Page 714 - Williams Hematology ( PDFDrive )

689

CHAPTER 47 from oxidative damage. The maturation of reticulocytes into erythrocytes is

ERYTHROCYTE ENZYME 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
DISORDERS 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 neu-
romuscular abnormalities. Glucose-6-phosphate dehydrogenase (G6PD) defi-
Wouter W. van Solinge and Richard van Wijk ciency is the most common erythrocyte enzyme defect. In some populations,
more than 20 percent of people may be affected by this enzyme deficiency. In
the common polymorphic forms, such as G6PD A–, G6PD Mediterranean, or
SUMMARY G6PD Canton, hemolysis occurs only during the stress imposed by infection or
administration of “oxidative” drugs, and in some individuals upon ingestion of
Red cells possess active metabolic machinery that provides energy to pump fava beans. Neonatal icterus, which appears largely with the interaction with
ions against electrochemical gradients, to maintain red cell shape, to keep an independent defect in bilirubin conjugation, is the clinically most serious
hemoglobin iron in the reduced form, and to maintain enzyme and hemo- complication of G6PD deficiency. Patients with uncommon, functionally very
globin sulfhydryl groups. The main source of metabolic energy comes from severe, genetic variants of G6PD experience chronic hemolysis, a disorder des-
glucose. Glucose is metabolized through the glycolytic pathway and through ignated hereditary nonspherocytic hemolytic anemia.
the hexose monophosphate shunt. Glycolysis catabolizes glucose to pyruvate Hereditary nonspherocytic hemolytic anemia (HNSHA) also occurs as
and lactate, which represent the end products of glucose metabolism in the a consequence of other enzyme deficiencies, the most common of which is
erythrocyte, because it lacks the mitochondria required for further oxidation pyruvate kinase (PK) deficiency. Glucose phosphate isomerase (GPI), triose-
of pyruvate. Adenosine diphosphate (ADP) is phosphorylated to ATP, and phosphate isomerase (TPI), and pyrimidine 5′-nucleotidase (P5′N) deficiency
nicotinamide adenine dinucleotide (NAD) is reduced to NADH in glycoly- are included among the relatively rare causes of hereditary nonspherocytic
+
sis. 2,3-Bisphosphoglycerate, an important regulator of the oxygen affinity hemolytic anemia. In the case of some deficiencies, notably those of gluta-
of hemoglobin, is generated during glycolysis. The hexose monophosphate thione synthetase (GS), TPI, and phosphoglycerate kinase (PGK), the defect is
shunt oxidizes glucose-6-phosphate, reducing NADP to reduced nicotinamide expressed throughout the body, and neurologic and other defects may be a
+
adenine dinucleotide phosphate (NADPH). In addition to glucose, the red cell prominent part of the clinical syndrome.
has the capacity to utilize some other sugars and nucleosides as a source of Diagnosis is best achieved by determining red cell enzyme activity either
energy. The red cell lacks the capacity for de novo purine synthesis, but has with a quantitative assay or a screening test. Except for the basophilic stippling
a salvage pathway that permits synthesis of purine nucleotides from purine of erythrocytes that is characteristic, but not specific, of pyrimidine 5′-nucleo-
bases. The red cell contains high concentrations of glutathione, which is main- tidase deficiency, red cell morphology is of little or no help in differentiating
tained almost entirely in the reduced state by NADPH through the catalytic one red cell enzyme deficiency from another. A variety of molecular lesions
activity of glutathione reductase. Glutathione is synthesized from glycine, have been defined in most of these enzyme deficiencies. Confirmation of the
cysteine, and glutamic acid in a two-step process that requires ATP as a source diagnosis by DNA analysis is recommended: it is necessary for genetic counsel-
of energy. Catalase and glutathione peroxidase serve to protect the red cell ing and is helpful in recommendations for treatment, as patients with some
enzyme deficiencies (e.g., GPI deficiency) tend to respond favorably to sple-
nectomy whereas others do not (e.g., G6PD deficiency). Some of the defects,
such as PK and GPI deficiencies, are transmitted as autosomal recessive disor-
ders, whereas G6PD and PGK deficiencies are X linked.

Acronyms and Abbreviations: ADA, adenosine deaminase; ADP, adenosine diphos-
phate; AK, adenylate kinase; AP-1, a transcription factor; 2,3-BPG, 2,3-bisphospho-
glycerate; BPGM, bisphosphoglycerate mutase enzyme; CDP, cytidine diphosphate; DEFINITION AND HISTORY
2,3-DPG, 2,3-diphosphoglycerate; EMP, Embden-Meyerhof direct glycolytic path-
way; FAD, flavin adenine dinucleotide; G6PD, glucose-6-phosphate dehydrogenase; Deficiencies in the activities of a number of erythrocyte enzymes may
GAPDH, glyceraldehyde phosphate dehydrogenase; GCL, glutamate cysteine ligase; lead to shortening of the red cell life span. Glucose-6-phosphate dehy-
GLUT1, glucose transporter 1; GPI, glucose phosphate isomerase; GR, glutathione drogenase (G6PD) deficiency was the first of these to be recognized and
reductase; GS, glutathione synthetase; GSH, reduced glutathione; GSSG, oxidized is the most common.
glutathione; HFE, the gene associated with hereditary hemochromatosis; HK, hexok- The recognition of G6PD deficiency was the result of investigations
inase; KLF1, key erythroid transcription factor; LDH, lactate dehydrogenase; miRNA, of the hemolytic effect of the antimalarial drug primaquine, carried out
microRNA; MRP1, multidrug resistance protein 1; NAD, nicotinamide adenine dinu- in the 1950s and described in detail elsewhere. These early studies
1–3
cleotide; NADPH, nicotinamide adenine dinucleotide phosphate (reduced form); defined G6PD deficiency as a hereditary sex-linked enzyme deficiency
nt, nucleotide; P5′N1, pyrimidine-5′-nucleotidase-1; PFK, phosphofructose kinase; that affected primarily the erythrocytes, older cells being more severely
PFKM, gene encoding muscle subunit of PFK; PGK, phosphoglycerate kinase; PK, affected than newly formed ones because of age-dependent decline of
pyruvate kinase; PKLR, gene encoding PK enzyme activity in red cells and liver; SNP, mutant enzyme activity. They showed that this enzyme deficiency was
single nucleotide polymorphism; SOD1, superoxide dismutase type 1; TPI, triose- very prevalent in individuals of African, Mediterranean, and Asian
phosphate isomerase; WHO, World Health Organization. ethnic origins, but that it could be found in virtually any population.
The common (polymorphic) forms of G6PD deficiency were found

Kaushansky_chapter 47_p0689-0724.indd 689 9/17/15 6:43 PM