Sections View Full Chapter Figures Tables Videos Annotate Full Chapter Figures Tables Videos Supplementary Content + INTRODUCTION Download Section PDF Listen +++ ++ Clinical manifestations of inherited red cell enzyme deficiencies are diverse and may entail: ++ 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 ++ However, only hemolytic complications will be reviewed here. Methemoglobinemia is reviewed in Chap. 18 and polycythemia in Chap. 27. + MECHANISM OF HEMOLYSIS IN PATIENTS WITH RED CELL ENZYME ABNORMALITIES Download Section PDF Listen +++ ++ 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). + GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY Download Section PDF Listen +++ ++ 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. +++ Drugs that Can Incite Hemolysis ++ 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. ++Table Graphic Jump LocationTABLE 14–1DRUGS THAT CAN TRIGGER HEMOLYSIS IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE–DEFICIENT INDIVIDUALSView Table||Download (.pdf) TABLE 14–1 DRUGS THAT CAN TRIGGER HEMOLYSIS IN GLUCOSE-6-PHOSPHATE DEHYDROGENASE–DEFICIENT INDIVIDUALS Category of Drug Predictable Hemolysis Possible Hemolysis Antiparasitics Dapsone Primaquine Methylene blue Chloroquine Quinine Analgesics/Antipyretic Phenazopyridine Aspirin (high doses) Paracetamol (Acetaminophen) Antibacterials Cotrimoxazole Sulfadiazine Quinolones (including nalidixic acid, ciprofloxacin, ofloxacin) Nitrofurantoin Sulfasalazine Other Rasburicase Toluidine blue Chloramphenicol Isoniazid Ascorbic acid Glibenclamide Vitamin K Isosorbide dinitrate Reproduced with permission from Luzzatto L, Seneca E: G6PD deficiency: A classic example of pharmacogenetics with on-going clinical implications, Br J Haematol 2014 Feb;164(4):469-480 +++ 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 may be suppressed, and recovery from anemia is delayed until after the active infection is over. +++ Favism ++ Favism is potentially one of the most severe hematologic consequences of G6PD 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 G6PD-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, this condition is more likely with variants that cause severe deficiency. + HEREDITARY NONSPHEROCYTIC HEMOLYTIC ANEMIA (HNSHA) Download Section PDF Listen +++ ++ HNSHA may occur with severely deficient variants of G6PD deficiency (however, these are very rare; referred to as class 1 G6PD deficiency) and with deficiency of a variety of other red cell metabolic enzymes. Anemia may range from severe, transfusion-dependent, 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 neurologic abnormalities in glucose phosphate isomerase deficiency and phosphoglycerate kinase deficiency. Nonhematologic symptoms may sometimes even be predominant, such as myopathy in phosphofructokinase deficiency, or severe neuromuscular disease in triosephosphate isomerase deficiency. Even nontransfused subjects have increased risk of development of iron overload (see Chap. 9). Pyruvate kinase (PK) deficiency: — PK deficiency is the most common cause of HNSHA. — It is estimated to occur at the rate of approximately 50 per 1,000,000 in persons of European descent. — It 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: — This deficiency is the 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 good. Triosephosphate isomerase deficiency: — This deficiency is 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 6 years. Pyrimidine 5′-nucleotidase deficiency: — This deficiency is characterized basophilic stippling (see Chap. 1) and is, therefore, the only cause of HNSHA in which a provisional diagnosis is possible from morphological analysis. — Acquired deficiency of pyrimidine-5′-nucleotidase may result from lead poisoning (lead preferentially occupies the enzyme’s active site). +++ 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 or specific. Increased serum bilirubin concentration, decreased haptoglobin levels, and increased reticulocyte counts may be present when hemolysis occurs. Secondary thrombocytosis may be present. High transferrin saturation and increased ferritin may be present. Mild to moderate leukopenia and thrombocytopenia may occur in patients with splenomegaly. +++ Differential Diagnosis ++ This depends on demonstration of deficient enzyme deficiency. Start with screening tests for G6PD and PK deficiency. Enzyme tests may require retesting more than 2 months after patient is fully recovered from hemolytic episode because some enzymes levels are higher in reticulocytes and young red cells. This is especially common during a hemolytic episode in G6PD A– patients because residual young red cells have normal levels of G6PD. Assays or screening tests for G6PD deficiency are most reliable in healthy affected (hemizygous) males and may be normal in females with G6PD deficiency. DNA analysis allows for reliable confirmation of G6PD deficiency in female carriers. Family history and signs of nonhematologic pathologies can be very helpful in establishing the diagnosis. Presence of basophilic stippling suggests pyrimidine 5′-nucleotidase deficiency, if there is no evidence for lead poisoning. DNA analysis is recommended to enable genetic counseling is contemplated. +++ Treatment ++ G6PD-deficient individuals should avoid “oxidant” drugs (see Table 14–1). Transfusions should be given only in the most severe cases of G6PD 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 when phototherapy fails (see Chap. 25). Splenectomy should be considered in certain patients with pyruvate kinase and triosephosphate isomerase deficiencies. — Severity of disease and functional impairment are important considerations. — If cholecystectomy is required, splenectomy may be done at the same time. If concomitant iron overload is present, iron chelation is indicated (see Chap. 9). 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 contraindicated unless unrelated causes of iron deficiency are operative. An ongoing trial is testing an oral agent that stabilizes PK multimers and ameliorates PK metabolic defect. + ICTERUS NEONATORUM Download Section PDF Listen +++ ++ This condition may occur in some newborns with G6PD deficiency but also with other congenital enzyme and red cell membrane disorders (see Chap. 13). If not treated, it may lead to kernicterus and mental retardation. It is rare in neonates with the A– variant but more common in Mediterranean and various Asian variants. It occurs particularly in infants who are G6PD deficient or inheriting red cell membrane disorders who have also inherited a mutation of the UDP-glucuronosyltransferase-1 gene promoter (Gilbert syndrome). It results probably principally from in adequate bilirubin processing, but shortened red cell span plays a contributory role. ++ For a more detailed discussion, see Wouter W. van Solinge and Richard van Wijk: Disorders of Red Cells Resulting from Enzyme Abnormalities, Chap. 47 in Williams Hematology, 9th ed.