Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

Updated: Apr 07, 2016
  • Author: Paul Schick, MD; Chief Editor: Emmanuel C Besa, MD  more...
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Overview

Background

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 can present as neonatal hyperbilirubinemia. [2] In addition, persons with this disorder can experience episodes of brisk hemolysis after ingesting fava beans or being exposed to certain infections or drugs. [3] Less commonly, they may have chronic hemolysis. However, many individuals with G6PD deficiency are asymptomatic. G6PD deficiency confers partial protection against malaria [4] , which probably accounts for the persistence and high frequency of the responsible genes. [5, 6, 7, 8, 9]

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

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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.

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. [10]

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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. More than 60 mutations in the G6PD gene have been documented. Most are single-base changes that result in an amino acid substitution. [11]

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. [8, 9]

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. [8, 9]

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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 [12, 13, 14, 1] :

  • 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. [8, 9]

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. [12, 13, 17, 18] Chronic hemolysis occurs in severe G6PD deficiency. Fatality rarely occurs.

Racial and sexual disparities

G6PD deficiency affects all races. The highest prevalence is in persons of African, Asian, or Mediterranean descent. [12, 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. [19]

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