients. Packed red-cell transfusion is indicated in the presence of severe symptomatic anemia, signs of tissue hypoxia or hemodynamic instability, considering the overall clinical picture. In adults, transfusion need is assessed case by case;
• Monitoring for complications: particular attention should be paid to acute kidney injury from massive hemoglobinuria, severe hyperbilirubinemia, and fluid, electrolyte and acid-base disturbances. In newborns, intensive phototherapy and, in the most severe cases, exchange transfusion may be required to prevent kernicterus.

The chronic nonspherocytic form, although rare, can be disabling and requires specialist follow-up and individualized supportive care, including transfusion when indicated. Splenectomy does not correct the metabolic defect and is not standard treatment. Steroids and immunosuppressants have no role because the anemia is not immune-mediated.

Genetic counseling is a key component, particularly in high-prevalence areas and families already known to carry severe deficiency variants. Informing at-risk couples and implementing newborn-screening programs can drastically reduce morbidity from neonatal complications.

Prognosis is excellent for most people with G6PD deficiency provided prevention is adequate and crises are recognized and managed promptly. Acute hemolytic crises are often self-limited after trigger removal; spontaneous limitation is more evident in variants in which young red blood cells retain greater G6PD activity, whereas severe variants may cause more prolonged hemolysis. Long-term complications such as kidney injury and neurologic deficits from kernicterus are now preventable with careful surveillance and prompt access to care, although they remain genuine risks where healthcare resources are limited.

In summary, quality of life and survival in G6PD deficiency depend on individual awareness, knowledge among healthcare professionals, effective prevention programs, and timely care during acute episodes.

Complications

The complications of G6PD deficiency are mainly consequences of acute hemolytic crises that are unrecognized or inadequately treated, but may also arise from chronic forms or associated conditions, especially in newborns and people with comorbidities.

Major complications include:

• Acute kidney injury: massive intravascular hemolysis and resulting hemoglobinuria may cause acute tubular necrosis and kidney injury, especially without adequate hydration and correction of hypovolemia.
• Kernicterus: in newborns, rapidly developing unconjugated hyperbilirubinemia can lead to bilirubin encephalopathy and permanent neurologic injury if phototherapy or exchange transfusion is not provided promptly.
• Severe anemia and organ decompensation: in the most severe cases, the abrupt reduction in red-cell mass can cause acute heart failure, tissue hypoxia and increased risk of ischemic events, especially in already vulnerable or older patients.
• Chronic nonspherocytic hemolytic anemia: in class A variants, hemolysis may persist even without acute exposures and requires specialist hematologic management.
• Psychological and social complications: in high-prevalence areas or vulnerable social settings, stigma, social exclusion and difficulty accessing care can adversely affect quality of life for affected individuals and their families.

The incidence and severity of complications are closely related to timeliness of diagnosis, individual and collective awareness, and healthcare-system effectiveness in providing acute care and prevention. In developed countries, severe morbidity and mortality are now uncommon, whereas in resource-limited settings they still represent a major public health emergency.

Preventing complications of G6PD deficiency means not only treating hemolytic crises when they occur but above all anticipating and preventing exposure to triggers and ensuring rapid care for neonatal jaundice or acute anemia.

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