Williams Hematology



Definition and History
Etiology and Pathogenesis

The Mechanism of Hemolysis

Biochemical Genetics and Molecular Biology

Other Enzyme Deficiencies
Prevalence, Geographic Distribution, and Population Genetics
Clinical Features

Common Forms of G-6-PD Deficiency

Hereditary Nonspherocytic Hemolytic Anemia
Laboratory Features
Differential Diagnosis
Therapy, Course, and Prognosis

Therapy of G-6-PD Deficiency

Splenectomy in Nonspherocytic Hemolytic Anemia


Course and Prognosis
Chapter References

Erythrocyte enzyme deficiencies may lead to hemolytic anemia and sometimes to other systemic pathology. G-6-PD deficiency is the most common of these. In some populations more than 20 percent of the population may be affected by this enzyme deficiency. In the common polymorphic forms, such as G-6-PD A–, G-6-PD Mediterranean, or G-6-PD Canton, hemolysis occurs only during the stress imposed by infection or administration of “oxidative” drugs, and in some individuals upon ingestion of fava beans. Neonatal icterus, which appears largely to be due to a defect in bilirubin conjugation, is the clinically most serious complication of G-6-PD deficiency. Patients with less common, functionally very severe, genetic variants of G-6-PD 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, triosephosphate isomerase, and pyrimidine-5′-nucleotidase deficiency are included among the relatively 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 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 stippling of erythrocytes that is characteristic of pyrimidine-5′-nucleotidase deficiency, red cell morphology is of little or no help in differentiation of red cell enzyme deficiencies from one another. A variety of molecular lesions have been defined in most of these enzyme deficiencies. Accurate diagnosis is helpful in recommendations for treatment, since patients with some enzyme deficiencies (e.g., glucosephosphate isomerase deficiency) tend to respond more favorably to splenectomy than patients with other deficiencies (e.g., G-6-PD deficiency). It is also essential for genetic counseling since some of the defects, such as pyruvate kinase and glucosephosphate isomerase deficiencies, are transmitted as autosomal recessive disorders, while G-6-PD and phosphoglycerate kinase deficiencies are X-linked.

Acronyms and abbreviations that appear in this chapter include: AD, autosomal dominant; AMP, adenosine monophosphate; G-6-PD, glucose-6-phosphate dehydrogenase; GR, glutathione reductase; GSH, glutathione; GSSG, glutathione disulfide; HNSHA, hereditary nonspherocytic hemolytic anemia; ITP, inosine triphosphate; NAD, nicotinamide-adenine dinucleotide; NADP, nicotinamide-adenine dinucleotide phosphate; NADH, reduced nicotinamide-adenine dinucleotide; NADPH, reduced nicotinamide-adenine dinucleotide phosphate; PCR, polymerase chain reaction; PK, pyruvate kinase; TPI, triosephosphate isomerase.

Deficiencies in the activities of a number of erythrocyte enzymes may lead to shortening of the red cell life span. G-6-PD deficiency was the first of these to be recognized and is the most common.
The recognition of G-6-PD deficiency was the result of investigations of the hemolytic effect of the antimalarial drug primaquine, carried out in the 1950s and described in detail elsewhere.1,2 and 3 These early studies defined G-6-PD deficiency as a hereditary sex-linked enzyme deficiency that affected primarily the erythrocytes, older cells being more severely affected than newly formed ones. They showed that this enzyme deficiency was very prevalent in individuals of African, Mediterranean, and East Asian ethnic origins, but that it could be found in virtually any population. The common (polymorphic) forms of G-6-PD deficiency were found to be associated with anemia only under conditions of stress, such as the administration of oxidative drugs, infection, or the neonatal period.
Chronic hemolysis in the absence of a stress occurs in uncommon, functionally severe forms of G-6-PD deficiency and in patients with a variety of other red cell enzyme deficiencies. Such patients have hereditary nonspherocytic hemolytic anemia. Although patients fitting the description of hereditary nonspherocytic hemolytic anemia had been documented earlier, the designation was first introduced by Crosby4 in 1950. Dacie and his colleagues5 subsequently reported several families in which affected members manifested hemolytic anemia from an early age and in whom the osmotic fragility of the red cells was normal. The latter finding, and the fact that most of the affected individuals failed to benefit from splenectomy, distinguished this disorder from hereditary spherocytosis. Thus, defined essentially by exclusion as a hereditary hemolytic anemia that is not hereditary spherocytosis, it is not at all surprising that hereditary nonspherocytic hemolytic anemia has proven to be extremely heterogeneous, both in etiology and in clinical manifestations. Sometimes this disorder is also designated congenital nonspherocytic hemolytic anemia, but the name hereditary is more accurate and is therefore preferable. While hereditary ovalocytosis, pyropoikilocytosis, stomatocytosis, and even sickle cell disease and thalassemia major are hereditary hemolytic anemias that are not spherocytic, they are not included in this category. Rather, the diagnosis of hereditary nonspherocytic hemolytic anemia is reserved for those patients who have no major aberration of red cell morphology.
Although a deficiency of G-6-PD was found to be responsible for hemolysis in a few patients with hereditary nonspherocytic hemolytic anemia,6 in the overwhelming majority of cases the cause remained obscure. In 1954 Selwyn and Dacie7 studied autohemolysis (spontaneous lysis of red cells after sterile incubation for 24 to 48 h at 37° C) in four patients with hereditary nonspherocytic hemolytic anemia and found that in two of them lysis was only slightly increased and was prevented by glucose; these patients were designated as type 1, while the others, in whom glucose failed to correct hemolysis, were classified as type 2. Autohemolysis of the erythrocytes of type 2 patients was modified by the addition of ATP, a substance that we now recognize does not penetrate the red cell membrane. Instead, its modifying influence was probably exerted chiefly by virtue of its effect on the osmolarity and pH of the suspending solution. However, the findings suggested to De Gruchy et al8,9 that patients with type 2 autohemolysis suffered from a defect in ATP generation. This proposal, born of a misunderstanding of red cell biochemistry, turned out to be correct: one of the major causes of hereditary nonspherocytic hemolytic anemia proved to be a deficiency of the ATP-generating enzyme pyruvate kinase (PK),10 but this was only the first of a large number of enzyme defects that have been shown to account for this heterogeneous syndrome.11,12
Red cell enzyme deficiencies that cause hemolytic anemia are hereditary. Most are inherited as autosomal recessive disorders, but G-6-PD deficiency and phosphoglycerate kinase deficiency are X-linked.
The erythrocyte enzyme deficiencies that have been shown to cause hemolytic anemia and other hematologic diseases are listed in Table 45-1. Other red cell enzyme deficiencies, listed in Table 45-2, do not appear to cause a functional abnormality of the erythrocyte.13 For example, acatalasemia, the state in which there is a virtually total absence of red cell catalase, is devoid of hematologic manifestations. Similarly, red cells without cholinesterase14 seem to survive normally in most cases. The lack of clinical manifestations is not always clear-cut. In some instances hemolytic anemia is reported in some individuals with a given deficiency but not in others. For example, most subjects with lactate dehydrogenase deficiency have had no anemia, but cases with hemolysis have been reported.15 Such ambiguity could be due to differences in environmental and genetic factors, but also to the bias of ascertainment. Erythrocyte enzyme assays are usually carried out on patients with hemolytic anemia. Thus, a benign enzyme defect may be thought mistakenly to cause hemolysis because it is found in a patient with hemolytic anemia. Deficiencies of phosphoglycerate16,17 kinase and of glutathione synthetase are usually associated with hereditary nonspherocytic hemolytic anemia, but cases have been reported in which these deficiencies were unassociated with any hematologic manifestations. It has at times been suggested that moderate decreases in the activity of glutathione reductase and of glutathione peroxidase caused hemolytic anemia, but the best available evidence indicates that these enzymes are not ordinarily rate limiting in erythrocyte metabolism and are not associated with hemolytic anemia.12 Even the total absence of glutathione reductase in the red cells of members of one family was associated with only rare episodes of hemolysis, possibly caused by fava beans, in otherwise hematologically normal individuals.18 Included in Table 45-2 are deficiencies that may cause hemolytic anemia but for which a cause-and-effect relationship has not been clearly established, such as those of phosphogluconolactonase,19 enolase,20 glutathione-S-transferase,21 and adenylate kinase.22



Patients with unstable hemoglobins (see Chap. 48) may present with the clinical picture of hereditary nonspherocytic hemolytic anemia. Hemolytic anemia due to abnormalities in the lipid composition of the red cell membrane, particularly increased phosphatidyl choline, occur rarely23,24,25 and 26 (see Chapter 44).
The life span of G-6-PD-deficient red cells is shortened under many circumstances, particularly during drug administration and infection. The exact reason for this is not known.
Drug-induced Hemolysis Drug-induced hemolysis in G-6-PD-deficient cells is generally accompanied by the formation of Heinz bodies, particles of denatured hemoglobin and stromal protein (see Chap. 22) formed only in the presence of oxygen.27 The mechanism by which Heinz bodies are formed and become attached to red cell stroma has been the subject of considerable investigation and speculation. Exposure of red cells to certain drugs results in the formation of low levels of hydrogen peroxide as the drug interacts with hemoglobin.28 In addition, some drugs may form free radicals that oxidize GSH without the formation of peroxide as an intermediate.29 The formation of free radicals of GSH through the action of peroxide or by the direct action of drugs may be followed either by oxidation of GSH to the disulfide form (GSSG) or complexing of the glutathione with hemoglobin to form a mixed disulfide. Such mixed disulfides are believed to form initially with the sulfhydryl group of the b-93 position of hemoglobin.30 The mixed disulfide of GSH and hemoglobin is probably unstable and undergoes conformational changes exposing interior sulfhydryl groups to oxidation and mixed disulfide formation. Globin chain separation into free a and b chains also occurs.31 Phenylhydrazine-like drugs also have been shown to form a hemochromogen directly with hemoglobin, a complex forming between the iron of ferriheme and the nitrogen bound to the benzene ring of the drug.32 Once such oxidation has occurred, hemoglobin is denatured irreversibly and will precipitate as Heinz bodies. Normal red cells can defend themselves to a considerable extent against such changes by reducing GSSG to GSH and by reducing the mixed disulfides of GSH and hemoglobin through the glutathione reductase reaction.33 However, the reduction of these disulfide bonds requires a source of NADPH. Since G-6-PD-deficient red cells are unable to reduce NADP+ to NADPH at a normal rate, they are unable to reduce hydrogen peroxide or the mixed disulfides of hemoglobin and GSH. Moreover, because catalase apparently contains tightly bound NADPH34 that is required for activity, the lack of NADPH generation may impede an alternate pathway for the disposal of hydrogen peroxide.35 When such cells are challenged by drugs they form Heinz bodies more readily than do normal cells. Cells containing Heinz bodies encounter difficulty in traversing the splenic pulp36 and are eliminated relatively rapidly from the circulation. The metabolic events that may lead to red cell damage and eventually destruction are summarized in Fig. 45-1.

FIGURE 45-1 Reactions through which hydrogen peroxide is generated and detoxified in the erythrocyte. In G-6-PD deficiency inadequate generation of NADPH results in accumulation of GSSG and probably of H2O2. The accumulation of these substances leads to hemoglobin denaturation, Heinz body formation, and consequently to decreased red cell survival. GR, glutathione reductase; GSH Px, glutathione peroxide; Sup Dismut, superoxide dismutase; GSSG, glutathione disulfide (oxidized glutathione).

The formation of methemoglobin frequently accompanies the administration of drugs that have the capacity to produce hemolysis of G-6-PD-deficient cells.37 The heme groups of methemoglobin become detached from the globin more readily than do the heme groups of oxyhemoglobin.38 It is not clear whether methemoglobin formation plays an important role in the oxidative degradation of hemoglobin to Heinz bodies or whether formation of methemoglobin is merely an incidental side effect of oxidative drugs.39,40
Infection-induced Hemolysis The mechanism of hemolysis induced by infection or occurring spontaneously in G-6-PD-deficient subjects is not well understood. It has been suggested that the generation of hydrogen peroxide by phagocytizing leukocytes may play a role in this type of hemolytic reaction.40 Substances capable of destroying red cell GSH have been isolated from fava beans.41 Favism occurs only in G-6-PD-deficient subjects, but not all deficient individuals in a particular family may be sensitive to the hemolytic effect of the beans. Nonetheless, some tendency toward familial occurrence has suggested the possibility that an additional, genetic factor may be important.42 The observation of increased excretion of glucaric acid43 led to the suggestion that a defect in glucuronide formation might be present. An excess of individuals with the acid phophatase ACP1 A/C genotype has been found and attributed to a decrease in the f isoform of this tyrosine phosphatase.44 Immunologic factors do not seem to play a role in favism.45 Increased levels of red cell calcium46,47 and consequent “cross-bonding” of membranes may occur. Such bonding of the facing inner membrane surfaces48 may play a role in the destruction of red cells.
Neonatal Jaundice Icterus neonatorum in G-6-PD deficiency probably is due principally to inadequate processing of bilirubin by the immature liver of G-6-PD-deficient infants, although shortening of red cell life span may play a role. Anemia does not appear to be present in these infants and there is only a slight increase in CO production, signifying a minimal decrease in red cell life span.49 Severe jaundice due to G-6-PD deficiency seems to be limited to infants who have also inherited a mutation of the uridine diphosphoglucuronate glucuronosyltransferase 1 (UDPGT-1) gene promoter,50 the same mutation that in adults is associated with Gilbert syndrome. The limited data available on liver G-6-PD in deficient adults51 suggest that a considerable degree of deficiency may be present. If such a deficiency also is present in infants, it may play a role in impairing the borderline ability of infant livers with the UDPGT-1 promoter defect to catabolize bilirubin. While an increased incidence of neonatal icterus has been observed in Mediterranean infants with G-6-PD deficiency and among the Chinese,52 jaundice seems to be less common among neonates with the A– type of enzyme deficiency. Some cases have been reported in G-6-PD-deficient infants53,54 and 55 in Africa, but in the United States the incidence of jaundice in G-6-PD A– does not appear to be increased.56,57 The cause of the relatively low incidence of neonatal jaundice in infants with G-6-PD A– mutation is not clear. It could be due to the higher residual enzyme activity, but it does not appear to be related to the incidence of the UDPGT-1 promotor mutation, which is actually more common in Africans and less common in Asians than it is in Europeans.58
Deficiencies of g-glutamyl synthetase59,60 and of glutathione synthetase60,61 are associated with a decrease in red cell GSH levels, and the mild hemolysis that occurs in these disorders probably has a pathogenesis similar to the hemolysis that occurs in G-6-PD deficiency. The same is probably true of the single case of glutathione reductase deficiency that has been documented.18 Other defects of the hexose monophosphate and associated metabolic pathways, such as 6-phosphogluconolactone deficiency19 and 6-phosphogluconate dehydrogenase deficiency62 are not associated with hemolysis.
How deficiencies of enzymes other than those of the hexose monophosphate pathway result in shortening of red cell life span remains unknown, although it has been the object of much experimental work and of speculation. It is often believed that ATP depletion is a common pathway in producing damage to the cell leading to its destruction,63 but the evidence that this is the case is not always compelling.64 It is possible that, at least in some cases, alteration of the levels of red cell intermediate metabolites interferes with synthesis of cell components in early stages of development of the cell.
G-6-PD deficiency has been encountered in rats,65 dogs,66 mice,67,68 and horses.69,70 Pyruvate kinase deficiency is polymorphic in Basenji dogs71 and has been found in mice.72,73 and 74 Phosphofructokinase deficiency causes hemolytic anemia in dogs,75 and glucosephosphate isomerase deficiency has been detected in mice.76
The “normal” enzyme is designated as G-6-PD B. It represents the most common type of enzyme encountered in all the population groups that have been studied. Many variants of G-6-PD have been detected all over the world. Before it became possible to characterize these variants at the DNA level they were distinguished from each other on the basis of biochemical characteristics, such as electrophoretic mobility, Km for NADP and glucose-6-phosphate, ability to utilize substrate analogs, pH activity profile, and thermal stability. To facilitate comparison of variants characterized in different laboratories, international standards for the methodology were established.77 In the case of the common G-6-PD A– and G-6-PD Mediterranean mutations, the abnormal enzyme may be synthesized at normal or near-normal rates but has decreased stability in vivo.78 The amount of enzyme antigen in the red cells declines concurrently with enzyme activity.79,80 This suggests that the mutant protein in these variants is rendered unusually sensitive to proteolysis in the environment of the erythrocyte.81 Other mutations also result in the formation of enzyme molecules with decreased enzyme activity80 and with altered kinetic properties,82 some of which may render them functionally inadequate. For example, G-6-PD Oklahoma83 manifests a marked decrease in its affinity for the substrates glucose-6-phosphate and NADP, and G-6-PD Manchester and G-6-PD Tripler84 are abnormally sensitive to the inhibitory effect of NADPH. Detailed biochemical characteristics of some 400 putatively distinct G-6-PD variants have been tabulated.85 Fig. 45-2 is a semischematic representation of the biochemical properties of two of the more common variants.

FIGURE 45-2 The biochemical properties of two common variants of G-6-PD. (a) The biochemical characteristics of G-6-PD A–. (b) The biochemical characteristics of G-6-PD Mediterranean. In each panel the characteristics of the normal enzyme (types A and B) are indicated by the shaded areas.

Molecular Biology The gene for G-6-PD is over 20 kb in length, containing 13 exons. The coding sequence begins in exon 2. The intron between exons 2 and 3 is extraordinarily long, spanning 9857 base pairs.86 Methylation of certain cytidines at the 3′ end is believed to have a regulatory function.87 The enzyme is composed of 515 amino acids, with a calculated molecular weight of 59,256. Aggregation of the inactive monomers into catalytically active dimers and higher forms requires the presence of NADP.88 Thus, NADP appears to be bound to the enzyme both as a structural component and as one of the substrates of the reaction.89,90 and 91 The glucose-6-phosphate binding site has been identified at amino acid 205 by locating a lysine that is reactive in competition with glucose-6-phosphate at this position.92,93 Examination of mutants suggested that amino acids 386 and 387 bind one of the phosphates of NADP.94 However, the crystal structure of G-6-PD from Leuconostoc mesenteroides95 is interpreted as indicating that it is actually His 201 that is the binding site, a location 36 A° distant from the 386–387 site.95
African Variants Among persons of African descent a mutant enzyme with normal activity is very prevalent. Known as G-6-PD A+, it migrates electrophoretically more rapidly than the normal B enzyme. A single amino acid substitution of Asn®Asp has been identified both by peptide analysis96 and by DNA sequencing (376 A®G).97 G-6-PD A– is the principal deficient variant found among people of African origin. The red cells contain only 5 to 15 percent of the normal amount of enzyme activity. The mobility of the enzyme present is rapid and is indistinguishable from that of the A+ variant in conventional electrophoretic systems. The fact that these two electrophoretically rapid variants are common in African populations is not a coincidence. Sequence analysis of G-6-PD A+ and G-6-PD A– has shown that these two mutations have in common a nucleotide substitution at cDNA nucleotide 376 that produces the amino acid substitution responsible for the rapid electrophoretic mobility. Most samples with G-6-PD A– manifest an additional mutation at nucleotide 202 that accounts for its in vivo instability.98 Apparently the interaction of the two mutations results in the deficiency.99 Less commonly, the additional mutation is at a different site (Table 45-3). Thus, it is evident that G-6-PD A– arose in an individual who already had the G-6-PD A+ mutation. However the ancestral human sequence has been deduced to be that of G-6-PD B, both by showing that this is the sequence of the chimpanzee,100 our nearest relative, and by analysis of linkage dysequilibrium.101


Variants in the Mediterranean Region Among Caucasian populations G-6-PD deficiency is most common in Mediterranean countries. The most common enzyme variant in this region is G-6-PD Mediterranean.82 The enzyme activity of the red cells of individuals who have inherited this abnormal gene is barely detectable. Other variants are also prevalent in the Mediterranean region, including G-6-PD A– and G-6-PD Seattle (see Table 45-3).
Variants in Asia A great many different variants have been described in East Asian populations. Some of these proved to be identical at a molecular level (e.g., G-6-PD Gifu, Agrigento, Canton, and Taiwan-Hakka all have the same mutation at cDNA nt 1376), but DNA analysis has shown that over 10 different mutations are found in various East Asian populations.102,103,104 and 105
Variants Producing Hereditary Nonspherocytic Hemolytic Anemia Some mutations of G-6-PD result in chronic hemolysis without precipitating causes. From a functional point of view these mutations are more severe than the more commonly occurring polymorphic forms of the enzyme, such as G-6-PD Mediterranean and G-6-PD A–, but the in vitro enzyme activity may actually be greater in such variants. It has been suggested that specific biochemical characteristics such as susceptibility to inhibition by NADPH might explain the chronic hemolysis that occurs in patients with such variants,84 but no unifying principle that accounts for the clinical effects of variants has been found. On a molecular level, such variants usually are located in exon 1094 or in the region of the glucose-6-phosphate binding site.106 There are, however, exceptions to this rule. For example, deletion of a triplet near the 5′ end of the coding region107 and a mutation very near the carboxy terminus of the enzyme also have been found to result in hemolysis.108
Pyruvate kinase deficiency, like G-6-PD deficiency, is genetically heterogeneous, with different mutations causing different kinetic and electrophoretic changes in the enzyme that is formed. Abnormalities include altered affinity for the substrate phosphoenolpyruvate (PEP) and the allosteric activator fructose 1,6-diphosphate (FDP).109,110,111 There are even cases in which the activity of pyruvate kinase as measured in vitro is higher than normal but a kinetically abnormal enzyme is responsible for the occurrence of hemolytic anemia.112 Kinetic characterization and analysis of pyruvate kinase mutants is considerably more complex, however, than analysis of G-6-PD mutants. Since two alleles are expressed in each cell, five different tetramers will be formed if the mutations are different: the two homotetramers and mixed tetramers containing different proportions of different subunits. Moreover, there are several different molecular forms of pyruvate kinase, formed from two different genes: the M, or muscle, type of enzyme, which is found in leukocytes and many other tissues, and the L, or liver, type of enzyme. Erythrocytes contain only a product of the L gene, designated the R type of enzyme. Thus, it is mutations of the pyruvate kinase L gene that cause hemolytic anemia. There has been international agreement on standard methods for characterizing pyruvate kinase variants,113 but because of the complexities mentioned above, the biochemical information is even less robust than that obtained with G-6-PD variants. It has been suggested that some correlation exists between the quantity and biochemical characteristics of the residual enzyme in enzyme-deficient patients and these patients’ clinical course.114
The cDNA for human L type pyruvate kinase has been cloned,115,116 and mutations identified in many deficient patients (Table 45-4).117,118 The same mutations are encountered repeatedly in apparently unrelated individuals, although the existence of a common haplotype in such persons indicates that they are presumably offspring of a common ancestor.119,120 The 1529A mutation in particular is encountered repeatedly, even in the homozygous state, in unrelated individuals.121 Deletion of exon 11 is characteristic of the mutation found among Gypsies.119 The nature of the mutation has relatively little predictive value with respect to the severity of the clinical course.120,122


The mutations that cause other enzyme deficiencies have been identified in many instances. Table 45-2 provides references to some of the more recent studies in which the abnormalities in DNA sequence have been documented.
The prevalence of G-6-PD deficiency among Caucasian populations ranges from less than 1 in 1000 among northern European populations to 50 percent of the males among Kurdish Jews. G-6-PD deficiency is also found among certain Chinese populations and in Southeast Asia but it is rare in Japan. G-6-PD deficiency of the A– type is very common in West Africa, and the prevalence among African American males is approximately 11 percent.123 Some 16 percent of African American males carry the nondeficient G-6-PD A+ gene. The distribution of G-6-PD deficiency among various population groups has been presented in detail elsewhere.124,125
The high frequency of G-6-PD-deficient genes in many populations implies that G-6-PD deficiency confers a selective advantage. The suggestion126 that resistance to malaria could account for the frequency of G-6-PD deficiency was supported by studies in heterozygotes for G-6-PD A– that showed a higher degree of infestation of G-6-PD sufficient cells than of G-6-PD-deficient cells.127 It has been suggested that deficient cells infested with malaria parasites may be phagocytosed more efficiently than normal cells.128
It has been suggested129,130 that a higher prevalence of G-6-PD deficiency in individuals with sickle cell disease than in the general African population reflects a favorable effect of the enzyme deficiency on the clinical course of the sickling disorders. However, it seems that the increased prevalence of G-6-PD deficiency in patients with sickle disease may merely result from the markedly heterogeneous genetic composition of African Americans; those with more African genes are more likely to inherit sickle hemoglobin and G-6-PD A–.131,132 and 133 Similar factors may be responsible for the slight excess of G-6-PD deficiency observed among patients with SS hemoglobin in Arab populations.134
Pyruvate kinase deficiency is the most common cause of hereditary nonspherocytic hemolytic anemia. Estimates of heterozygote frequency have ranged from 0.24135 to 3.1 percent136 using screening techniques. More quantitative studies performed on a large number of cord blood samples have provided estimates of 1 percent in the white population and 2.4 percent in African Americans.137 A gene frequency of about 0.005 has been deduced from study of a large number of DNA samples from subjects of the European origin. Estimates of other deficiency alleles, such as those for adenylate kinase, diphosphoglycerate mutase, enolase, triosephosphate isomerase, and phosphoglycerate kinase have also been made on large numbers of cord bloods.137 A particularly high incidence of heterozygous TPI deficiency of over 4 percent in African Americans is supported by family studies.138 Since it is not reflected in a correspondingly high birth incidence, the allele might be lethal in the homozygous state. It was suggested that a promoter mutation at the -5 and -8 positions created such a lethal gene,139 but the finding of normal adult homozygotes for these mutations shows that this is not the case.140
In addition to the common G-6-PD mutations there are mutations in other enzymes that are repeatedly encountered in a population. Included are the 1529A mutation of pyruvate kinase,120,121 the deletion of exon 11 found among Gypsies,119 and the 1591 C mutation of TPI.141 In each of these instances the existence of each mutation in the context of the same haplotype implies that there has been a founder effect, that is, the mutation occurred only once and all individuals now carrying it are descendants of the person who sustained the original mutation. The expansion of the mutation could represent a selective advantage for heterozygotes but may also be due to random factors or to a selective advantage provided by one or more tightly linked genes.
Individuals who inherit the common (polymorphic) forms of G-6-PD deficiency, such as G-6-PD A– or G-6-PD Mediterranean usually have no clinical manifestations. The major clinical consequence of G-6-PD deficiency is hemolytic anemia in adults and neonatal icterus in infants. Usually the anemia is episodic, but some of the unusual variants of G-6-PD may cause hereditary nonspherocytic hemolytic disease (see below). In general, hemolysis is associated with stress, most notably drug administration, infection, and, in certain individuals, exposure to fava beans.
A large number of drugs and other chemicals that may have the capacity to precipitate hemolytic reactions in G-6-PD-deficient individuals are listed in Table 45-5. Some drugs, such as chloramphenicol, may induce mild hemolysis in a person with severe, Mediterranean-type G-6-PD deficiency142 but not in those with the milder A– or Canton143 types of deficiency. Drugs that are innocuous when given in normal doses (Table 45-5) may be hemolytic when given in excessive doses. A case in point is ascorbic acid, which does not cause hemolytic anemia when even as much as 40 g is given intravenously,144 but which can produce severe, even fatal, hemolysis at doses of 80 g or more intravenously.144,145 and 146 There appears, furthermore, to be a difference in the severity of the reaction to the same drug of different individuals with the same G-6-PD variant. For example, red cells from a single G-6-PD-deficient individual were hemolyzed in the circulation of some recipients who were given thiazolsulfone, but their survival was normal in the circulation of others.27 Sulfamethoxazole, which was clearly hemolytic in experimental studies, does not appear to be a common cause of hemolysis in a clinical setting.147 Undoubtedly, individual differences in the metabolism and excretion of drugs influence the extent to which G-6-PD-deficient red cells are destroyed.148,149


Typically, an episode of drug-induced hemolysis in G-6-PD-deficient individuals begins 1 to 3 days after drug administration is initiated.150 Heinz bodies appear in the red cells, and the hemoglobin concentration begins to decline rapidly.151 As hemolysis progresses Heinz bodies disappear from the circulation, presumably as they or the erythrocytes that contain them are removed by the spleen. In severe cases abdominal or back pain may occur. The urine may turn dark—even black. Within 4 to 6 days there is generally an increase in the reticulocyte count, except in instances in which the patient has received the offending drug in treatment of an active infection. Because of the tendency of infections and certain other stressful situations to precipitate hemolysis in G-6-PD-deficient individuals, many drugs have been incorrectly implicated as a cause. Other drugs, such as aspirin, have appeared on many lists of proscribed medications because very large doses could slightly reduce the red cell life span. It is important to recognize that such drugs, listed in Table 45-6, do not produce clinically significant hemolytic anemia. Advising patients not to ingest these drugs may not only deprive patients of potentially helpful medications but will also weaken their confidence in the advice that they have received. Most G-6-PD-deficient patients, after all, have taken aspirin without untoward effect and are likely to distrust an advisor who counsels them that the ingestion of aspirin would have catastrophic effects.


In the A– type of G-6-PD deficiency the hemolytic anemia is self-limited150 because the young red cells produced in response to hemolysis have nearly normal G-6-PD levels and are relatively resistant to hemolysis.152 The hemoglobin level may return to normal even while the same dose of drug that initially precipitated hemolysis is administered. In contrast, hemolysis is not self-limited in the more severe Mediterranean type of deficiency.153
Anemia often develops rather suddenly in G-6-PD-deficient individuals within a few days of onset of a febrile illness. The anemia is usually relatively mild, with a decline in the hemoglobin concentration of 3 or 4 g/dl. Hemolysis has been noted particularly in patients suffering from pneumonia and in those with typhoid fever. The fulminating form of the disease occurs particularly frequently among G-6-PD-deficient patients who are infected with Rocky Mountain spotted fever.154 Jaundice is not a prominent part of the clinical picture, except where hemolysis occurs in association with infectious hepatitis.155,156 In that case it can be quite intense. Presumably because of the effect of the infection reticulocytosis is usually absent, and recovery from the anemia is generally delayed until after the active infection has abated.
Diabetic ketoacidosis has usually been considered a cause of hemolysis in G-6-PD-deficient individuals, but a review of 36 episodes of diabetic ketoacidosis in G-6-PD-deficient subjects yielded only 10 in whom hemolysis occurred, and these all were associated with infection or drug ingestion.157 It has been suggested that hypoglycemia may precipitate hemolysis.158
Favism is potentially one of the gravest clinical consequences of G-6-PD deficiency. It occurs much more commonly in children than in adults and occurs almost exclusively in persons who have inherited variants of G-6-PD that cause severe deficiency, but rarely the disorder has been noted in patients with G-6-PD A–.159 The onset of hemolysis may be quite sudden, having been reported to occur within the first hours after exposure to fava beans. More commonly the onset is gradual, hemolysis being noticed 1 to 2 days after ingestion of the beans.160 The urine becomes red or quite dark, and in severe cases shock may develop within a short time. Occasionally ingestion of other foodstuffs, such as unripe peaches161 or a spiced Nigerian barbecued meat known as red suya,162 has been reported to precipitate hemolysis.
Icterus neonatorum without evidence of immunologic incompatibility occurs in some infants with G-6-PD deficiency.163 The jaundice may be quite severe and if untreated may result in kernicterus. Thus, G-6-PD deficiency is a preventable cause of mental retardation,164,165 and this aspect of the disorder has considerable public health significance.
In the common variants of G-6-PD such as G-6-PD A– and G-6-PD Mediterranean, and even in most of the severely deficient variants, there is usually no demonstrated defect in leukocyte number or function.166 However, there have been reports of isolated instances of leukocyte dysfunction associated with rare, severely deficient variants of G-6-PD.167,168 and 169 Patients with G-6-PD deficiency do not have a bleeding tendency, and studies of platelet function have yielded conflicting results.170,171 Occasionally, cataracts have been observed in patients with variants of G-6-PD that produce nonspherocytic hemolytic anemia.172,173 and 174 The incidence of senile cataracts may be increased in G-6-PD deficiency,175,176 but this remains controversial.177 Although claims have been made that an association exists between various kinds of G-6-PD deficiency and cancer178,179 the data are not convincing, and a detailed investigation of hematologic malignancies in patients with G-6-PD Mediterranean shows no effect.180 Decrease in insulin release181 and in cortisol levels after ACTH stimulation182 have been reported to occur in G-6-PD-deficient men.
Most patients with hereditary nonspherocytic hemolytic anemia manifest only the usual clinical signs and symptoms of chronic hemolysis. The degree of anemia in this group of disorders varies widely. In some cases of very severe pyruvate kinase deficiency scarcely any deficient cells survive in the circulation and only transfused cells are found, or steady-state hemoglobin levels as low as 5 g/dl may be encountered. Other patients with hereditary nonspherocytic hemolytic anemia may manifest compensated hemolysis with a normal steady-state hemoglobin concentration. Chronic jaundice is a common finding and splenomegaly is often present. Gallstones are common. As in other forms of chronic hemolytic anemia, ankle ulcers may be present.183,184 Pregnancy has been thought to precipitate hemolysis in patients with pyruvate kinase deficiency, perhaps even in heterozygotes.185,186
In the case of some enzyme defects, characteristic nonhematologic systemic manifestations may be present, and these may be the only sign of the enzyme deficiency. For example, patients with phosphofructokinase deficiency may have type VII muscle glycogen storage disease. In some with this defect hemolysis is present without muscle manifestations, but in others both muscle abnormalities and hemolysis occur.187 Glutathione synthetase deficiency may be associated with 5-oxoprolinuria and neuromuscular disturbances, and such abnormalities may occur either with188 or without17 hematologic abnormalities. On the other hand, some patients with glutathione synthetase deficiency manifest only the hematologic abnormalities.60 Spinocerebellar degeneration was documented in the first case of g-glutamylcysteine synthetase described189,190 but was not present in subsequently investigated patients.60,191 Patients with TPI deficiency nearly always manifest serious neuromuscular disease, and most of the patients who inherit this abnormality die in the first decade of life192,193 and 194 but there are exceptions, since only one of two brothers with the same genotype manifested neurologic disease.195,196 Neurologic symptoms have also been noted in a patient with glucosephosphate isomerase deficiency.197 This enzyme seems to be identical to neuroleukin, which could explain the existence of neurologic manifestations. Myoglobinuria has been encountered in patients with phosphoglycerate kinase,16,198 aldolase,199 and G-6-PD deficiency.200 The clinical features of enzyme deficiencies causing nonspherocytic hemolytic anemia are summarized in Table 45-1.
In the absence of hemolysis, the light-microscopic morphology of G-6-PD-deficient red cells appears to be normal. Differences in the texture of the stroma of the cells have, however, been observed under the electron microscope.201
Varying degrees of anemia and reticulocytosis are the main routine hematologic laboratory features of patients with hereditary nonspherocytic hemolytic anemia. Heinz bodies often are found in the erythrocytes of G-6-PD-deficient patients undergoing drug-induced hemolysis and in splenectomized but not in unsplenectomized patients with unstable hemoglobins. When a hemolytic drug is administered to a G-6-PD-deficient patient, Heinz bodies (see Chap. 22) develop in the erythrocytes immediately preceding and in the early phases of the hemolytic episode. If the hemolytic anemia is very severe, spherocytosis and red cell fragmentation may be seen in the stained film. Although “bite cells” have been noted in the blood of a G-6-PD-deficient patient undergoing drug-induced hemolysis,202 such cells have also been noted in nondeficient patients.203,204
The presence of small, densely staining cells has often been noted in the blood films of patients with hereditary nonspherocytic hemolytic anemia with defects other than G-6-PD deficiency. Particularly when manifesting an echinocytic appearance, such cells have been thought to be common in pyruvate kinase deficiency. In one reported case205 spectacular numbers of such cells were observed. However, cells of this type are seen in many blood films both from patients with glycolytic enzyme deficiencies and from those with other disorders, and it is hazardous to attempt to make an enzymatic diagnosis on the basis of such findings. Basophilic stippling of the erythrocytes is prominent in most patients with pyrimidine-5′-nucleotidase deficiency but may not be apparent in blood that has been collected in EDTA anticoagulant. Leukopenia occasionally is observed in patients with hereditary nonspherocytic hemolytic anemia, possibly secondary to splenic enlargement. Other laboratory stigmata of increased hemolysis may include increased levels of serum bilirubin, decreased haptoglobin levels, and increased serum lactic dehydrogenase activity.
Diagnosis of red cell enzyme deficiencies depends on the demonstration of decreased enzyme activity through either a quantitative assay or a screening test.113,206,207 and 208 Assay of most of the enzymes generally is carried out by measuring the rate of reduction or oxidation of nicotinamide adenine nucleotides in an ultraviolet spectrophotometer, and a number of screening tests that depend upon the development or loss of fluorescence have been devised.206
Although detection of G-6-PD deficiency in the healthy, fully affected (hemizygous) male can be achieved readily through either assay or screening tests, difficulties arise when a patient with G-6-PD deficiency of the A– type has undergone a hemolytic episode. As the older, more enzyme-deficient cells are removed from the circulation and are replaced by young cells, the level of the enzyme begins to increase toward normal. Under such circumstances, suspicion that the patient may be G-6-PD deficient should be raised by the fact that enzyme activity is not increased even though the reticulocyte count is elevated. Centrifugation of the blood followed by testing of the most dense, reticulocyte-depleted red cells has been employed as a means for the detection of G-6-PD deficiency in persons with the A– defect who have recently undergone hemolysis.209,210 It is helpful to carry out family studies or to wait until the circulating red cells have aged sufficiently to betray their lack of enzyme.
Even greater difficulties are encountered in attempting to diagnose heterozygotes for G-6-PD deficiency.211 Because the gene is X-linked, a population of normal red cells coexists with the deficient cells (see Chap. 9). This may mask the enzyme deficiency when screening tests are used. Even enzyme assays carried out on erythrocytes of heterozygous females frequently may be in the normal range. Here methods that depend upon histochemical demonstration of individual red cell enzyme activity may be useful.212,213 In addition, the ascorbate-cyanide test,214 in which screening is carried out on a whole-cell population rather than on a lysate, may be more sensitive than the other screening procedures. However, when the nucleotide substitution is known, heterozygotes are easily detected by PCR-based analysis of the mutation.215 Prenatal diagnosis of G-6-PD deficiency is also possible using this approach.216
Identifying specific G-6-PD variants on the basis of biochemical variations requires the use of relatively sophisticated techniques. The enzyme must be partially purified, and then its Km for NADP+ and glucose-6-phosphate, its utilization of substrate analogs, its pH optima, and its electrophoretic mobility must be determined in standard systems.77 At best there is often uncertainty regarding minor differences in the characteristics of enzymes studied in this way. Detailed biochemical characterization of G-6-PD variants has therefore largely been replaced by PCR-based DNA analysis.217,218
Drug-induced hemolytic anemia due to G-6-PD deficiency is similar in its clinical features and in certain laboratory features to drug-induced hemolytic anemia associated with unstable hemoglobins (see Chap. 48). Other enzyme defects affecting the pentose-phosphate shunt, such as a deficiency of GSH synthetase, also may mimic G-6-PD deficiency. The diagnosis of hemoglobinopathies can be excluded by performing a hemoglobin stability test and electrophoresis. Both of these are normal in G-6-PD deficiency. Some of the screening tests, particularly the ascorbate-cyanide test,214 may give positive results in the above-named disorders, but a G-6-PD assay or the fluorescent screening test will be positive only in G-6-PD deficiency.
Physicians often attempt to establish the cause of hereditary nonspherocytic hemolytic anemia on the basis of the appearance of red cells on a blood film and the results of the autohemolysis test. In reality, red cell morphology is helpful only in the diagnosis of pyrimidine-5′-nucleotidase deficiency, because of the characteristic stippling of the red cells that is observed in that disorder. After splenectomy, the appearance of Heinz bodies suggests the possible presence of an unstable hemoglobin. Autohemolysis tests provide no diagnostic information of value, except occasionally in the confirmation of the presence of hereditary spherocytosis.219
Since the laboratory diagnosis of these disorders may entail considerable expenditure of time and effort, it is prudent to perform the simplest tests for the most common causes of hereditary nonspherocytic hemolytic anemia first. Accordingly, it is useful to carry out screening tests206,207 for G-6-PD and PK activity and an isopropanol stability test220 to detect an unstable hemoglobin. The characteristically elevated levels of red cell 2,3-bisphosphoglycerate and of 3-phosphoglyceric acid221 are also helpful in the diagnosis of PK deficiency. If the levels of these intermediates are normal it is extremely unlikely that the patient has PK deficiency. If prominent stippling of erythrocytes is present, examination of the ultraviolet spectrum of a perchloric acid extract of the erythrocytes may help to establish the diagnosis of pyrimidine-5′-nucleotidase deficiency.222 Beyond these relatively simple procedures it is probably rarely profitable to pick and choose individual enzyme assays on the basis of family history or clinical manifestations. Rather, it is usually appropriate to submit a blood sample to a reference laboratory that has the capability of performing all the enzyme assays listed in Table 45-1. Prenatal diagnosis of some of the defects causing hereditary nonspherocytic hemolytic anemia has been achieved,223 but diagnosis of pyruvate kinase deficiency in the unborn has not yet been achieved.
The estimation of the red cell membrane lipid composition and the study of membrane proteins usually are carried out only in research laboratories.
G-6-PD-deficient individuals should avoid drugs that might induce hemolytic episodes (see Table 45-5). However, it is important to realize that such patients are able to tolerate most drugs. Unfortunately, in the 1950s and 1960s a number of case reports incorrectly suggested that some drugs had hemolytic potential that subsequently were shown to be safe. Table 45-6 lists such drugs. While it is possible that some of these may be hemolytic in some patients or under some circumstances, this is unlikely, and G-6-PD-deficient patients should not be deprived of the possible benefit of these drugs.
If hemolysis occurs as a result of drug ingestion or infection, particularly in the milder A– type of deficiency, transfusion usually is not required. If, however, the rate of hemolysis is very rapid, as may occur for example in favism, transfusions of whole blood or packed cells may be useful. Good urine flow should be maintained in patients with hemoglobinuria to avert renal damage. Infants with neonatal jaundice due to G-6-PD deficiency may require exchange transfusion; in areas in which G-6-PD deficiency is prevalent, care must be taken not to give G-6-PD-deficient blood to such newborns.224
Patients with hereditary nonspherocytic hemolytic anemia due to G-6-PD deficiency usually do not require any therapy. Splenectomy is generally ineffective, although some improvement occasionally has been reported12 following removal of the spleen. In most cases the anemia is not very severe, but in some instances frequent transfusions have been necessary.225 The anti-oxidant properties of vitamin E have been tested in G-6-PD-deficient subjects, and a slight but statistically significant reduction in hemolysis was observed.226,227 These results could not be confirmed in other studies.228,229 It has been suggested that desferrioxamine decreases hemolysis.230,231
The principal decision that the physician must make regarding patients with hereditary nonspherocytic hemolytic anemia is whether or not they require a splenectomy. This decision is not made easily, since the response is not predictable and some patients who fail to respond may develop serious thrombotic complications. The recommendation that is made should be based upon the following considerations: (1) severity of the disease; (2) family history of response to splenectomy; (3) the underlying defect; and (4) the need for cholecystectomy. Since it is unusual to obtain more than a partial response to splenectomy, this procedure should probably be reserved for patients whose quality of life is impaired by their anemia. The operation needs to be particularly considered for patients who need frequent transfusion and for those who require gallbladder surgery, in which splenectomy might be carried out as part of the same procedure. The best guide to the likely efficacy of splenectomy is probably the response to splenectomy of other affected family members. Unfortunately, such information is only occasionally available. The physician must therefore rely upon the experience of other patients with hereditary nonspherocytic hemolytic anemia of similar etiology to serve as a guide. However, even as the large group of patients with hereditary nonspherocytic hemolytic anemia represents a heterogeneous population, so individuals with a single enzymatic lesion, such as pyruvate kinase deficiency, are heterogeneous. Each family is likely to be afflicted with a distinct mutant enzyme, and the various mutants may differ both with respect to clinical manifestations and with respect to response to splenectomy. Some of the available information regarding response to splenectomy of patients with hereditary nonspherocytic hemolytic anemia has been reviewed12 and is summarized in Table 45-1. Relatively little is known of the response of patients with unstable hemoglobins to splenectomy (see Chap. 48).
Glucocorticoids are of no known value in this group of disorders. Folic acid is often given, as in other patients with increased bone marrow activity, but without proven hematologic benefit. In the absence of iron deficiency, iron is contraindicated. Iron overload is not a frequent complication in this group of disorders but has been reported to occur, particularly in connection with pyruvate kinase deficiency.232
Hemolytic episodes in the A– type of deficiency are usually self-limited, even if drug administration is continued. This is not the case in the more severe Mediterranean type of deficiency. In patients with hereditary nonspherocytic hemolytic anemia due to G-6-PD deficiency, gallstones may occur, and the incidence of cholelithiasis may be increased even in patients with polymorphic forms of G-6-PD deficiency in Sardinia.233 During periods of infections or drug administration, anemia may increase in severity. Otherwise, the hemoglobin level of affected subjects remains relatively stable.
Nearly all patients with drug- or infection-induced hemolysis recover uneventfully. Favism must be considered, by comparison, a relatively dangerous disease. Prior to the institution of modern hospital therapy, fatalities from favism were not uncommon.
In one large population study, a decreasing incidence of G-6-PD deficiency was noted with increasing age of the population,234 but no such change was observed in another.133 While age stratification might represent evidence of a shorter life span for individuals with the A– deficiency, other factors are more likely explanations. Examination of the health records of over 65,000 U.S. Veterans Administration males failed to reveal any higher frequency of any illness in G-6-PD-deficient compared to nondeficient subjects.123 In view of the benign nature of the common types of G-6-PD deficiency, community-based population screening is not recommended. However, screening for G-6-PD deficiency of all patients admitted to the hospital may be useful in anticipating hemolytic reactions and in understanding them if they occur. This is particularly prudent if a drug such as dapsone, known to cause hemolysis in G-6-PD-deficient individuals, is to be given. Study of family members of patients with this X-linked enzyme deficiency can be helpful in providing appropriate counseling to affected individuals.
The diagnosis of hereditary nonspherocytic hemolytic anemia has been made as late as the seventh decade,13 and the disease can be fatal in the first few years of life. Triosephosphate isomerase deficiency appears to have the worst prognosis of all of the known defects that cause this disorder. With few exceptions, patients with this deficiency have died by the fifth or sixth year of life, usually of cardiopulmonary failure. Pyruvate kinase deficiency, too, can be fatal in early childhood; the gene prevalent among the Amish of Pennsylvania produces particularly severe disease.235 Unless the affected homozygous children have their spleens removed, the disorder is commonly lethal. In general, however, hereditary nonspherocytic hemolytic anemia is a relatively mild disease and most affected individuals lead a relatively normal life, apparently without much compromise of life span.

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Copyright © 2001 McGraw-Hill
Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn
Williams Hematology




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