Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency 

Updated: Jul 19, 2021
Author: Srikanth Nagalla, MD, MS, FACP; Chief Editor: Emmanuel C Besa, MD 

Overview

Practice Essentials

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is a hereditary condition resulting from a structural defect in G6PD, a "housekeeping" enzyme that is particularly important for the survival of red blood cells and their ability to respond to oxidative stress.[1] G6PD deficiency is the most common enzyme deficiency in humans, affecting about 400 million people worldwide, with a high prevalence in persons of African, Asian, and Mediterranean descent.[2] It is inherited as an X-linked recessive disorder, and thus most often affects males. G6PD deficiency is polymorphic, with more than 300 variants.

G6PD deficiency confers partial protection against malaria, and geographic prevalence of the disorder correlates with the historical distribution of malaria. This probably accounts for the persistence and high frequency of the responsible genes.[3, 4, 5, 6, 7]

Signs and symptoms of G6PD deficiency

Most patients with G6PD deficiency are asymptomatic. Clinical manifestations may include the following:

  • Neonatal jaundice
  • Episodes of intravascular hemolysis and consequent anemia, triggered by infections, medicines that induce oxidative stresses, fava beans, and ketoacidosis. Hemolysis begins 24 to 72 hours after exposure to oxidant stress. Patients with severe hemolysis present with weakness, tachycardia, jaundice, and hematuria.
  • Chronic hemolytic anemia

See Presentation

Workup in G6PD deficiency

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 (with Heinz body prep)

Tests for G6PD deficiency include the following:

  • Semi-quantitative tests -The fluorescent spot test (not reliable in females)
  • Quantitative tests (spectrophotometric) - the criterion standard.
  • Point-of-care tests – Newer versions are quantitative; potential for use in both males and females, in basic clinical laboratories in both high- and low-resource settings

See Workup

Management

Most individuals with G6PD deficiency do not require any treatment. Acute hemolytic anemia in G6PD-deficient patients is largely preventable by avoiding exposure to fava beans, drugs, and chemicals that can cause oxidant stress. Identification and discontinuation of the precipitating agent is critical in the management of hemolysis in patients with G6PD deficiency.

Acute hemolysis is usually self-limiting, often resolving after 8 to 14 days. Rarely, transfusion is needed in cases of severe anemia.

Infants with prolonged neonatal jaundice as a result of G6PD deficiency should receive phototherapy. Exchange transfusion may be necessary in cases of severe neonatal jaundice.

Persons with chronic hemolysis or nonspherocytic anemia should be placed on daily folic acid supplements. Consultations with a hematologist are ideal for long-term follow up

See Treatment.

Pathophysiology

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.

G6PD deficiency: Heinz bodies in a peripheral smea G6PD deficiency: Heinz bodies in a peripheral smear stained with a supravital stain. Heinz bodies are denatured hemoglobin, which 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.[8]

Etiology

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. Currently, 186 mutations in the G6PD gene have been documented. Most are single-base changes that result in an amino acid substitution.[7]

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]

Epidemiology

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[9, 10, 2] :

  • Tropical Africa
  • The Middle East
  • Tropical and subtropical Asia
  • Some areas of the Mediterranean
  • Papua New Guinea

Mortality/morbidity

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,[11] 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 (see Unconjugated Hyperbilirubinemia).

Acute episodic hemolytic anemia can occur due to oxidant stress induced by exposure to certain drugs or chemicals (including some anesthetic agents[12] ), infections, ketoacidosis, or the ingestion of fava beans.[9, 13, 14, 15] 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).[16] Certain G6PD gene variants in Africans and East Asians (G6PD-Asahi, G6PD-Canton, G6PD-Kaiping) have been shown to lower glycosylated hemoglobin (HbA1c) levels independent of glycemia, so patients who are carriers of those variants may be at risk for underdiagnosis of diabetes or pre-diabetes if screened by HbA1c without confirmation by direct glucose measurements.[17]

However, G6PD deficiency may have a protective effect on ischemic heart disease, cerebrovascular disease, and colorectal cancer.[18, 19]

Racial and sexual disparities

G6PD deficiency affects all races, but the highest prevalence is in persons of African, Asian, or Mediterranean descent.[9, 13] 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.[20]

 

Presentation

History

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.[2, 21] 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.[22] 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.

 

DDx

 

Workup

Approach Considerations

Indications for testing for glucose-6-phosphate dehydrogenase (G6PD) deficiency include the following[20] :

  • 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.

G6PD deficiency: Heinz bodies in a peripheral smea G6PD deficiency: Heinz bodies in a peripheral smear stained with a supravital stain. Heinz bodies are denatured hemoglobin, which 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.[20]  Positive screening results should be confirmed by quantitative tests. The molecular analysis may be useful for population screening, family studies, females, and prenatal diagnosis.[10]  Diagnosis of G6PD may be difficult in females, who may be hemizygous or have skewed X chromosome inactivation or G6PD gene mosaicism.[20]

Standard tests include the Beutler test and a quantitative assay of GPD activity.[9, 10, 20, 23] 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.[24, 25]

A number of rapid point-of-care diagnostic tests for determining G6PD deficiency status have been developed.[26, 27, 28]  These have a potential role in malaria-endemic areas for permitting safe use of primaquine, which can provoke hemolysis in persons with G6PD deficiency.[29, 30] Newer versions of these tests are quantitative and can be used in males, females, and neonates.

 G6PD activity is higher in premature infants than in term infants. This should be considered when testing for G6PD deficiency in infants.[31]

 

 

Treatment

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.[32]

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.

Deterrence/Prevention

Persons with G6PD deficiency need to avoid foods, drugs, and chemicals that can precipitate hemolysis. The risk posed by those substances is determined in part by the person's G6PD variant (see Etiology) and thus the degree of enzyme deficiency.

Fava beans are the food best known for precipitating hemolysis; indeed, favism—the term for symptomatic attacks of hemolytic anemia from eating fava beans—has been recognized since antiquity.[10] Other foods that some persons with G6PD deficiency may prefer to avoid include the following[33] :

  • Red wine
  • All legumes
  • Blueberries
  • Soya products
  • Tonic water

For most persons with G6PD deficiency, the following drugs pose a definite risk:[1]

  • Dapsone and other sulfones (higher doses for dermatitis herpetiformis more likely to cause problems)
  • Methylthioninium chloride
  • Niridazole
  • Nitrofurantoin
  • Pamaquin
  • Primaquine (30 mg weekly for 8 weeks has been found to be without undue harmful effects in African and Asian people)
  • Quinolones (ciprofloxacin, moxifloxacin, nalidixic acid, norfloxacin, ofloxacin)
  • Rasburicase
  • Sulfonamides (including co-trimoxazole; however, some sulfonamides, such as sulfadiazine, have been found not to be hemolytic in many G6PD-deficient individuals)

Drugs that pose a possible risk in some persons with G6PD deficiency include the following:

  • Aspirin (acceptable up to a dose of at least 1g daily in most G6PD-deficient individuals)
  • Chloroquine (acceptable in acute malaria and malaria chemoprophylaxis)
  • Menadione (vitamin K3) and water-soluble derivatives (eg, menadol sodium phosphate)
  • Quinidine (acceptable in acute malaria)
  • Quinine (acceptable in acute malaria)
  • Sulfonylureas
  • Naphthalene in (mothballs)

Intravenous vitamin C is currently undergoing testing as adjunctive treatment for sepsis. Case reports describe episodes of hemolysis in patients with G6PD deficiency who received high doses of intravenous (IV) vitamin C (> 60 g). However, Marik cites dramatic reductions of methemoglobinemia and hemolysis that have been reported in patients treated with IV vitamin C in low to moderate doses (1-10 g every 6 hours), and proposes that those data suggest that vitamin C at a dosage of 6 g/day should not be considered contraindicated in patients with known or suspected G6PD deficiency—that indeed, IV vitamin C may be the treatment of choice in G6PD-deficient patients with drug-induced hemolysis.  Sepsis can cause methemoglobinemia, and methylene blue—the first-line treatment for acquired methemoglobinemia—is contraindicated in patients with G6PD deficiency.[34]

 

 

Medication

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.[35] Prophylactic oral phenobarbital does not decrease the need for phototherapy or exchange transfusions in G6PD-deficient neonates.[36] The heme analogue tin-mesoporphyrin (SnMP) has been successful in inhibiting bilirubin production in newborns, but remains an experimental agent.[21, 37]

 

Questions & Answers

Overview

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 is the mortality and morbidity associated with glucose-6-phosphate dehydrogenase (G6PD) deficiency?

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

Presentation

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?

DDX

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

Workup

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?

Treatment

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?

Medications

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