Zinkham WH. J Pediatr 1962;60:614-22Acute hemolysis after the ingestion of fava beans has been recognized and described since antiquity. In the 1950s, it was noted that 10% of African-American men experienced similar hemolysis during primaquine anti-malarial therapy, although Caucasian men rarely did. This mystery was partially solved when this hemolysis was associated with an X-linked deficiency in glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in erythrocyte glucose metabolism.1Carson P.E. Flanagan C.L. Ickes C.E. Alving A.S. Enzymatic deficiency in primaquine-sensitive erythrocytes.Science. 1956; 124: 484-485Crossref PubMed Scopus (433) Google Scholar (Of historic note, identification of G6PD deficiency as the etiology of primaquine-induced hemolysis followed drug treatment of prisoners from the Illinois State Penitentiary, a population now recognized as vulnerable.) After linking G6PD deficiency to acute drug-induced hemolytic anemia, other patients with chronic anemia including congenital non-spherocytic hemolytic anemia (CNSHA) were studied, and some of these patients also had G6PD deficiency.2Newton Jr., W.A. Bass J.C. Glutathione sensitive chronic non-spherocytic anemia.Am J Dis Child. 1958; 96: 501-502Google ScholarIn this 1962 article in The Journal, Zinkham provided an important review of the then-current literature of erythrocyte glucose metabolism and its relationship to congenital hemolytic disorders, including G6PD deficiency. He summarized two key metabolic pathways within erythrocytes, namely glycolysis and the hexose monophosphate shunt. He noted a recently described autosomal recessive deficiency of pyruvate kinase, which is now recognized as a major cause of CNSHA. He also astutely noted that G6PD activity paradoxically can be increased when measured during acute hemolysis; this phenomenon is now understood to reflect analysis of residual normal cells (after hemolysis of the most deficient cells) and frequently leads to false-negative interpretations.Now, 50 years later, we recognize a wide spectrum of CNSHA diagnoses, including at least 15 distinct erythrocyte enzymopathies, all rarer than G6PD deficiency. We also understand much more about G6PD deficiency itself, with hundreds of variants described, ranging from the mild A− mutation found in 10% to 15% of African-American people to severe forms found in persons of Mediterranean descent. Clinically, G6PD deficiency is highly variable, ranging from a benign course to episodic acute hemolysis or even chronic hemolytic anemia that defines CNSHA. Comprehensive erythrocyte enzyme testing aids in diagnosis, but is costly and available only in selected commercial laboratories. Zinkham WH. J Pediatr 1962;60:614-22 Acute hemolysis after the ingestion of fava beans has been recognized and described since antiquity. In the 1950s, it was noted that 10% of African-American men experienced similar hemolysis during primaquine anti-malarial therapy, although Caucasian men rarely did. This mystery was partially solved when this hemolysis was associated with an X-linked deficiency in glucose-6-phosphate dehydrogenase (G6PD), an enzyme involved in erythrocyte glucose metabolism.1Carson P.E. Flanagan C.L. Ickes C.E. Alving A.S. Enzymatic deficiency in primaquine-sensitive erythrocytes.Science. 1956; 124: 484-485Crossref PubMed Scopus (433) Google Scholar (Of historic note, identification of G6PD deficiency as the etiology of primaquine-induced hemolysis followed drug treatment of prisoners from the Illinois State Penitentiary, a population now recognized as vulnerable.) After linking G6PD deficiency to acute drug-induced hemolytic anemia, other patients with chronic anemia including congenital non-spherocytic hemolytic anemia (CNSHA) were studied, and some of these patients also had G6PD deficiency.2Newton Jr., W.A. Bass J.C. Glutathione sensitive chronic non-spherocytic anemia.Am J Dis Child. 1958; 96: 501-502Google Scholar In this 1962 article in The Journal, Zinkham provided an important review of the then-current literature of erythrocyte glucose metabolism and its relationship to congenital hemolytic disorders, including G6PD deficiency. He summarized two key metabolic pathways within erythrocytes, namely glycolysis and the hexose monophosphate shunt. He noted a recently described autosomal recessive deficiency of pyruvate kinase, which is now recognized as a major cause of CNSHA. He also astutely noted that G6PD activity paradoxically can be increased when measured during acute hemolysis; this phenomenon is now understood to reflect analysis of residual normal cells (after hemolysis of the most deficient cells) and frequently leads to false-negative interpretations. Now, 50 years later, we recognize a wide spectrum of CNSHA diagnoses, including at least 15 distinct erythrocyte enzymopathies, all rarer than G6PD deficiency. We also understand much more about G6PD deficiency itself, with hundreds of variants described, ranging from the mild A− mutation found in 10% to 15% of African-American people to severe forms found in persons of Mediterranean descent. Clinically, G6PD deficiency is highly variable, ranging from a benign course to episodic acute hemolysis or even chronic hemolytic anemia that defines CNSHA. Comprehensive erythrocyte enzyme testing aids in diagnosis, but is costly and available only in selected commercial laboratories.
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May 1, 2020
Dennis Lund Hansen + 7
Open Access
