(See also Overview of Hemolytic Anemia.)
G6PD deficiency, a defect in the hexose monophosphate shunt pathway, is the most common disorder of red blood cell (RBC) metabolism. The G6PD gene is located on the X chromosome and exhibits a high amount of variation (polymorphism), resulting in a range of G6PD activity from normal to severely deficient. Variants are classified I through V by the amount of activity of the G6PD enzyme. Because the gene is X-linked, males are more likely to present with clinically significant hemolysis, although females who are homozygous, or who are heterozygous with skewed X inactivation that results in a high proportion of affected X chromosomes (see Mosaicism) may also be affected.
This defect occurs in about 10% of black males and in < 10% of black females in the US and in lower frequencies among people with ancestors from the Mediterranean basin (eg, Italians, Greeks, Arabs, Sephardic Jews) and people with ancestors from Asia.
Pathophysiology
G6PD deficiency renders RBCs susceptible to oxidative stress, which shortens RBC survival. Hemolysis occurs following an oxidative challenge, commonly after fever, acute viral or bacterial infections, and diabetic ketoacidosis. Hemolysis is episodic and self-limited, although rare patients have chronic, ongoing hemolysis in the absence of oxidative challenge.
Less commonly, hemolysis occurs after exposure to drugs or to other substances that produce peroxide and cause oxidation of hemoglobin and RBC membranes. These drugs and substances include primaquine, salicylates, sulfonamides, nitrofurans, phenacetin, naphthalene, some vitamin K derivatives, dapsone, phenazopyridine, nalidixic acid, methylene blue, and, in some cases, fava beans. The amount of hemolysis depends on the degree of G6PD deficiency and the oxidant potential of the drug.
Symptoms and Signs
In most cases, hemolysis affects < 25% of RBC mass and causes transient jaundice and dark urine. Some patients have back and/or abdominal pain. However, when the deficiency is more severe, profound hemolysis may lead to hemoglobinuria and acute kidney injury.
Diagnosis
The diagnosis is considered in patients with evidence of acute hemolysis, particularly males with a direct antiglobulin–negative hemolytic anemia (see Diagnosis of Hemolytic Anemia). Anemia, jaundice, and reticulocytosis develop during hemolysis.
The peripheral smear may reveal RBCs that appear to have had one or more bites (1-micron wide) taken from the cell periphery (bite or blister cells) and RBCs with inclusions termed Heinz bodies, which are particles of denatured hemoglobin, which can be recognized only by special stains. These cells may be visible early during the hemolytic episode but do not persist in patients with an intact spleen, which removes them.
Testing for G6PD activity is available. However, during and immediately after a hemolytic episode, tests may yield false-negative results because of destruction of the older, more deficient RBCs and the production of reticulocytes, which are rich in G6PD. Thus, testing may need to be repeated several weeks after the acute event. Several screening tests are available, including point-of-care tests; positive results should be confirmed with a quantitative test.
Treatment
Key Points
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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common inherited disorder of red blood cell metabolism and can cause hemolysis in the presence of triggers.
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Incidence is higher in certain ethnic groups (eg, American blacks, people from the Mediterranean basin, people with Asian ancestry).
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Triggers include acute illnesses (eg, infections), drugs (eg, salicylates) and other substances (eg, fava beans) that cause oxidative stress.
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Diagnose using peripheral smear and G6PD assay; false negative G6PD assays are possible during acute hemolysis so repeat testing after several weeks if initial G6PD assay is negative.
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Avoid triggers to limit hemolytic episodes.
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
phenazopyridine |
No US brand name |
methylene blue |
PROVAYBLUE |
dapsone |
ACZONE |
