Chapter 14: Hemolytic Anemia Related to Red Cell Enzyme Defects

INTRODUCTION

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

Two principal types of hemolysis

— Enzyme abnormalities that make the red cell susceptible to acute and/or episodic hemolysis after exposure to oxidants or infection or after eating fava beans (favism)

— Enzyme abnormalities that result in chronic hemolytic anemia (hereditary nonspherocytic anemia)
Icterus neonatorum
Methemoglobinemia

— Chronic benign cyanosis

— Developmental defects with early fatality and chronic cyanosis
Erythrocytosis enzyme abnormalities that result in a compensatory erythrocytosis
No hematologic manifestations

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

In glucose-6-phosphate dehydrogenase (G6PD) deficiency, oxidant challenge leads to the formation of denatured hemoglobin (ie, Heinz bodies), which makes the red cells less deformable and liable to splenic and/or intravascular destruction.
Metabolic aberrations in most red cell enzymopathies cause hemolysis by undefined mechanism(s).

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.376A>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.202G>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.563C>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 and cause hemolysis chronically without an inciting exposure. Examples include G6PD Canton, Viangchan, Bangkok, and Kaiping.

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 ...

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