AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is the most common disease-producing enzymopathy in humans. Inherited as an X-linked disorder, glucose-6-phosphatase dehydrogenase (G6PD) deficiency affects 400 million people worldwide. The disease is highly polymorphic, with more than 300 reported variants. It confers protection against malaria, which probably accounts for its high gene frequency.

For excellent patient education resources, visit eMedicine's Children's Health Center. Also, see eMedicine's patient education article Newborn Jaundice.

Related eMedicine topics:
Glucose-6-Phosphatase Deficiency [in the Endocrinology section]
Hemolytic Disease of Newborn
Kernicterus
Methemoglobinemia

Related Medscape topics:
Resource Center Genomic Medicine
Specialty Site Diabetes & Endocrinology
Specialty Site Hematology-Oncology
Specialty Site Pediatrics
CME/CE New Recommendations Issued for Treatment of Malaria in the United States
Dried Blood Spots as a Source of Anti-malarial Antibodies for Epidemiological Studies
FDA Releases List of Genomic Biomarkers Predictive of Drug Interactions
Hemolysis and Failed Hematopoiesis (Slides With Transcript)
Malaria in Refugees From Tanzania -- King County, Washington, 2007

Pathophysiology

The G6PD enzyme catalyzes the oxidation of glucose-6-phosphate to 6-phosphogluconate while concomitantly reducing the oxidized form of nicotinamide adenine dinucleotide phosphate (NADP⁺) to nicotinamide adenine dinucleotide phosphate (NADPH). NADPH, a required cofactor in many biosynthetic reactions, maintains glutathione in its reduced form.

Reduced glutathione acts as a scavenger for dangerous oxidative metabolites in the cell. With the help of the enzyme glutathione peroxidase, reduced glutathione also converts harmful hydrogen peroxide to water. Red blood cells rely heavily upon glucose-6-phosphatase dehydrogenase (G6PD) activity because it is the only source of NADPH that protects the cells against oxidative stresses; therefore, people deficient in glucose-6-phosphatase dehydrogenase (G6PD) are not prescribed oxidative drugs, because their red blood cells undergo rapid hemolysis under this stress.

The 5 classes of glucose-6-phosphatase dehydrogenase (G6PD) deficiency include low, normal, or increased levels of the enzyme.

Frequency

International

The highest prevalence rates (with gene frequencies from 5-25%) of glucose-6-phosphatase dehydrogenase (G6PD) deficiency are found in tropical Africa, the Middle East, tropical and subtropical Asia, some areas of the Mediterranean, and Papua New Guinea.^{1, 2}

Mortality/Morbidity

The most common clinical feature of glucose-6-phosphatase dehydrogenase (G6PD) deficiency is a lack of symptoms. Symptomatic patients present with neonatal jaundice and acute hemolytic anemia.

• Neonatal jaundice: Jaundice usually appears by age 1-4 days, at the same time as or slightly earlier than so-called physiologic jaundice and later than in in-blood group alloimmunization.^{3, 4} Kernicterus is a rare complication.⁵
• Acute hemolytic anemia: Clinical expression results from stress factors such as oxidative drugs or chemicals, infection, or ingestion of fava beans.^{1, 2}

Related Medscape topics:
Resource Center Neonatal Medicine
Specialty Site Gastroenterology

Race

Glucose-6-phosphatase dehydrogenase (G6PD) deficiency affects all races. The highest prevalence is among persons of African, Asian, or Mediterranean descent.^{1, 2} The severity of glucose-6-phosphatase dehydrogenase (G6PD) deficiency varies significantly among racial groups because of different variants of the enzyme. Severe deficiency variants primarily occur in the Mediterranean population. The enzymatic variants in the African population have more activity and produce a milder form of the disease.

Sex

• Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is an X-linked inherited disease that primarily affects men.
• Homozygous women are found in populations in which the frequency of glucose-6-phosphatase dehydrogenase (G6PD) deficiency is quite high.
• Heterozygous (carrier) women can develop hemolytic attacks.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Most patients with glucose-6-phosphatase dehydrogenase (G6PD) deficiency are asymptomatic. Some patients present with or report a history of neonatal jaundice, often requiring exchange transfusion. A history of infection or drug-induced hemolysis is also common. Gallstones may be a prominent feature. Splenomegaly may be present.

Related Medscape topics:
Resource Center Adverse Drug Events Reporting
Resource Center Sepsis

Physical

Jaundice and splenomegaly may be present during a glucose-6-phosphatase dehydrogenase (G6PD) deficiency crisis.

Causes

Glucose-6-phosphatase dehydrogenase (G6PD) deficiency is a genetic condition. The molecular basis for this disease results from mutations in the G6PD locus at Xq28. The gene is 18 kilobases (kb) long with 13 exons, leading to an enzyme of 515 amino acids. More than 60 mutations in the G6PD gene have been documented; most of the mutations are single-base changes that result in an amino acid substitution.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

The laboratory workup for glucose-6-phosphatase dehydrogenase (G6PD) deficiency includes the following^{1, 2, 6}:

• Measure the actual enzyme activity of G6PD rather than the amount of glucose-6-phosphatase dehydrogenase (G6PD) protein. Performing assays for the protein rather than enzyme activity of G6PD during hemolysis and reticulocytosis may affect levels and not reflect baseline values.
• Obtain a complete blood cell (CBC) count with the reticulocyte count to determine the level of anemia and bone marrow function.
• Indirect bilirubinemia occurs with excessive hemoglobin degradation and can produce clinical jaundice.
• Serum haptoglobin levels serve as an index of hemolysis and will be decreased.

Imaging Studies

• Abdominal ultrasound may be useful in assessing for splenomegaly and gallstones in cases of glucose-6-phosphatase dehydrogenase (G6PD) deficiency.

Related Medscape topic:
Specialty Site Radiology

Histologic Findings

Acute hemolysis from glucose-6-phosphatase dehydrogenase (G6PD) deficiency is associated with the formation of Heinz bodies, which consist of denatured hemoglobin (see Image 1).

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

Identification and discontinuation of the precipitating agent is critical in cases of glucose-6-phosphatase dehydrogenase (G6PD) deficiency. Affected individuals are treated with oxygen and bed rest, which may afford symptomatic relief.

Consultations

Consultations with the following specialists should be sought in cases of glucose-6-phosphatase dehydrogenase (G6PD) deficiency:

• Hematologists
• Geneticists

Diet

Patients must avoid broad beans (ie, fava beans). Favism occurs only in the Mediterranean variety of glucose-6-phosphatase dehydrogenase (G6PD) deficiency.

Activity

Curtailment of physical activity may be necessary if severe anemia results from hemolysis.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

The data show that jaundice in glucose-6-phosphatase dehydrogenase (G6PD)–deficient neonates is the result of an imbalance between the production and conjugation of bilirubin, with a tendency for inefficient bilirubin conjugation over increased hemolysis in its pathogenesis. Borderline premature infants are at special risk of the bilirubin production-conjugation imbalance.⁷ Prophylactic oral phenobarbital does not decrease the need for phototherapy or exchange transfusions in glucose-6-phosphatase dehydrogenase (G6PD)–deficient neonates.⁸

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Infants with prolonged neonatal jaundice as a result of glucose-6-phosphatase dehydrogenase (G6PD) deficiency are placed under special lights (ie, bili lights) that alleviate jaundice.
• Exchange transfusion may be necessary in cases of severe neonatal jaundice or hemolytic anemia caused by favism.

In/Out Patient Meds

• The heme analogue Sn-mesoporphyrin (SnMP) has been successful in inhibiting bilirubin production in newborns.

Deterrence/Prevention

Patients with glucose-6-phosphatase dehydrogenase (G6PD) deficiency should heed the following precautions:

• Avoid oxidant drugs such as the antimalarial drugs primaquine, chloroquine, pamaquine, and pentaquine.
• Avoid nitrofurantoin.
• Avoid nalidixic acid, ciprofloxacin niridazole, norfloxacin, methylene blue, chloramphenicol, phenazopyridine, and vitamin K analogues.
• Avoid sulfonamides such as sulfanilamide, sulfamethoxypyridazine, sulfacetamide, sulfadimidine, sulfapyridine, sulfamerazine, and sulfamethoxazole.
• Avoid exposure to certain chemicals such as those in mothballs.

The following substances should also be avoided in individuals with glucose-6-phosphatase dehydrogenase (G6PD) deficiency:

• Acetanilid
• Doxorubicin
• Isobutyl nitrite
• Naphthalene
• Phenylhydrazine
• Pyridium

Complications

• In those with glucose-6-phosphatase dehydrogenase (G6PD) deficiency, severe neonatal jaundice can result in kernicterus.

Prognosis

• Most individuals with glucose-6-phosphatase dehydrogenase (G6PD) deficiency do not need treatment.

Patient Education

• Teach patients with glucose-6-phosphatase dehydrogenase (G6PD) deficiency to avoid drugs and chemical exposures that can cause hemolytic anemia.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Avoid prescribing medications that can cause hemolytic anemia.

Related Medscape topics:
Resource Center Medical Malpractice and Legal Issues
Specialty Site Hematology-Oncology

Special Concerns

• Neonatal jaundice that is associated with glucose-6-phosphatase dehydrogenase (G6PD) deficiency can have life-threatening consequences.
• Certain variants of glucose-6-phosphatase dehydrogenase (G6PD) deficiency can be life threatening following exposure to oxidant drugs.

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Heinz bodies.
	View Full Size Image
Media type:  Histology

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

1. Beutler E. Glucose-6-phosphate dehydrogenase deficiency. N Engl J Med. Jan 17 1991;324(3):169-74. [Medline].
2. Beutler E. G6PD deficiency. Blood. Dec 1 1994;84(11):3613-36. [Medline]. [Full Text].
3. Valaes T, Drummond GS, Kappas A. Control of hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient newborns using an inhibitor of bilirubin production, Sn-mesoporphyrin. Pediatrics. May 1998;101(5):E1. [Medline]. [Full Text].
4. Kaplan M, Hammerman C, Vreman HJ, Stevenson DK, Beutler E. Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase-deficient heterozygotes. J Pediatr. Jul 2001;139(1):137-40. [Medline].
5. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. Semin Perinatol. Oct 2004;28(5):356-64. [Medline].
6. Minucci A, Giardina B, Zuppi C, Capoluongo E. Glucose-6-phosphate dehydrogenase laboratory assay: How, when, and why?. IUBMB Life. Oct 21 2008;[Medline].
7. Mesner O, Hammerman C, Goldschmidt D, et al. Glucose-6-phosphate dehydrogenase activity in male premature and term neonates. Arch Dis Child Fetal Neonatal Ed. Nov 2004;89(6):F555-7. [Medline]. [Full Text].
8. Murki S, Dutta S, Narang A, Sarkar U, Garewal G. A randomized, triple-blind, placebo-controlled trial of prophylactic oral phenobarbital to reduce the need for phototherapy in G6PD-deficient neonates. J Perinatol. May 2005;25(5):325-30. [Medline].
9. Au WY, Pang A, Lam KK, et al. G6PD deficiency from lyonization after hematopoietic stem cell transplantation from female heterozygous donors. Bone Marrow Transplant. Oct 2007;40(7):677-81. [Medline].
10. Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood. Jan 1 2008;111(1):16-24. [Medline]. [Full Text].
11. Beutler E, Westwood B, Prchal JT, et al. New glucose-6-phosphate dehydrogenase mutations from various ethnic groups. Blood. Jul 1 1992;80(1):255-6. [Medline]. [Full Text].
12. McDade J, Abramova T, Mortier N, Howard T, Ware RE. A novel G6PD mutation leading to chronic hemolytic anemia. Pediatr Blood Cancer. Dec 2008;51(6):816-9. [Medline].
13. Ozbay Hosnut F, Ozcay F, et al. Etiology of hemolysis in two patients with hepatitis A infection: glucose-6-phosphate dehydrogenase deficiency or autoimmune hemolytic anemia. Eur J Pediatr. Dec 2008;167(12):1435-9. [Medline].
14. Sklar GE. Hemolysis as a potential complication of acetaminophen overdose in a patient with glucose-6-phosphate dehydrogenase deficiency. Pharmacotherapy. May 2002;22(5):656-8. [Medline].

Article Last Updated: Nov 13, 2008