Chapter 15: Hemolytic Anemia Related to Red Cell Enzyme Defects

• 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.

• 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).

• 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.

Drugs that Can Incite Hemolysis

• 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.

Febrile Illnesses that Can Incite Hemolysis

• Hemolysis may occur within 1 to 2 days of onset of a febrile illness, usually resulting in mild anemia.

• Hemolysis occurs especially in patients with pneumonia or typhoid fever.

• Jaundice may be particularly severe in association with infectious hepatitis.

• Reticulocytosis is usually suppressed, and recovery from anemia is delayed until after the active infection is over.

Favism

• Potentially one of the most severe hematologic consequences of G-6-PD deficiency.

• Hemolysis occurs within hours to days after ingestion of the beans.

• Urine becomes red or dark, and shock, sometimes fatal, may develop rapidly.

• Not all G-6-PD–deficient subjects develop hemolysis when they ingest fava beans. The enzyme deficiency is a necessary but not sufficient factor. The other factors required are not known, but believed to be, in part, genetic.

• More common in children than in adults, and occurs usually with variants that cause severe deficiency.

Icterus Neonatorum

• May occur in some newborns with G-6-PD deficiency and, if not treated, may lead to kernicterus and mental retardation.

• Rare in neonates with the A- variant, but more common in Mediterranean and various Asian variants.

• Is not caused by hemolysis, but rather by impaired conjugation in the liver.

• Occurs particularly in infants who are G-6-PD–deficient who have also inherited a mutation of the UDP-glucuronosyltransferase-1 gene promoter (Gilbert syndrome).

• May occur with severely deficient variants of G-6-PD deficiency (however, these are very rare; referred to as class 1 G-6-PD deficiency) and with deficiency of a variety of other red cell metabolic enzymes.

• Anemia may range from severe (hemoglobin level 5 g/dL) to a fully compensated state with near normal hemoglobin concentration.

• Chronic jaundice, splenomegaly, and gallstones are common, and some patients develop ankle ulcers.

• Nonhematologic manifestations may occur, such as cataracts in some patients with G-6-PD deficiency, muscle glycogen storage deficiency in phosphofructokinase deficiency, or severe neuromuscular disease in triosephosphate isomerase deficiency.

• Pyruvate kinase (PK) deficiency:

  — The most common cause of HNSHA.

  — Estimated to occur at the rate of approximately 50 per 1,000,000 in the white population.

  — Can be so severe that chronic transfusion therapy is required.

  — A partial response to splenectomy is usually observed. As young PK-deficient red cells are selectively sequestered by the spleen in PK deficiency, the postsplenectomy response is accompanied by a paradoxical increase in the number of reticulocytes.

• Glucose phosphate isomerase deficiency:

  — Second most common cause of HNSHA.

  — Anemia is usually relatively mild, but fetal hydrops has been observed several times with this enzyme deficiency.

  — Response to splenectomy is usually very good.

• Triosephosphate isomerase deficiency:

  — The most devastating of the red cell enzyme defects.

  — Adults with the disease are rare because most patients die of neuromuscular complications before the age of 5 years.

• Pyrimidine 5′ nucleotidase deficiency:

  — Characterized by stippled red cells and is, therefore, the only cause of HNSHA in which a provisional morphologic diagnosis is possible.

  — Because of the age-related decay of the normal enzyme, a partial deficiency occurs in patients with decreased erythropoiesis, particularly children with transient erythroblastopenia of childhood.

Laboratory Features

• Erythrocytes with enzyme deficiencies have normal morphology in the absence of hemolysis, except as noted above, or have mild changes that are not distinctive.

• Increased serum bilirubin concentration, decreased haptoglobin levels, and increased serum lactic dehydrogenase activity all may be present when hemolysis occurs.

• Leukopenia may occur in patients with splenomegaly.

Differential Diagnosis

• Depends on demonstration of the enzyme deficiency.

• Start with screening tests for G-6-PD and PK activity.

• Assays or screening tests for G-6-PD deficiency are most reliable in healthy affected (hemizygous) males.

• Diagnosis may be difficult during a hemolytic episode in G-6-PD A– patients because residual young red cells have normal levels of G-6-PD.

• Dense red cells (reticulocyte-depleted) can be tested following differential centrifugation.

• Family studies can be very helpful.

• May have to retest 1 month after patient is fully recovered from hemolytic episode.

• Presence of basophilic stippling suggests lead poisoning or pyrimidine 5′-nucleotidase deficiency.

• When the nucleotide substitution is known, heterozygotes are easily detected by PCR-based analysis, which is also useful for prenatal diagnosis.

Treatment

• G-6-PD–deficient individuals should avoid "oxidant" drugs (see Table 15–1).

• Transfusions should be given only in the most severe cases of G-6-PD deficiency, such as favism, but may be commonly required in PK or other enzyme deficiencies accompanied by severe anemia.

• Exchange transfusion may be necessary in infants with neonatal icterus.

• Splenectomy is sometimes considered in certain patients with HNSHA.

  — Severity of disease and functional impairment are important considerations.

  — Benefit of splenectomy differs according to family defect, and family history of response to splenectomy, if available, is the most useful guide.

  — If cholecystectomy is required, splenectomy may be done at the same time.

• If concomitant iron overload is present, iron chelation is indicated.

• Glucocorticoids are of no known value.

• Folic acid therapy is often given, but is without proven hematologic benefit unless a deficiency is found in the red cells.

• Iron therapy is probably contraindicated unless unrelated causes of iron deficiency are operative.