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G6PD Deficiency

  • Author: Lawrence C Wolfe, MD; Chief Editor: George T Griffing, MD  more...
 
Updated: Jul 28, 2015
 

Background

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. 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.[3, 4]

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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.

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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.[5]

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.

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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.[6, 7, 8, 9, 10]

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.[11]

Massive hemolysis complicating G6PD deficiency has also been reported in patients with hepatitis infections, specifically hepatitis A and E in the Indian subcontinent.[12]

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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.[13]

If a mother is a heterozygote, the chances of recurrence is 50% with every subsequent male pregnancy.[14]

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.[13]

Additional resources are available at G6PD Deficiency Association - Favism.

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Contributor Information and Disclosures
Author

Lawrence C Wolfe, MD Associate Chief for Hematology and Safety, Division of Pediatric Hematology-Oncology, Cohen Children's Medical Center

Lawrence C Wolfe, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Pediatrics, American Association of Blood Banks, American Society of Hematology, Children's Oncology Group, Eastern Society for Pediatric Research

Disclosure: Nothing to disclose.

Coauthor(s)

Shilpa Shukla, MBBS Fellow in Pediatric Hematology/Oncology, North Shore-LIJ Cohen Children’s Medical Center

Shilpa Shukla, MBBS is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Society of Pediatric Hematology/Oncology, Medical Council of India, Hemostasis and Thrombosis Research Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.

Additional Contributors

Frederick H Ziel, MD Associate Professor of Medicine, University of California, Los Angeles, David Geffen School of Medicine; Physician-In-Charge, Endocrinology/Diabetes Center, Director of Medical Education, Kaiser Permanente Woodland Hills; Chair of Endocrinology, Co-Chair of Diabetes Complete Care Program, Southern California Permanente Medical Group

Frederick H Ziel, MD is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Endocrinology, American College of Physicians, American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Federation for Medical Research, American Medical Association, American Society for Bone and Mineral Research, California Medical Association, Endocrine Society, International Society for Clinical Densitometry

Disclosure: Nothing to disclose.

Acknowledgements

Bernard Corenblum, MD, FRCP(C) Professor of Medicine, Director, Endocrine-Metabolic Testing and Treatment Unit, Ovulation Induction Program, Department of Internal Medicine, Division of Endocrinology, University of Calgary, Canada

Disclosure: Nothing to disclose. Gregory A Kline, MD Associate Professor, Department of Medicine, Division of Endocrinology, Richmond Road Diagnostic Centre, University of Calgary Faculty of Medicine, Canada

Gregory A Kline, MD is a member of the following medical societies: Canadian Medical Association and Christian Medical & Dental Society

Disclosure: Nothing to disclose.

Vasudevan A Raghavan, MBBS, MD, MRCP(UK) Director, Cardiometabolic and Lipid (CAMEL) Clinic Services, Division of Endocrinology, Scott and White Hospital, Texas A&M Health Science Center College of Medicine

Vasudevan A Raghavan, MBBS, MD, MRCP(UK) is a member of the following medical societies: American College of Physicians-American Society of Internal Medicine, American Diabetes Association, American Heart Association, National Lipid Association, Royal College of Physicians, and The Endocrine Society

Disclosure: Nothing to disclose.

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