G6PD Deficiency

Updated: Mar 13, 2018
  • Author: Lawrence C Wolfe, MD; Chief Editor: George T Griffing, MD  more...
  • Print
Overview

Practice Essentials

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells, affecting 400 million people worldwide. [1] Paul Carlson and colleagues first reported G6PD deficiency in 1956 while working on a patient previously identified as "primaquine sensitive." [2]

G6PD is an enzyme involved in the pentose monophosphate pathway. G6PD deficiency leads to free radical–mediated oxidative damage to red blood cells, which in turn causes hemolysis. [3] It is an X-linked disorder with high prevalence particularly in people of African, Asian, and Mediterranean descent. G6PD deficiency is polymorphic, with more than 400 variants.

Patients with G6PD-deficient alleles have selective advantage against severe malaria; hence, it is highly prevalent in populations where malaria is endemic.

The clinical presentation of glucose-6-phosphate dehydrogenase (G6PD) deficiency includes a spectrum of hemolytic anemia ranging from mild to severe hemolysis in response to oxidative stress. The likelihood of developing hemolysis and its severity depends on the level of the enzyme deficiency, which in turn depends on the G6PD variant. [4, 5]

Workup

Semi-quantitative tests

The fluorescent spot test is a direct test that measures the generation of reduced nicotinamide adenine dinucleotide phosphate (NADPH) from nicotinamide adenine dinucleotide phosphate (NADP+); the test is positive if the blood spot fails to show fluorescence under ultraviolet light. It is rapid, simple, sensitive, and inexpensive. [6, 7, 8]

The methemoglobin reduction test is a rapid indirect test that measures the reduced methemoglobin levels produced after NADPH oxidation. [6]

The cytofluorimetric method is a cytochemical typing assay that provides a fluorometric readout of the classic methemoglobin reduction test at the level of an individual red blood cell. [7]

Quantitative test

Quantitative tests for G6PD activity are considered the criterion standard. The rate of NADPH generation is spectrophotometrically measured at a wavelength of 340 nm. The G6PD activity is finally expressed as G6PD IU/red blood cell and G6PD IU/hemoglobin ratios. [6, 7, 8]

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.

Anemia secondary to mild to moderate hemolysis in G6PD deficient patients is usually self-limited and often resolves in 8-14 days. Transfusion is rarely 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 or hemolytic anemia caused by favism.

Systematic assessment for the risk of severe hyperbilirubinemia should be performed before discharge in neonates in whom G6PD deficiency is suspected to provide early and focused follow-up to prevent bilirubin encephalopathy. [9, 10, 11]

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.

Next:

Pathophysiology

The G6PD enzyme catalyzes the oxidation of glucose-6-phosphate and the reduction of nicotinamide adenine dinucleotide phosphate (NADP+) to nicotinamide adenine dinucleotide phosphate (NADPH) in the pentose monophosphate shunt. NADPH is important in maintaining glutathione in its reduced form, which protects the red blood cell against oxidative stress.

Red blood cells carry oxygen and hence are more susceptible to oxidative stress than other cells. The pentose monophosphate shunt is the only means of NADPH generation in red blood cells and therefore crucial in protecting red cells against oxidative damage.

 In a G6PD deficient patient, oxidative stresses can denature hemoglobin and cause intravascular hemolysis.  

Drugs, chemical agents, infections, ingestion of fava beans, or ketoacidosis can trigger oxidative stress leading to hemolysis.

Jaundice in G6PD-deficient neonates is considered to be due to an imbalance between the production and conjugation of bilirubin, with a tendency towards inefficient bilirubin conjugation. Premature infants are at special risk of the bilirubin production-conjugation imbalance.

Previous
Next:

Epidemiology

G6PD deficiency is prevalent worldwide. In the United States, African Americans are primarily affected, with a prevalence of about 10%; however it is also seen among Italians (especially Sardinian ancestry), Greeks, Turks, South East Asians, people of Asian ancestry, and Sephardic Jews. [11]

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:

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

The heterogeneity of polymorphic G6PD variants is proof of their independent origin, and it supports the notion that they have been selected by a common environmental agent, in keeping with the concept of convergent evolution.

G6PD deficiency affects all races, although the severity of G6PD deficiency varies significantly among racial groups. The highest prevalence is among the people of African, Asian, or Mediterranean descent. 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.

Previous
Next:

Prognosis

Many people with G6PD deficiency are asymptomatic. However, case reports of acute massive hemolysis with jaundice have been reported especially in the neonatal period, leading to kernicterus and fatality. [12, 13, 14, 15, 16]

Kernicterus or bilirubin encephalopathy is a rare complication of neonatal jaundice complicated by G6PD deficiency. Kernicterus, although infrequent, has about 10% mortality and 70% long-term morbidity usually evident in infants with a bilirubin level higher than 20 mg/dL. [9]

Massive hemolysis complicating G6PD deficiency has also been reported in patients with hepatitis infections, specifically hepatitis A and E in the Indian subcontinent. [17]

A literature review by Lai et al suggested that G6PD deficiency is a risk factor for diabetes, with the risk being greater in men than in women (odds ratio of 2.22 vs 1.87, respectively). [18]

A study by Rostami-Far et al indicated that G6PD deficiency increases the likelihood of neonatal sepsis. The study involved 76 neonates with sepsis and 1214 without sepsis, with the prevalence of G6PD deficiency being significantly greater in the sepsis group than in the controls. [19]

Previous
Next:

Patient Education

The X linked pattern of inheritance of G6PD deficiency and its clinical severity should be discussed with parents and counseling with regard to their risk for having other children should be provided, especially in populations in which G6PD deficiency is highly prevalent. [10]

If a mother is a heterozygote, the chances of recurrence is 50% with every subsequent male pregnancy. [20]

Parental-child G6PD deficiency self-care discussions are associated with better child health, and parental involvement in these discussions is facilitated by the thoroughness and clarity of patient education received from provider. [10]

Additional resources are available at G6PD Deficiency Association - Favism.

Previous