Basics
Description
Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in the RBC, which may result in hemolytic anemia. Several types of genetic mutations result either in deficient enzyme production or in production of an enzyme with diminished activity.
- Although most patients with this deficiency are never anemic and have mild to no hemolysis, the classic manifestation is acute hemolytic anemia in response to oxidative stress.
- World Health Organization classification of G6PD:
- Class 1: congenital nonspherocytic hemolytic anemia: rare. Chronic hemolysis without exposure to oxidative stressors-splenomegaly in 40%. Affected individuals tend to be white males of Northern European background.
- Class 2: severe deficiency (1-10% enzymatic activity): oxidative stress-induced hemolysis. Prototype is G6PD-Mediterranean.
- Class 3: mild deficiency (10-60% enzymatic activity): most common type. Acute hemolytic anemia uncommon, occurs only with stressors
- Class 4: nondeficient variant (60-100% enzymatic activity): no symptoms, even during oxidant stressors (e.g., G6PD A+ [variant with normal activity]); 20-40% allelic frequency in Africans
- Class 5: >150% of normal activity
- Deficient neonates may have hyperbilirubinemia out of proportion to their anemia.
- May, in part, account for increased prevalence of African Americans among patients with bilirubin encephalopathy
- Should be considered as cause of hyperbilirubinemia in neonates of appropriate racial background and may contribute to kernicterus
General Prevention
Avoid drugs and toxins known to cause hemolysis. Prompt follow-up with febrile illness and signs of hemolysis.
Epidemiology
Prevalence
- Most common of all clinically significant enzyme defects, affecting ~400 million people worldwide
- X linked (Xq28): primarily affects males
- Almost 400 allelic variants
- Frequency of different mutations varies by population:
- Africans: 20-40% of X chromosomes are G6PD A+ (mutant enzyme with normal activity).
- Sardinians (some regions): 30% have G6PD-Mediterranean.
- Saudi Arabians: 13% have G6PD deficiency.
- African Americans: 10-15% have G6PD A- (mutant enzyme with decreased activity).
- High incidence of mutant genes in some regions may relate to survival advantage against malarial infection (Plasmodium falciparum).
Genetics
Gene is on the X chromosome (Xq28).
- Males express the enzyme (mutant or normal) from their single X chromosome (hemizygotes).
- Female homozygotes (rare) are more severely affected than female heterozygotes.
- Heterozygote females show variable intermediate expression because of random X inactivation.
Pathophysiology
- RBCs lose G6PD activity throughout their lifespan; therefore, older cells are more prone to oxidative hemolysis.
- Normal RBC lifespan of ~120 days is unaffected in unstressed states, even with severe enzyme deficiency, but may be shortened during oxidant stress.
- Enzyme-deficient RBCs are destroyed by intravascular hemolysis on exposure to the oxidative stressor and acute hemolytic anemia results.
- Oxidant stressors include infections and chemicals (mothballs, antimalarials, some sulfonamides, methylene blue).
- Hemolysis usually follows stressor by 1-3 days, and nadir occurs 8-10 days postexposure. Obtain hemoglobins for >1 week after the initial exposure.
- Favism: severe hemolytic anemia in patients with more severe forms of G6PD deficiency after fava bean ingestion
- Normal G6PD activity is 7-10 IU/g hemoglobin.
Diagnosis
History
- Symptoms of anemia include fatigue, irritability, and malaise.
- Dark urine (cola or tea colored) may follow moderate to severe hemolysis. May develop jaundice (particularly scleral icterus).
- Patient may have required phototherapy in newborn period for hyperbilirubinemia.
- Recent drug, chemical, or food (fava bean) exposures may precipitate moderate to severe hemolysis.
- Family history of intermittent jaundice, splenectomy, cholecystectomy, or blood transfusion may indicate an inherited condition.
- Ethnicity may help determine type/severity of disease.
Physical Exam
- Tachycardia, a flow murmur, or pallor: signs of anemia
- Jaundice or scleral icterus: signs of hemolysis
Diagnostic Tests & Interpretation
Lab
- CBC
- Usually reveals a normochromic normocytic anemia with appropriate reticulocytosis
- Hemoglobin can drop precipitously; should be monitored closely until stable or trending upward; checking a single hemoglobin the day of exposure to the stressor is not sufficient.
- Peripheral blood smear
- Often shows bizarre RBC morphology with marked anisocytosis and poikilocytosis
- Can see schistocytes, hemighost cells (uneven distribution of hemoglobin), bite cells, blister cells, and occasional Heinz bodies (on supravital staining)
- Hemoglobinemia: seen as plasma (pinkish red supernatant) or measured as free serum hemoglobin
- Hemoglobinuria: occurs when hemoglobin-binding sites in the plasma (haptoglobin and hemopexin) are saturated; may be visible as dark urine-heme positive on dipstick and no RBC on microscopy
- Free haptoglobin levels decrease.
- Direct and indirect Coombs tests
- Must be done to exclude autoimmune hemolytic anemia
- Should be negative in G6PD deficiency
- Other: Plasma indirect bilirubin, lactate dehydrogenase, and aspartate aminotransferase may be elevated; hemosiderin may be found in the urine several days after hemolysis. Liver function tests should be normal. Renal functions to rule out thrombotic thrombocytopenic purpura and hemolytic uremic syndrome:
- Rapid screening tests for G6PD activity in RBCs are qualitative; will miss some female heterozygotes with measurable but low enzyme levels
- Necessary to confirm a deficiency or to diagnose a suspected heterozygote with a test to quantify G6PD activity
- Normal activity: 7-10 IU/g hemoglobin
- Accurately detects deficiency in males and homozygous females with no recent hemolysis
- Helpful with heterozygous women/
- Newborn screening for G6PD deficiency
- Included in some panels of genetic screening tests performed on newborns
- Typically performed by DNA-based methods that detect a few of the most common variants in U.S. populations. Does not screen for all G6PD variants and can miss severe but rare variants.
- Results may be reported in terms of predicted enzyme levels but not a true measurement of enzymatic activity.
Alert
- Screening tests may be falsely negative during rapid red cell turnover (reticulocytosis).
- Most cost-effective approach: Defer screening until 1-2 weeks after resolution of hemolysis. Smear may be normal during steady state.
- Heterozygote female detection:
- 2 RBC populations exist because of mosaicism from random X inactivation.
- On average, 50% are normal and 50% are deficient, but there may be variability.
Differential Diagnosis
Intravascular hemolysis is very rare in children, but other causes include the following:
- Acute hemolytic transfusion reactions (Coombs test is positive)
- Microangiopathic hemolytic disease, such as hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, and prosthetic cardiac valves
- Physical trauma (e.g., March hemoglobinuria); severe burns (uncommon)
- Other inherited RBC enzyme deficiencies
- Paroxysmal nocturnal hemoglobinuria
- Extravascular hemolysis can also be confused with G6PD deficiency and includes the following:
- Hereditary spherocytosis (spherocytes on smear)
- Autoimmune hemolysis and delayed hemolytic transfusion reactions (both Coombs positive)
- Hemoglobinopathies
- Hypersplenism
- Severe liver disease
- Gilbert disease
Treatment
General Measures
- Removal of the oxidant stressor is of primary importance:
- Discontinue the suspected drug and/or treat the infection.
- In class 3 and 4 patients, essential drug therapy may be continued while monitoring for signs of severe hemolysis.
- Transfusion may be necessary (especially in some class 1 and 2 deficiencies), but any patient who is symptomatic with anemia or has a low hemoglobin and signs of ongoing brisk hemolysis should be transfused immediately with packed RBCs.
- Supportive care, evaluation of renal function (risk of acute tubular necrosis with brisk hemolysis), and monitoring degree of anemia and ongoing hemolysis are important.
- For the affected neonate:
- Monitor the bilirubin closely and start phototherapy early.
- If necessary, exchange transfusion should be carried out.
- Phenobarbital may decrease bilirubin level.
- Early discharge is not recommended in newborn infants with jaundice and known risk for G6PD deficiency.
Ongoing Care
Follow-up Recommendations
- Most deficient individuals remain asymptomatic.
- When hemolysis does occur, it tends to be self-limited and resolves spontaneously, with a return to normal hemoglobin levels in 2-6 weeks.
- Development of renal failure is extremely rare in children, even with massive hemolysis and hemoglobinuria.
Diet
- Avoid fava beans (Vicia faba). Fava beans have a variety of names in different cultures (e.g., faba bean, broad bean, tick bean, field bean, bell bean, bakela [Ethiopia], faviera [Portugal], ful masri [Sudan], winter field bean [United Kingdom]).
Prognosis
- For those with the milder forms, the prognosis is excellent.
- Can cause significant morbidity, but rarely mortality, in those with the more severe forms
Complications
Neonates can be at risk for hyperbilirubinemia, requiring treatment. Kernicterus has been reported in infants with G6PD deficiency.
Additional Reading
- Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet. 2008;371(9606):64-74. [View Abstract]
- Frank JE. Diagnosis and management of G6PD deficiency. Am Fam Physician. 2005;72(2):1277-1282. [View Abstract]
- Nkhoma ET, Poole C, Vannappagari V, et al. The global prevalence of glucose-6 phosphate dehydrogenase deficiency: a systematic review and meta-analysis. Blood Cells Mol Dis. 2009;42(3):267-278. [View Abstract]
- Youngster I, Arcavi L, Schechmaster R, et al. Medications and glucose-6-phosphate dehydrogenase deficiency: an evidence-based review. Surg Saf. 2010;33(9):713-726. [View Abstract]
- Watchko JF. Hyperbilirubinemia in African American neonates. Semin Fetal Neonatal Med. 2010;15(3):176-182. [View Abstract]
Codes
ICD09
- 282.2 Anemias due to disorders of glutathione metabolism
ICD10
- D55.0 Anemia due to glucose-6-phosphate dehydrogenase deficiency
SNOMED
- 62403005 Glucose-6-phosphate dehydrogenase deficiency anemia (disorder)
- 22933009 Glucose-6-phosphate dehydrogenase deficiency class I variant anemia (disorder)
- 34852006 Glucose-6-phosphate dehydrogenase deficiency class II variant anemia (disorder)
- 24661004 Glucose-6-phosphate dehydrogenase deficiency class III variant anemia (disorder)
- 82003006 Glucose-6-phosphate dehydrogenase deficiency class IV variant anemia (disorder)
- 80963002 Glucose-6-phosphate dehydrogenase deficiency class V variant anemia (disorder)
FAQ
- Q: Do I need to follow a special diet or avoid medications if I have G6PD deficiency?
- A: Although most patients will have no symptoms of their disease, certain medications may cause transient hemolytic anemia, and these should be avoided. When prescribing medications, your physician and pharmacist should know about your G6PD, but most necessary medications are safe and well tolerated. People with severe variants of the deficiency should also avoid fava beans, but otherwise no dietary restrictions are necessary.
- Q: Do I need to know which variant of G6PD I have?
- A: It may be clear which variant you are likely to have based on your clinical symptoms and ethnic background.
- Q: Should my family be screened if someone has G6PD deficiency?
- A: In families of patients with G6PD, screening members may help provide meaningful genetic counseling to female carriers and affected but asymptomatic males.
- Q: How does G6PD affect sickle cell anemia and vice versa?
- A: Having sickle cell disease is somewhat protective in patients with G6PD A deficiency because their RBC population is young and, therefore, has higher enzymatic activity. On the other hand, G6PD has no effect on the clinical characteristics of sickle cell disease.