Chapter 48: Erythrocyte Enzyme Disorders

Abstract

Red cells possess an active metabolic machinery that provides energy to pump ions against electrochemical gradients, to maintain red cell shape, to keep hemoglobin iron in the reduced form, and to maintain enzyme and hemoglobin sulfhydryl groups. The main source of metabolic energy comes from glucose. Glucose is metabolized through the glycolytic pathway and through the hexose monophosphate shunt. Glycolysis catabolizes glucose to pyruvate and lactate, which represent the end products of glucose metabolism in the erythrocyte, because it lacks the mitochondria required for further oxidation of pyruvate. Adenosine diphosphate (ADP) is phosphorylated to adenosine triphosphate (ATP), and nicotinamide adenine dinucleotide (NAD)+ is reduced to its reduced form, nicotinamide adenine dinucleotide (NADH), during glycolysis. 2,3-Bisphosphoglycerate, an important regulator of the oxygen affinity of hemoglobin, is generated during glycolysis. The hexose monophosphate shunt oxidizes glucose-6-phosphate, reducing nicotinamide adenine dinucleotide phosphate (NADP+) to reduced nicotinamide adenine dinucleotide phosphate (NADPH). In addition to glucose, the red cell has the capacity to use some other sugars and nucleosides as a source of energy. The red cell lacks the capacity for de novo purine synthesis, but has a salvage pathway that permits synthesis of purine nucleotides from purine bases. The red cell contains high concentrations of glutathione, which is maintained almost entirely in the reduced state by NADPH through the catalytic activity of glutathione reductase. Glutathione is synthesized from glycine, cysteine, and glutamic acid in a 2-step process that requires ATP as a source of energy. Catalase and glutathione peroxidase serve to protect the red cell from oxidative damage. The maturation of reticulocytes into erythrocytes is associated with a rapid decrease in the activity of several enzymes. However, the decrease in activities of other enzymes occurs much more slowly or not at all with aging. Erythrocyte enzyme deficiencies may lead to hemolytic anemia; expression of the defect in other cell lines may lead to pathologic changes such as neuromuscular abnormalities. Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common erythrocyte enzyme defect. In some populations, more than 20% of people may be affected by this enzyme deficiency. In the common polymorphic forms, such as G6PD A−, G6PD Mediterranean, or G6PD Canton, hemolysis occurs only during the stress imposed by infection or administration of “oxidative” drugs, and in some individuals upon ingestion of fava beans (favism). Neonatal icterus, which appears largely as a result of an interaction with an independent defect in bilirubin conjugation, is the clinically most serious complication of G6PD deficiency, but can be the presenting symptom of other enzyme deficiencies as well. Patients with uncommon, functionally very severe, genetic variants of G6PD experience chronic hemolysis, a disorder designated hereditary nonspherocytic hemolytic anemia. Hereditary nonspherocytic hemolytic anemia also occurs as a consequence of other enzyme deficiencies, the most common of which is pyruvate kinase deficiency. Glucosephosphate isomerase, hexokinase, and pyrimidine 5′-nucleotidase deficiency are included among the rare causes of hereditary nonspherocytic hemolytic anemia. In the case of some deficiencies, notably those of glutathione synthetase, triosephosphate isomerase, and phosphoglycerate kinase, the defect is expressed throughout the body, and neurologic and other defects may be a prominent part of the clinical syndrome. Diagnosis is best achieved by determining red cell enzyme activity either with a quantitative assay or a screening test. Except for the basophilic stippling of erythrocytes that is characteristic, but not specific, of pyrimidine 5′-nucleotidase deficiency, red cell morphology is of little or no help in differentiating one red cell enzyme deficiency from another. A variety of molecular lesions have been defined in most of these enzyme deficiencies. Confirmation of the diagnosis by DNA analysis is recommended: it is necessary for genetic counseling and is helpful in recommendations for treatment, as patients with some enzyme deficiencies (eg, glucosephosphate isomerase deficiency) tend to respond more favorably to splenectomy than do others (eg, G6PD deficiency). Some of the defects, such as pyruvate kinase and glucosephosphate isomerase deficiencies, are transmitted as autosomal recessive disorders, whereas G6PD and phosphoglycerate kinase deficiencies are X linked.