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INTRODUCTION

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Clinical manifestations of inherited red cell enzyme deficiencies are diverse and may entail:

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  • Hemolysis

    — Acute and or episodic hemolysis after exposure to oxidants or infection, or after eating fava beans (favism)

    — Chronic hemolytic anemia (hereditary nonspherocytic anemia)

  • Icterus neonatorum

  • Methemoglobinemia

    — Chronic benign cyanosis

    — Developmental defects with early fatality and chronic cyanosis

  • Polycythemia

  • No hematologic manifestations

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However, only hemolytic complications will be reviewed here. Methemoglobinemia is reviewed in Chap. 18 and polycythemia in Chap. 27.

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MECHANISM OF HEMOLYSIS IN PATIENTS WITH RED CELL ENZYME ABNORMALITIES

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  • In glucose-6-phosphate dehydrogenase (G6PD) deficiency, oxidant challenge leads to the formation of denatured hemoglobin (ie, Heinz bodies), which make the red cells less deformable and liable to splenic destruction.

  • Metabolic aberrations in most red cell enzymopathies cause hemolysis by undefined mechanism(s).

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GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY

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  • G6PD is an X-linked disorder.

  • The normal enzyme is designated G6PD B.

  • A mutant enzyme with normal activity, or G6PD A(+), is polymorphic among persons of African descent. It has a single mutation at nt c. 376 (c. 376 A>G, amino acid substitution: p.Asn126Asp).

  • G6PD A– is the principal deficient variant found among people of African ancestry. It has the nt c. 376 mutation and an additional mutation, almost always c. 202 G>A, p.Val68Met. G6PD A– has decreased stability in vivo, and affected hemizygotes have 5% to 15% of normal activity. Prevalence of G6PD A– in American men of African descent is 11%.

  • G6PD deficiency in Europe is most common in the southern part of the continent and is most often a result of a Mediterranean variant that has a single base substitution at nt c. 563 (c. 563 C>T, p.Ser188Phe). Although there is scarcely any detectable enzymatic activity in the erythrocytes, there are no clinical manifestations unless the patient is exposed to oxidative drugs, infection, or fava beans. Other variants, such as G6PD Seattle (p.Asp282His) and G6PD A–, are also encountered in Europe.

  • Many different G6PD mutations are also found in the Indian subcontinent and Southeast Asia. Most of these are severe variants. Examples include G6PD Canton, Viangchan, Bangkok, and Kaiping.

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Drugs that Can Incite Hemolysis

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  • Individual differences in the metabolism of certain drugs as well as the specific G6PD mutation influence the extent of red blood cell destruction (see Table 14–1).

  • Typically, drug-induced hemolysis begins 1 to 3 days after drug exposure. When severe, it may be associated with abdominal or back pain. The urine may become dark, even black.

  • Heinz bodies appear in circulating red cells and then disappear as they are removed by the spleen. The hemoglobin concentration then decreases rapidly.

  • Hemolysis is self-limited in the G6PD A– type but is the more severe and more prolonged in Mediterranean type and some Asian G6PD-deficient variants.

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Table Graphic Jump Location
TABLE 14–1DRUGS THAT CAN TRIGGER ...

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