Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency 

Updated: Feb 19, 2019
Author: Srikanth Nagalla, MBBS, MS, FACP; Chief Editor: Emmanuel C Besa, MD 


Practice Essentials

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzyme deficiency in humans, affecting 400 million people worldwide.[1] It has a high prevalence in persons of African, Asian, and Mediterranean descent. It is inherited as an X-linked recessive disorder. G6PD deficiency is polymorphic, with more than 300 variants. G6PD deficiency confers partial protection against malaria[2] , which probably accounts for the persistence and high frequency of the responsible genes.[3, 4, 5, 6, 7]

G6PD deficiency can present as neonatal hyperbilirubinemia.[8, 9] In addition, persons with this disorder can experience episodes of brisk hemolysis after ingesting fava beans or being exposed to certain infections or drugs.[10] Less commonly, they may have chronic hemolysis. However, many individuals with G6PD deficiency are asymptomatic.

Most individuals with G6PD deficiency do not need treatment. However, they should be taught to avoid drugs and chemicals that can cause oxidant stress. Infants with prolonged neonatal jaundice as a result of G6PD deficiency should receive phototherapy with a bili light. See Treatment.

For patient education information, see the Children's Health Center, as well as Newborn Jaundice.


The G6PD enzyme is part of the pentose monophosphate shunt. It catalyzes the oxidation of glucose-6-phosphate and the reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to nicotinamide adenine dinucleotide phosphate (NADPH). NADPH maintains glutathione in its reduced form, which acts as a scavenger for dangerous oxidative metabolites.

The pentose monophosphate shunt is the only source for NADPH in red blood cells. Therefore, red blood cells depend on G6PD activity to generate NADPH for protection. Thus, red blood cells are more susceptible to oxidative stresses than other cells. In persons with G6PD deficiency, oxidative stresses can denature hemoglobin and cause intravascular hemolysis. Denatured hemoglobin can be visualized as Heinz bodies in peripheral blood smears processed with supravital staining. Heinz bodies are shown in the figure below.

Heinz bodies in a peripheral smear stained with a Heinz bodies in a peripheral smear stained with a supravital stain. Heinz bodies are denatured hemoglobin. Denatured hemoglobin occurs in G6PD deficiencies and in unstable hemoglobin disorders.

The degree of G6PD deficiency determines the clinical expression of the disorder. Individuals with minimally reduced enzyme levels do not experience hemolysis. Others with a greater degree of deficiency have episodes of brisk hemolysis triggered by infections, taking drugs that increase oxidative stress, ingesting fava beans, or ketoacidosis. Hemolysis due to oxidant stresses are usually self-limiting within 8 to 14 days due to the compensatory production of young red blood cells with high levels of G6PD. Patients with severe G6PD deficiency have chronic hemolysis and are often thought to have non-spherocytic hemolytic anemia.

Jaundice in G6PD-deficient neonates is considered to be due to an imbalance between the production and conjugation of bilirubin, with a tendency for inefficient bilirubin conjugation. Borderline premature infants are at special risk of the bilirubin production-conjugation imbalance.[11]


The gene that codes for G6PD is located in the distal long arm of the X chromosome at the Xq28 locus. The G6PD gene is 18 kilobases (kb) long with 13 exons, and the G6PD enzyme has 515 amino acids. More than 60 mutations in the G6PD gene have been documented. Most are single-base changes that result in an amino acid substitution.[12]

G6PD deficiency is an X-linked recessive disorder, with an inheritance pattern similar to that of hemophilia and color blindness: males usually manifest the abnormality and females are carriers. Females may be symptomatic if they are homozygous or if inactivation of their normal X chromosome occurs. The allele for G6PD has been used to establish clonality.[6, 7]

Specific G6PD alleles are associated with G6PD variants with different enzyme levels and, thus, different degrees of clinical disease severity. The variation in G6PD levels accounts for differences in sensitivity to oxidants. Chronic hemolysis occurs with extremely low enzyme levels.

The G6PD A+ variant is associated with high enzyme levels and, hence, no hemolysis. G6PD A- is associated with lower enzyme levels and acute intermittent hemolysis. G6PD A- occurs in high frequency in African, Mediterranean, and Asian variants. Mediterranean G6PD A- (also called G6PD Mediterranean) is characterized by enzyme deficiencies that are more severe than in the other G6PD A- alleles. Fava bean hemolysis usually occurs in Mediterranean G6PD deficiency disorders. G6PD B is the wild type of allele (normal variant).

The World Health Organization has classified the different G6PD variants according to the degree of enzyme deficiency and severity of hemolysis, into classes I-V. Class I deficiencies are the most severe. G6PD Mediterranean deficiency usually is a class II deficiency and G6PD A- deficiency is a class III deficiency. Classes IV and V are of no clinical significance.[6, 7]


Glucose-6-phosphatase dehydrogenase (G6PD) deficiency occurs worldwide. In the United States, black males are primarily affected, with a prevalence of about 10%. Internationally, the geographic prevalence of the disorder correlates with the distribution of malaria. The highest prevalence rates (with gene frequencies from 5-25%) are found in the following regions[13, 14, 1] :

  • Tropical Africa

  • The Middle East

  • Tropical and subtropical Asia

  • Some areas of the Mediterranean

  • Papua New Guinea


Most persons with G6PD deficiency are asymptomatic. Symptomatic patients can present with neonatal jaundice and acute hemolytic anemia.[6, 7]

Kernicterus is a rare complication of neonatal jaundice,[15] but can occur in certain populations and can be fatal. Other mechanisms may contribute to hyperbilirubinemia in G6PD deficiency, such as an underlying defect in uridine diphosphoglucoronate-glucuronosyltransferase, the enzyme affected in Gilbert syndrome.

Acute episodic hemolytic anemia can occur due to oxidant stress induced by exposure to certain drugs or chemicals (including some anesthetic agents[16] ), infections, ketoacidosis, or the ingestion of fava beans.[13, 17, 18, 19] Chronic hemolysis occurs in severe G6PD deficiency. Fatality rarely occurs.

G6PD deficiency appears to be a risk factor for the development of diabetes mellitus. A systematic review and meta-analysis by Lai and colleagues of publications involving involving 949,260 persons with G6PD deficiency found an odds ratio (OR) of 2.37 (95% confidence interval 1.50-3.73) for diabetes. The risk was higher in men than in women (OR 2.22 versus 1.87, respectively).[20]

Racial and sexual disparities

G6PD deficiency affects all races. The highest prevalence is in persons of African, Asian, or Mediterranean descent.[13, 17] The severity of G6PD deficiency varies significantly among racial groups. Variants producing severe deficiency primarily occur in the Mediterranean population. African populations have milder hemolysis due to higher enzyme levels.

G6PD deficiency is an X-linked inherited disease that primarily affects men. Women may be affected if they are homozygous, which occurs in populations in which the frequency of G6PD deficiency is quite high. Heterozygous women (carriers) can experience clinical disease as a result of X chromosome inactivation, gene mosaicism, or hemizygosity.[21]




Most patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency are asymptomatic. Neonatal jaundice may occur. Jaundice usually appears within 24 hours after birth, at the same time as or slightly earlier than physiologic jaundice but later than in blood group alloimmunization.[1, 22] Exchange transfusions are often required.

Most patients are usually not anemic, but episodes of intravascular hemolysis and consequent anemia can be triggered by infections, medicines that induce oxidative stresses, fava beans, and ketoacidosis.[23] Hemolysis begins 24 to 72 hours after exposure to oxidant stress. When hemolysis is severe, patients present with weakness, tachycardia, jaundice, and hematuria. Some patients have a history of chronic hemolytic anemia.

Acute hemolysis is self-limiting, resolving after 8 to 14 days. Hemolytic episodes destroy aging red blood cells (RBCs) that have the lowest levels of G6PD, New RBCs produced to compensate for anemia contain high levels of G6PD. Young RBCs are not vulnerable to oxidative damage and hence limit the duration of hemolysis.

Physical Examination

Physical examination findings may be normal in patients with G6PD deficiency. Jaundice and splenomegaly may be present in patients with severe hemolysis.[6] . Patients may have right upper quadrant tenderness due to hyperbilirubinemia and cholelithiasis. Skin ulcers are an infrequent complication that may occur in patients with severe G6PD deficiency.





Approach Considerations

Indications for testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency include the following[21] :

  • Development of hemolysis after taking medications or experiencing conditions that can induce oxidant stress
  • Unexplained or prolonged neonatal hyperbilirubinemia
  • Non-spherocytic hemolytic anemia (since the underlying cause might be severe G6PD deficiency and chronic hemolysis)

Tests to diagnose hemolysis include the following:

  • Complete blood cell count (CBC) and reticulocyte count
  • Lactate dehydrogenase (LDH) level
  • Indirect and direct bilirubin level
  • Serum haptoglobin level
  • Urinalysis for hematuria
  • Urinary hemosiderin
  • Peripheral blood smear

Increased reticulocyte counts indicate increased bone marrow response to anemia. Increased indirect bilirubin and LDH levels indicate increased RBC destruction.

Decreased haptoglobin levels, hematuria, and presence of urinary hemosiderin indicate severe intravascular hemolysis. On the peripheral smear, routine staining may reveal polychromasia, representing increased RBC production. So-called bite cells caused by the splenic removal of denatured hemoglobin may be seen.

Heinz bodies (denatured hemoglobin) can be seen on the peripheral smear in G6PD deficiency. See the image below. Heinz bodies are not revealed by routine staining but are visualized by using a supravital stain (Heinz body prep). Heinz bodies are also seen in patients with unstable forms of hemoglobin, such as hemoglobin Köln. Heat stability and/or heat denaturation and high-performance liquid chromatography can be used to identify unstable hemoglobin and thereby rule out G6PD deficiency.

Heinz bodies in a peripheral smear stained with a Heinz bodies in a peripheral smear stained with a supravital stain. Heinz bodies are denatured hemoglobin. Denatured hemoglobin occurs in G6PD deficiencies and in unstable hemoglobin disorders.

Abdominal ultrasound may be useful in assessing for splenomegaly and gallstones. These complications are typically limited to patients with severe chronic hemolysis.

Tests to diagnose G6PD deficiency

Screening for G6PD deficiency is indicated in patients with a suggestive family history or in geographical areas with a high prevalence of the disorder. Screening tests are described by Minucci et al.[21]  Positive screening results should be confirmed by quantitative tests. The molecular analysis may be useful for population screening, family studies, females, and prenatal diagnosis.[14]  Diagnosis of G6PD may be difficult in females, who may be hemizygous or have skewed X chromosome inactivation or G6PD gene mosaicism.[21]

A number of rapid point-of-care diagnostic tests for determining G6PD deficiency status have been developed.[24, 25, 26]  These have a potential role in malaria-endemic areas for permitting safe use of primaquine, which can provoke hemolysis in persons with G6PD deficiency.[27, 28]

Testing should include the Beutler test and a quantitative assay of GPD activity.[13, 14, 21, 29] The Beutler test is a semi-quantitative rapid fluorescent spot test that detects the generation of nicotinamide adenine dinucleotide phosphate (NADPH) from nicotinamide adenine dinucleotide phosphate (NADP); the test is positive if the blood spot fails to fluoresce under ultraviolet light. The Beutler test is not reliable in females.[4]

A spectrophotometric analysis of G6PD activity in a leukocyte-depleted sample is the standard quantitative test. Testing for enzyme activity should be performed when patients are in remission, as results may be falsely negative during acute hemolysis. The reason is that older erythrocytes have been destroyed, because their diminished G6PD levels leaves them vulnerable to hemolysis while there is a compensatory increase of immature erythrocytes and reticulocytes that have increased G6PD levels.

However, spectrophotometric analysis may fail to detect G6PD deficiency in hemizygous patients. Also, spectrophotometric quantitation may fail to detect deficiency in heterozygous females due to residual activity in G6PD-sufficient cells. The identification of G6PD-deficient as well as G6PD-sufficient cells by a cytochemical method or cytofluorometry is more sensitive in the testing for G6PD deficiency in females. Chromate inhibition is a test that is more sensitive than spectrophotometric quantitation for heterozygous G6PD deficiency in females.[30, 31]

 G6PD activity is higher in premature infants than in term infants. This should be considered when testing for G6PD deficiency in infants.[32]




Approach Considerations

Most individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency do not need treatment. However, they should be taught to avoid drugs and chemicals that can cause oxidant stress. Patients should also avoid broad beans (ie, fava beans). Favism occurs primarily in the Mediterranean variety of G6PD deficiency.

Identification and discontinuation of the precipitating agent is critical to manage hemolysis in patients with G6PD deficiency. Anemia should be treated with appropriate measures, recognizing that hemolysis is self-limited and often resolves in 8 to 14 days. Transfusions are rarely indicated. Splenectomy is usually ineffective.

Infants with prolonged neonatal jaundice as a result of G6PD deficiency should receive phototherapy with a bili light (see Neonatal Jaundice). Exchange transfusion may be necessary in cases of severe neonatal jaundice or hemolytic anemia caused by favism. However, Samanta and colleagues found that in neonates with idiopathic hyperbilirubinemia, transfusion with G6PD-deficient blood was significantly less effective than transfusion with G6PD-normal blood.[33]

Patients with chronic hemolysis or non-spherocytic anemia should be placed on daily folic acid supplements. Consultations with a hematologist and a geneticist should be sought.


Patients with G6PD deficiency should avoid the following:

  • Oxidant drugs, such as the antimalarial drugs primaquine, chloroquine, pamaquine, and pentaquine

  • Nalidixic acid, ciprofloxacin, niridazole, norfloxacin, methylene blue, chloramphenicol, phenazopyridine, and vitamin K analogues

  • Sulfonamides, such as sulfanilamide, sulfamethoxypyridazine, sulfacetamide, sulfadimidine, sulfapyridine, sulfamerazine, and sulfamethoxazole

  •  Nonsteroidal anti-inflammatory drugs (NSAIDs), nitrofurantoin, and phenazopyridine

  • Isobutyl nitrite, naphthalene (moth balls), phenylhydrazine, and acetanilide



Medication Summary

Pharmacologic therapy is not used in glucose-6-phosphate dehydrogenase (G6PD) deficiency. Treatment of hyperbilirubinemia in G6PD-deficient neonates, when indicated, is with phototherapy and exchange transfusions.[34] Prophylactic oral phenobarbital does not decrease the need for phototherapy or exchange transfusions in G6PD-deficient neonates.[35] The heme analogue tin-mesoporphyrin (SnMP) has been successful in inhibiting bilirubin production in newborns, but remains an experimental agent.[22, 36]


Questions & Answers


What is glucose-6-phosphate dehydrogenase (G6PD) deficiency?

What are the treatment options for glucose-6-phosphate dehydrogenase (G6PD) deficiency?

What is the pathophysiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

How does the degree of glucose-6-phosphate dehydrogenase (G6PD) deficiency affect its clinical presentation?

What is the genetic etiology of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Which patient groups are at highest risk for glucose-6-phosphate dehydrogenase (G6PD) deficiency?

What are the complications of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

What are the racial predilections for glucose-6-phosphate dehydrogenase (G6PD) deficiency?


What are the signs and symptoms of glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Which physical findings are characteristic of glucose-6-phosphate dehydrogenase (G6PD) deficiency?


What are the differential diagnoses for Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency?


What are indications for glucose-6-phosphate dehydrogenase (G6PD) deficiency screening?

Which tests are performed to diagnose glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Which test findings indicate glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Who should be screened for glucose-6-phosphate dehydrogenase (G6PD) deficiency?

What tests should be performed in the diagnosis of glucose-6-phosphate dehydrogenase (G6PD) deficiency?


What are the treatment options for glucose-6-phosphate dehydrogenase (G6PD) deficiency?

How is prolonged neonatal jaundice treated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency?

How is chronic hemolysis or non-spherocytic anemia treated in patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency?

Which medications and chemical agents should patients with glucose-6-phosphate dehydrogenase (G6PD) deficiency avoid?


What is the role of drug treatment for glucose-6-phosphate dehydrogenase (G6PD) deficiency?