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G6PD Deficiency Clinical Presentation

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

History

The majority of people with G6PD deficiency may remain clinically asymptomatic. However, they can present with exacerbated neonatal jaundice or with episodes of acute hemolytic anemia following exposure to an oxidative agent or with chronic non-spherocytic hemolytic anemia.[3, 15, 6, 7, 8, 9, 10]  

Neonatal jaundice/hyperbilirubinemia 

G6PD deficiency is one of the major risk factors for severe neonatal jaundice.[11] Jaundice usually appears within first 24 hours of life, usually earlier than physiologic jaundice but later compared to jaundice seen in blood group alloimmunization.   

Jaundice can be very severe in some G6PD-deficient babies, especially in association with prematurity, infection, and/or environmental factors (such as naphthalene-camphor balls used in babies' bedding and clothing). Coexistence of a mutation in the uridyl transferase gene (UGT1A1; the same mutations are associated with the Gilbert syndrome) can also exacerbate neonatal jaundice.[16]

Hazardous hyperbilirubinemia defined as a total serum bilirubin greater than 30 mg/dL is a rare event, occurring in 5 per 100 000 live births after universal bilirubin screening. G6PD deficiency is the leading cause of hazardous hyperbilirubinemia when an etiology is identified.[17]

Some G6PD-deficient neonates, if undiagnosed soon after birth, could present later in the first week of life with generalized jaundice, poor feeding, lethargy, breathing difficulty, or seizures. If inadequately managed, neonatal jaundice associated with G6PD deficiency can produce kernicterus or bilirubin encephalopathy and permanent neurologic damage.[6, 7, 8, 9, 10, 16]

Acute hemolytic anemia 

Acute episodic hemolytic anemia occurs on exposure to oxidant stress like certain medications, chemicals, infections, ketoacidosis, or after ingestion of fava beans. Hemolysis usually begins 24-72 hours after exposure to oxidant stress and in cases of severe hemolysis, patients present with malaise, irritability, weakness, jaundice, tachycardia due to moderate to severe anemia, and often dark urine (cola- or tea-colored) due to hemoglobinuria usually within 6-24 hours. The onset can be extremely abrupt, especially with favism in children.

Acute hemolysis is usually self-limited and resolves within 8-14 days due to the compensatory production of young red blood cells, which have high levels of G6PD enzyme. Young red blood cells are not vulnerable to oxidative damage and, hence, limit the duration of hemolysis. Acute renal failure is a rare complication of acute hemolytic anemia in adults.[3, 16]

Chronic nonspherocytic hemolytic anemia  (CNSHA)

A small percentage of G6PD-deficient patients have chronic nonspherocytic hemolytic anemia (CNSHA) of variable severity. G6PD Brighton, G6PD Harilaou, and G6PD Serres are included in this category.[1, 16, 18]

The patient is usually a male with a history of neonatal jaundice who may present with anemia, unexplained jaundice, or gallstones later in life. Although they have chronic hemolysis, they are also vulnerable to acute oxidative damage on exposure to an oxidative agent.[16]

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Physical

Jaundice, pallor, and splenomegaly may be present in patients with severe hemolysis. Patients may have right upper quadrant tenderness due to hyperbilirubinemia and cholelithiasis. 

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Causes

G6PD deficiency is an X-linked recessive enzymopathy caused by a missense mutation in the housekeeping G6PD gene.[19] The pattern of inheritance is similar to that of hemophilia and color blindness: males usually manifest the abnormality and females are carriers. Females can be symptomatic if they are homozygous or if their normal X chromosome is inactivated.

The G6PD gene is located in the distal long arm of the X chromosome at the Xq28 locus. More than 160 mutations in the G6PD gene (OMIM #305900) have been reported.[19] Most are single-base changes that result in an amino acid substitution. These substitutions affect enzyme activity by decreasing intracellular stability of the protein or by affecting their catalytic activity.[14, 20, 15]

A large deletion in the G6PD gene is incompatible with life. Although small deletion mutation is rare, it has been reported and presents with severe G6PD deficiency.[15]

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.

The most common G6PD variants includes G6PD A-, G6PD Mediterranean, G6PD Canton, and G6PD Union.[15]

G6PD A- occurs in high frequency in Africa, Southern Europe, and North and South America. It is associated with lower enzyme levels and acute intermittent hemolysis.[3, 15, 21, 16]

G6PD Mediterranean is seen mainly in the Middle East, including Israel, and it accounts for almost all G6PD deficiency in Kurdish Jews, India, and Indonesia.[3, 15, 22, 23, 24, 25, 26, 27, 28, 21, 16]  It is characterized by enzyme deficiency that is more severe than G6PD A- alleles. Hemolysis after ingestion of fava beans (Favism) is most frequently associated with the Mediterranean variant of G6PD deficiency.

G6PD Canton is seen mainly in China and G6PD Union is seen worldwide.

G6PD B is the wild type of allele (normal variant). The G6PD A+ variant is associated with high enzyme levels and, hence, no hemolysis.

In addition, severe forms of G6PD deficiency are associated with chronic nonspherocytic hemolytic anemia. Mutations causing severe chronic non-spherocytic hemolytic anemia commonly cluster in Exon 10, a region important for protein dimerization.[15, 9]

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:[29]

  • Class I - Severe enzyme deficiency, chronic nonspherocytic hemolysis
  • Class II - Severe enzyme deficiency (1-10% residual activity), intermittent acute hemolysis
  • Class III - Moderate enzyme deficiency (10-60% residual activity), intermittent acute hemolysis
  • Class IV - No enzyme deficiency 60-150% activity
  • Class V - Increased enzyme activity (>150%)
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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.

References
  1. Nkhoma ET, Poole C, Vannappagari V, Hall SA, Beutler E. The global prevalence of glucose-6-phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis. 2009 May-Jun. 42 (3):267-78. [Medline].

  2. Alving AS, Carson PE, Flanagan CL, Ickes CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science. 1956 Sep 14. 124 (3220):484-5. [Medline].

  3. Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008 Jan 5. 371 (9606):64-74. [Medline].

  4. Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotype-phenotype association. Blood Rev. 2007 Sep. 21 (5):267-83. [Medline].

  5. Kaplan M, Hammerman C. The need for neonatal glucose-6-phosphate dehydrogenase screening: a global perspective. J Perinatol. 2009 Feb. 29 Suppl 1:S46-52. [Medline].

  6. Weng YH, Chiu YW. Clinical characteristics of G6PD deficiency in infants with marked hyperbilirubinemia. J Pediatr Hematol Oncol. 2010 Jan. 32 (1):11-4. [Medline].

  7. Dhillon AS, Darbyshire PJ, Williams MD, Bissenden JG. Massive acute hemolysis in neonates with glucose-6-phosphate dehydrogenase deficiency. Arch Dis Child Fetal Neonatal Ed. 2003. 88:F534-F536 doi:10.1136/fn.88.6.F534.

  8. Valaes T. Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl. 1994 Mar. 394:58-76. [Medline].

  9. Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia. A potential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol. 1998 Sep. 25 (3):575-90, viii. [Medline].

  10. Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. Semin Perinatol. 2004 Oct. 28 (5):356-64. [Medline].

  11. American Academy of Pediatrics Subcommittee on Hyperbilirubinemia. Management of hyperbilirubinemia in the newborn infant 35 or more weeks of gestation. Pediatrics. 2004 Jul. 114 (1):297-316. [Medline].

  12. Abid S, Khan AH. Severe hemolysis and renal failure in glucose-6-phosphate dehydrogenase deficient patients with hepatitis E. Am J Gastroenterol. 2002 Jun. 97 (6):1544-7. [Medline].

  13. Guan Y, Roter DL, Huang A, Erby LA, Chien YH, Hwu WL. Parental discussion of G6PD deficiency and child health: implications for clinical practice. Arch Dis Child. 2014 Mar. 99 (3):251-5. [Medline].

  14. Luzzatto L, Poggi V. Glucose-6-phosphate dehydrogenase deficiency. Orskin SH, Nathan DG, Ginsburg D, Look AT, Fisher DE, Lux SE, eds. Nathan & Oski's Hematology of Infancy and Childhood. 7th ed. Philadelphia PA: Saunders; 2009. 883-907.

  15. Vulliamy TJ, Luzzato L. Glucose-6-phosphatase dehydrogenase deficiency and related disorders. Blood Principles and Practice of Hematology. 2nd ed. 2002.

  16. Luzzatto L. Hemolytic anemia and anemia due to blood loss. Harrison’s Principles of Internal Medicine. 18th ed. McGraw-Hill Professional Publishing; 2011.

  17. Kuzniewicz MW, Wickremasinghe AC, Wu YW, McCulloch CE, Walsh EM, Wi S, et al. Incidence, etiology, and outcomes of hazardous hyperbilirubinemia in newborns. Pediatrics. 2014 Sep. 134 (3):504-9. [Medline].

  18. Makarona K, Caputo VS, Costa JR, et al. Transcriptional and epigenetic basis for restoration of G6PD enzymatic activity in human G6PD-deficient cells. Blood. 2014 Jul 3. 124 (1):134-41. [Medline].

  19. Bautista JM. Epigenetic therapy reprograms hereditary disease. Blood. 2014 Jul 3. 124 (1):7-8. [Medline].

  20. Gomez-Gallego F, Garrido-Pertierra A, Bautista JM. Structural defects underlying protein dysfunction in human glucose-6-phosphate dehydrogenase A(-) deficiency. J Biol Chem. 2000 Mar 31. 275 (13):9256-62. [Medline].

  21. Oppenheim A, Jury CL, Rund D, Vulliamy TJ, Luzzatto L. G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews. Hum Genet. 1993 Apr. 91 (3):293-4. [Medline].

  22. Cappellini MD, Martinez di Montemuros F, De Bellis G, Debernardi S, Dotti C, Fiorelli G. Multiple G6PD mutations are associated with a clinical and biochemical phenotype similar to that of G6PD Mediterranean. Blood. 1996 May 1. 87 (9):3953-8. [Medline].

  23. Martinez di Montemuros F, Dotti C, Tavazzi D, Fiorelli G, Cappellini MD. Molecular heterogeneity of glucose-6-phosphate dehydrogenase (G6PD) variants in Italy. Haematologica. 1997 Jul-Aug. 82 (4):440-5. [Medline].

  24. Cappellini MD, Sampietro M, Toniolo D, Carandina G, Martinez di Montemuros F, Tavazzi D, et al. G6PD Ferrara I has the same two mutations as G6PD A(-) but a distinct biochemical phenotype. Hum Genet. 1994 Feb. 93 (2):139-42. [Medline].

  25. Pinto FM, Gonzalez AM, Hernandez M, Larruga JM, Cabrera VM. Sub-Saharan influence on the Canary Islands population deduced from G6PD gene sequence analysis. Hum Biol. 1996 Aug. 68 (4):517-22. [Medline].

  26. Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-. Blood. 1989 Nov 15. 74 (7):2550-5. [Medline].

  27. Kurdi-Haidar B, Mason PJ, Berrebi A, Ankra-Badu G, al-Ali A, Oppenheim A, et al. Origin and spread of the glucose-6-phosphate dehydrogenase variant (G6PD-Mediterranean) in the Middle East. Am J Hum Genet. 1990 Dec. 47 (6):1013-9. [Medline].

  28. Karimi M, Martinez di Montemuros F, Danielli MG, Farjadian S, Afrasiabi A, Fiorelli G, et al. Molecular characterization of glucose-6-phosphate dehydrogenase deficiency in the Fars province of Iran. Haematologica. 2003 Mar. 88 (3):346-7. [Medline].

  29. Betke K, Beutler E, Brewer GJ, et al. Standardization of procedures for the study of glucose-6-phosphate dehydrogenase: report of a WHO Scientific Group. World Health Organ Tech Rep Ser. 1967. 366:1-53.

  30. Minucci A, Giardina B, Zuppi C, Capoluongo E. Glucose-6-phosphate dehydrogenase laboratory assay: How, when, and why?. IUBMB Life. 2009 Jan. 61 (1):27-34. [Medline].

  31. Shah SS, Diakite SA, Traore K, Diakite M, Kwiatkowski DP, Rockett KA, et al. A novel cytofluorometric assay for the detection and quantification of glucose-6-phosphate dehydrogenase deficiency. Sci Rep. 2012. 2:299. [Medline].

  32. Domingo GJ, Satyagraha AW, Anvikar A, et al. G6PD testing in support of treatment and elimination of malaria: recommendations for evaluation of G6PD tests. Malar J. 2013 Nov 4. 12:391. [Medline].

  33. Au WY, Ngai CW, Chan WM, Leung RY, Chan SC. Hemolysis and methemoglobinemia due to hepatitis E virus infection in patient with G6PD deficiency. Ann Hematol. 2011 Oct. 90 (10):1237-8. [Medline].

 
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