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INTRODUCTION

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

    — Episodic hemolysis after exposure to oxidants or infection.

    — Chronic hemolytic anemia (hereditary nonspherocytic anemia).

    — Acute hemolysis after eating fava beans (favism).

    — Methemoglobinemia.

    — Polycythemia.

    — Icterus neonatorum.

    — No hematologic manifestations.

  • However, only hemolytic complications will be reviewed here. Methemoglobinemia is reviewed in Chap. 19 and polycythemia in Chap. 29.

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MECHANISM OF HEMOLYSIS IN PATIENTS WITH RED CELL ENZYME ABNORMALITIES

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  • In glucose-6-phosphate dehydrogenase (G-6-PD) deficiency, oxidant challenge leads to the formation of denatured hemoglobin and 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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  • X-linked disorder.

  • The normal enzyme is designated G-6-PD B.

  • A mutant enzyme with normal activity [G-6-PD A(+)] is found in 16 percent of American men of African descent. It has a single mutation at nt c.376 (c. 376 A>G, amino acid substitution: p.Asn126Asp).

  • G-6-PD 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 at nt c.202 (c. 202 G>A, p.Val68Met). G-6-PD A– has decreased stability in vivo, and the affected hemizygotes have 5 to 15 percent of normal activity. Prevalence of G-6-PD A– in American men of African descent is 11 percent.

  • G-6-PD 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 G-6-PD Seattle (p.Asp282His) and G-6-PD A–, are also encountered in Europe.

  • Many different G-6-PD mutations, including G-6-PD Mediterranean, are encountered in Asia. Most of these are severe variants. Examples include G-6-PD Canton, Jammu, 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 G-6-PD mutation influence the extent of RBC destruction (see Table 15–1).

  • 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 G-6-PD A– type but is the more severe and more prolonged in Mediterranean type.

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Table Graphic Jump Location
TABLE 15–1DRUGS AND CHEMICALS THAT SHOULD BE AVOIDED BY PERSONS WITH G-6-PD DEFICIENCY

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