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Chapter 44 Red Blood Cell Enzymopathies 619

oxidize GSH without the formation of peroxide as an intermediate. haptoglobin occur. Heinz bodies (denatured precipitated hemoglobin)
Hemolysis begins in hours to 1–3 days after exposure to the offending may be visible in the erythrocytes during an acute hemolytic episode,
drug. However, many drugs implicated in acute hemolysis in G6PD but not under normal circumstances. “Bite cells” have been described,
deficiency may not be true culprits, as infection and other stressors but this is not specific for G6PD deficiency and these cells are usually
can also provoke hemolysis in these people. not present in acute hemolytic states of patients with common G6PD
The mechanism of hemolysis induced by infection is not well variants or in G6PD-deficient patients with chronic hemolysis.
understood, but the generation of hydrogen peroxide by phago- Individuals with the chronic hemolytic G6PD variants have
cytizing leukocytes or the diffusion of oxidants from neutrophils varying degrees of anemia and reticulocytosis.
undergoing oxidative bursts leading to the formation of disulfide
bridges of hemoglobin may be factors.
Depending on the G6PD variant, hemolysis can be self-limited Diagnosis
or protracted. The RBCs of G6PD A- contain only 5% to 15% of
the normal amount of enzyme activity and the age-dependent decline A biochemical diagnosis of G6PD deficiency can be made using
of the activity renders old RBCs severely deficient and susceptible quantitative spectrophotometric analysis to measure the generation
to hemolysis. As this subpopulation is eliminated, younger RBCs of NADPH from NADP in RBC hemolysates. A more convenient
and reticulocytes produced in response to hemolysis have higher rapid fluorescent screening test can be used to test at-risk populations.
G6PD activity and are typically not hemolyzed. Thus, the hemolytic False-negative results are not unusual, however, especially if enzy-
process is self-limited, even when the offending agent is continued. In matic analysis is performed shortly after resolution of acute hemolytic
contrast, in G6PD Mediterranean the enzyme activity of the young episodes or in heterozygous females. After acute hemolysis, reticulo-
RBCs is lower compared with G6PD A- and hemolysis continues cytes and young RBCs, which have much higher enzymatic activity,
longer, even days after discontinuation of the culprit drug. predominate. These false-negative test results are more likely to occur
when a screening test rather than a quantitative spectrophotometric
Favism analysis of the enzyme activity is used. Females heterozygous for
Fava beans are a staple food in many parts of the world where G6PD G6PD are particularly difficult to diagnose because of their mosa-
deficiency is found at a high gene frequency. The hemolysis precipi- icism for X-chromosome enzymes and may have total RBC enzymatic
tated by fava bean ingestion, favism, occurs only in people who are activity ranging anywhere from hemizygote to normal; however these
G6PD deficient. It is most frequently associated with the more severe females have a variable mixture of deficient and nondeficient RBCs
G6PD Mediterranean and G6PD Cairo variants, but rarely has been and their deficient RBCs are subject to hemolytic crises. Since the
seen with G6PD A-. Not all individuals with G6PD Mediterranean nucleotide substitutions of many G6PD-deficient isoenzymes have
are susceptible to favism and a tendency toward familial occurrence been identified, molecular diagnostic methods are more reliable for
suggests that additional genetic factors may be important. Favism is the accurate diagnosis of females who are heterozygous for G6PD
more common in children than adults. Hemolysis usually occurs one deficiency.
to several days after fava bean consumption, but onset within the first Severe sporadic variants causing chronic hemolytic anemia may be
hours after exposure has been reported. considered for prenatal diagnosis in some circumstances.
Chronic Hemolysis
The rare G6PD variants causing chronic hemolytic anemia occur Prognosis
sporadically. The severity of the hemolysis ranges from mild to trans-
fusion dependent. Exposure to the oxidants that cause hemolysis in Most patients with G6PD deficiency have normal life spans with
the acute hemolytic G6PD variants may further exacerbate hemolysis. no clinical sequelae. Neonatal icterus with resultant kernicterus and
mental retardation have the gravest consequences.
Neonatal Jaundice
Neonatal jaundice, which may result in kernicterus, is the most
common and often the most serious consequence of G6PD deficiency. Therapy
The icterus is not only caused by hemolysis but also to inadequate
processing of bilirubin by the immature liver of the G6PD deficient Treatment of an acute hemolytic crisis includes withdrawing any
infant. Thus, the coinheritance of polymorphic UGT1A1 promoter offending agent and supportive care, which in severe cases includes
alleles (Gilbert syndrome) exacerbates the icterus. Neonatal screening RBC transfusions. Folic acid supplementation is recommended for
for G6PD deficiency and early phototherapy treatment in endemic patients with chronic hemolysis. Rarely, chronic hemolytic anemia
areas has been associated with a decreased incidence of kernicterus. is severe enough to require chronic transfusions. Neonatal icterus
associated with G6PD deficiency is treated in the same manner as
Nonerythroid Effect of G6PD Deficiency neonatal icterus arising from other causes; G6PD deficiency should
Although patients with the common endemic G6PD variants are be considered in any neonate with hyperbilirubinemia, especially
not at increased risk for infections, neutrophil dysfunction has been those of high-risk ethnic descent.
described in some patients with rare severely deficient G6PD variants.
Occasionally, cataracts have been observed in patients with some rare
variants of G6PD that produce chronic hemolytic anemia. Small Future Directions
studies from the Middle East suggest that decreased G6PD activity
may predispose to the development of diabetes. Splenomegaly is In certain areas of the world where G6PD deficiency reaches epi-
generally not seen in G6PD deficient individuals. demic proportions and ingestion of fava beans is staple, screening for
endemic G6PD-deficient variants would be expected to reduce hospi-
talizations, RBC transfusions and even mortality (from kernicterus).
Laboratory Manifestations
Pyruvate Kinase Deficiency
Under normal conditions, most G6PD-deficient individuals are not
anemic and have no laboratory evidence of hemolysis. In the setting
of oxidative stress, laboratory findings indicative of acute hemolysis Introduction
including anemia and reticulocytosis are seen. As the hemolysis is
mainly extravascular with a variable intravascular component, vari- PK deficiency is the most common enzyme deficiency causing
able degrees of hyperbilirubinemia, increased LDH, and decreased hemolysis. Although this disorder is far less common than G6PD