Glucose-6-Phosphate Dehydrogenase Deficiency
The 5 Minute Pediatric Consult
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Glucose-6-Phosphate Dehydrogenase Deficiency |
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Susan R. Rheingold
DEFINITION
Deficiency of the enzyme glucose-6-phosphate dehydrogenase (G6PD) in the red blood cell, which in some individuals may result in a hemolytic anemia. Children inherit abnormal G6PD genes that result either in deficient enzyme production or in production of an enzyme with diminished activity.
- Although the majority of patients with G6PD deficiency are never anemic and have mild to no hemolysis, the classic manifestation is acute hemolytic anemia.
- (AHA) World Health Organization (WHO) classification
- Class 1: Congenital nonspherocytic hemolytic anemia: a rare form manifesting itself as a chronic hemolysis without exposure to oxidative stressors. Patients have a mild-to-moderate anemia, although some patients are transfusion dependent. Can present as neonatal jaundice, hemolytic anemia, or a secondary manifestation of the chronic hemolysis (e.g., gallstones). Splenomegaly is present in 40% of patients. Affected individuals tend to be white males of Northern European background.
- Class 2: Severe deficiency (<5% detectable enzyme activity): oxidative stress-induced hemolysis only. The prototype is G6PD-Mediterranean. Because of severe deficiency, all RBCs are sensitive to stressors, and hemolysis may be severe and persistent.
- Class 3: Mild deficiency (approximately 10% enzyme activity): the most common type of G6PD deficiency. Acute hemolytic anemia is uncommon and occurs only with stressors. The prototype is G6PD A (African or of African descent). Because the enzyme is present and active in young RBCs, the hemolysis preferentially affects older cells and is milder and self-limited (i.e., all cells produced in response to the anemia have adequate G6PD levels).
- Class 4: Nondeficient variant: no symptoms, even during oxidant stressors, e.g., G6PD A (variant with normal activity); 20% to 40% alleleic frequency in Africans.
- Deficient neonates may have hyperbilirubinemia out of proportion to their anemia. In severe subtypes, this may lead to kernicterus. Elevated bilirubin is only partially due to the hemolysis; the liver plays a role as well.
PATHOPHYSIOLOGY/PATHOLOGY
- Normal G6PD activity is 7 to 10 IU/g hemoglobin.
- G6PD is necessary for the prevention of cell damage during oxidative stress.
- It is critically important in RBCs because of continuous oxidant stress (from O2 metabolism) and because anuclear RBCs cannot synthesize more enzyme, unlike cells in other tissues.
- Also, all RBCs lose G6PD activity throughout their life span, so older cells are more prone to oxidative hemolysis.
- The normal RBC life span of approximately 120 days is unaffected in unstressed states, even with severe enzyme deficiency, but may be shortened during oxidant stress.
- G6PD-deficient RBCs are destroyed via intravascular hemolysis upon exposure to the oxidative stressor, and the acute hemolytic anemia results.
- Hemolysis usually follows stressor by 1 to 3 days.
- Hemoglobin nadir occurs 8 to 10 days post-exposure. It is therefore necessary to obtain hemoglobins for over a week after the initial exposure.
- Oxidant stressors include infections (bacterial, viral, hepatitis) and drugs (mothballs, antimalarials, some sulfonamides, methylene blue, among others).
- Favism, a severe hemolytic anemia related to fava bean ingestion, is always caused by G6PD deficiency, but not all deficient patients will develop this.
GENETICS
- G6PD gene is on the X chromosome (Xq28), meaning that it is inherited primarily from mother to son (sex-linked).
- Males express the enzyme (mutant or normal) from their single X chromosome (hemizygotes). Females inheriting two deficient X chromosomes are considered homozygotes (rare) and are more severely affected than are female heterozygotes. Because of random X inactivation (the Lyon hypothesis), approximately one-half of a female’s RBCs will have the deficiency and one-half will have normal G6PD activity, resulting in a milder phenotype.
- Different mutations have variable enzyme activity that in turn determines the clinical significance.
- Absolute deficiency of G6PD is not compatible with life.
EPIDEMIOLOGY
- G6PD is the most common of all clinically significant enzyme defects, as well as the most common inherited disorder of RBC defects.
- Primarily affects males
- Discovered in 1958 while studying individuals who developed hemolytic anemia when exposed to primaquine, an antimalarial drug
- Over 300 biochemical variants of G6PD have been identified, affecting almost 400 million people worldwide.
- The frequency of different G6PD mutations varies from population to population:
- Africans: 20% to 40% of African X-chromosomes are G6PD A (a mutant enzyme with normal activity).
- Sardinians (some regions): 30% have G6PD-Mediterranean.
- Saudi Arabians: 13% have G6PD deficiency.
- African-Americans: 10% to 15% have G6PD A- (a mutant enzyme with decreased activity; see below).
- The high incidence of mutant genes in some regions may relate to a survival advantage conferred against malarial infection (Plasmodium falciparum).
COMPLICATIONS
A generally asymptomatic condition with hemolysis, nausea, diarrhea, abdominal or back pain, and, frequently, low-grade fevers
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.
Intravascular hemolysis is very rare in children, but other causes include:
- 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:
- Hereditary spherocytosis (spherocytes) seen on smear or detected by osmotic fragility testing
- Autoimmune hemolysis and delayed hemolytic transfusion reactions (both Coombs-positive)
- Hemoglobinopathies (e.g., sickle cell anemia; often apparent from peripheral smear). Having G6PD deficiency and a hemoglobinopathy does not worsen either disease.
- Hypersplenism or severe liver disease: Gilbert disease may present with intermittent jaundice and indirect hyperbilirubinemia after infections.
- Bleeding (which may be occult) is more common than hemolysis as a cause of acute anemia with reticulocytosis and should be ruled out.
HISTORY
- Symptoms are generally those of anemia, such as pallor, fatigue, or malaise.
- Children undergoing active hemolysis are often irritable, with nausea, diarrhea, and abdominal or back pain, and they often have low-grade fevers.
- Dark urine (“coca-cola,” or tea-colored) may follow moderate-to-severe hemolysis.
- Seek information on recent drug, chemical, or food (fava bean) exposures, as well as recent or current illnesses.
- A detailed family history may reveal chronic anemia or intermittent jaundice or a known G6PD deficiency. Ask about a family history of splenectomy, cholecystectomy, or blood transfusion. Family ethnicity is also very important.
- Seek information on recent drug and chemical exposures, as well as recent or current illnesses.
- Signs include those referable to anemia, such as tachycardia, a flow murmur, or pallor.
- Significant hemolysis may cause jaundice or scleral icterus.
- Hepatosplenomegaly may occur but is unusual.
TESTS
- CBC usually reveals a normochromic normocytic anemia with an appropriate reticulocytosis. Hemoglobin can drop precipitously and should be monitored closely until stable or a trend upward is seen.
- Checking a single hemoglobin the day of exposure to the stressor is not acceptable.
- Peripheral blood smear often shows bizarre RBC morphology with marken anisocytosis and poikilocytosis.
- Can see schistocytes, hemi-ghost cells (uneven distribution of hemoglobin), bite cells, blister cells, and occasional Heinz bodies (on supravital staining)
- Hemoglobinemia can be seen in the plasma (pink-red supernatant) or may be measured as free serum hemoglobin.
- Hemoglobinuria occurs once hemoglobin-binding sites in the plasma (haptoglobin and hemopexin) are saturated and may be visible as hematuria or detected on routine urinalysis.
- Free serum haptoglobin levels decrease.
- Direct and indirect Coombs tests should be done to exclude autoimmune hemolytic anemia. They should be negative in G6PD deficiency.
- Plasma indirect bilirubin, LDH, and AST may be elevated, and hemosiderin may be found in the urine several days after hemolysis. LFTs should be normal.
- Renal functions should be obtained to rule out TTP and HUS.
Diagnostic Tests
- Rapid and relatively simple screening tests for G6PD activity in RBCs are available but are qualitative and will therefore not pick up all female heterozygotes who have a measurable but low enzyme level.
- It is necessary to confirm a deficiency or diagnose a suspected heterozygote with a test to quantify G6PD activity. Normal G6PD activity is 7 to 10 IU/g hemoglobin. This will accurately detect deficiency in males and homozygous females with no recent hemolysis and will be helpful with heterozygous women.
PITFALLS
- Measured enzyme levels will be higher immediately after an acute hemolytic event because younger RBCs (reticulocytes) with normal levels of G6PD will have replaced the older, more deficient population. Screening tests may be false-negative during this time. The most cost-effective approach is to defer screening until 1 to 2 weeks after the resolution of hemolysis.
- Heterozygote female detection: Two RBC populations exist because of mosaicism from random X-inactivation. On average, one-half are normal and one-half are deficient, but there may be variability. Therefore, quantitative results could be unreliable in extreme cases, which makes family counseling difficult.
- 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 is rarely necessary (except in some type 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. Transfused cells should not be G6PD deficient and will not undergo hemolysis.
- Supportive care, evaluation of renal function (risk of ATN with brisk hemolysis), and monitoring degree of anemia and ongoing hemolysis are important.
- Desferoxamine, xylitol, and vitamin E (strong antioxidant) have had mixed results in multiple clinical studies of their effect on severe G6PD hemolysis and are generally not warranted.
- For the affected neonate, one should monitor the bilirubin closely and start bilirubin lights early. Three-fourths of affected infants will have clinically apparent jaundice within 24 hours. If necessary, an exchange transfusion should be performed. Phenobarbital has shown some success in decreasing the bilirubin level. Early discharge is not recommended in infants with jaundice and known risk for having G6PD deficiency.
The majority of G6PD-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 to 6 weeks. The development of renal failure is extremely rare in children, even with massive hemolysis and hemoglobinuria.
PREVENTION
- Avoidance of drugs and toxins known to cause hemolysis is the best prevention.
- Education regarding drug avoidance, signs and symptoms of hemolysis, and family and genetic counseling should be provided.
| COMMON QUESTIONS AND ANSWERS |
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Q: Do I need to follow a special diet or avoid medications if I have G6PD deficiency?
A: Though 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 deficiency, 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 deficiency 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 deficiency, 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 higher in enzyme activity. On the other hand, G6PD has no affect on the clinical characteristics of sickle cell disease.
ICD-9-CM 282.2
Beutler E. G6PD deficiency. Blood 1994;84:3613–3636.
Beutler E. Study of glucose-6-phosphate dehydrogenase: history and molecular biology. Am J Hematol 1993;42:53–58.
Mason PJ. New insights into G6PD deficiency. Br J Haematol 1996;94[Suppl 4]:585–591.
Copyright © 2000 Lippincott Williams & Wilkins
M. William Schwartz, Louis M. Bell, Jr., Peter M. Bingham, Esther K. Chung, David F. Friedman and Andrew E. Mulberg, The 5 Minute Pediatric Consult