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Glucose-6-Phosphate Dehydrogenase (G6PD) Deficiency

By Evan M. Braunstein, MD, PhD, Assistant Professor of Medicine, Division of Hematology, Department of Medicine, Johns Hopkins School of Medicine

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Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked enzymatic defect common in blacks that can result in hemolysis after acute illnesses or intake of oxidant drugs (including salicylates and sulfonamides). Diagnosis is based on assay for G6PD, although tests are often falsely negative during acute hemolysis. Treatment is supportive.

G6PD deficiency, a defect in the hexose monophosphate shunt pathway, is the most common disorder of 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).

Pathophysiology

G6PD deficiency renders the RBC susceptible to oxidative stress, which shortens RBC survival. Hemolysis occurs following an oxidative challenge, commonly after fever, acute viral or bacterial infections, and diabetic acidosis. 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

  • Peripheral smear

  • G6PD assay

The diagnosis is considered in patients with evidence of acute hemolysis, particularly males with a direct antiglobulin–negative hemolytic anemia. , jaundice and Anemia, jaundice, and reticulocytosis develop during hemolysis. The peripheral smear may reveal RBCs that appear to have had one or more bites (1-μm wide) taken from the cell periphery (bite or blister cells) and RBCs with inclusions termed Heinz bodies, which are particles of denatured hemoglobin. These cells may be visible early during the hemolytic episode but do not persist in patients with an intact spleen because they are removed

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 presence of reticulocytes 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

  • Avoidance of triggers, removal of offending drug or agent, and supportive care

During acute hemolysis, treatment is supportive; transfusions are rarely needed. Patients are advised to avoid drugs or substances that initiate hemolysis.