Page 734 - Williams Hematology ( PDFDrive )

708 Part VI: The Erythrocyte Chapter 47: Erythrocyte Enzyme Disorders 709

active infection has abated. In rare cases, G6PD deficiency may present that produce nonspherocytic hemolytic anemia, 525–527 or in neonatal
as transient aplastic crisis caused by viral infection. 503,504 patients. The incidence of senile cataracts may be increased in G6PD
528
deficiency, 529,530 but this remains controversial. 531,532 Small studies from
Favism the Middle East are suggestive that decreased G6PD activity may pre-
Favism is potentially one of the gravest clinical consequences of G6PD dispose to the development of diabetes. 533–535
deficiency. It occurs much more commonly in children than in adults, A number of studies reported on acute rhabdomyolysis in patients
and occurs almost exclusively in persons who have inherited variants with G6PD deficiency, suggesting that this condition could predispose
541
of G6PD that cause severe deficiency (most frequently associated with to muscle damage, 535–540 probably through the depletion of NADPH.
the Mediterranean variant), but rarely has the disorder been noted in Others however, have demonstrated that G6PD-deficient individuals
patients with G6PD A–. The onset of hemolysis may be quite sud- can participate in various physical activities, even high-intensity mus-
505
542
den, having been reported to occur within the first hours after exposure cle damaging activities without a negative impact on muscle function
to fava beans. More commonly, the onset is gradual, hemolysis being and redox status. 543,544
506
noticed 1 to 2 days after ingestion of the beans. The urine becomes Although claims have been made that an association exists
red or quite dark, and in severe cases shock may develop within a short between various kinds of G6PD deficiency and cancer, 545,546 the relation-
time. Care should be taken to avoid acute renal failure. The oxidative ship between G6PD status and cancer is not clear as epidemiologic stud-
stress causes membrane changes in erythrocytes, leading to extravascu- ies have not demonstrated any difference in risk for cancers between
3
lar hemolysis (in addition to the intravascular destruction). Sometimes G6PD-deficient and normal patients. 547–549 Some role for G6PD in car-
the patient or parent does not realize that fava beans have been ingested, cinogenesis may be conceivable, though, given the finding that muta-
as they may be incorporated into foods such as Yew Dow, eaten by the tion of p53 abolishes the direct binding of this major tumor-suppressor
Chinese, or falafel, eaten in the Middle East. Occasionally ingestion of gene to G6PD, thereby enhancing hexose monophosphate shunt flux
507
508
other foodstuffs, such as unripe peaches or a spiced Nigerian barbe- and tumor cell biosynthesis. 550
cued meat known as red suya, has been reported to precipitate hemo- Population studies are needed to better elucidate the postulated
509
lysis. The toxic constituents of the fava beans are transmitted into the effects of G6PD deficiency on the development of cardiovascular
milk of breastfeeding mothers, putting affected babies at risk. 510 disease. 278,551
Neonatal Icterus ENZYME DEFICIENCIES OTHER THAN
Although serious, the clinical consequences of drug-induced hemolysis,
favism, or chronic hemolytic anemia are usually not devastating, and GLUCOSE-6-PHOSPHATE DEHYDROGENASE
death from favism is a very rare event. The most serious consequence Most patients with hereditary nonspherocytic hemolytic anemia man-
463
of G6PD deficiency is icterus neonatorum. G6PD-deficient neonates ifest only the usual clinical signs and symptoms of chronic hemolysis.
are an estimated three to four times more at risk for hyperbilirubinemia The degree of anemia in this group of disorders varies widely. In some
and phototherapy than G6PD-adequate neonates, depending on cases of very severe PK deficiency, scarcely any deficient cells survive
511
512
population groups and geographic area. Jaundice commences in the in the circulation, and only transfused cells are found or steady-state
immediate perinatal period, and is usually evident by 1 to 4 days of age, hemoglobin levels as low as 5 g/dL are encountered. Other patients with
similar to physiologic jaundice, but is seen at a later time than in blood hereditary nonspherocytic hemolytic anemia may manifest compen-
group alloimmunization. The jaundice may be quite severe and, if sated hemolysis with a normal steady-state hemoglobin concentration.
513
untreated, may result in kernicterus. Reports indicate an overrepresen- Chronic jaundice is a common finding, and splenomegaly is often pres-
tation of G6PD deficiency among cases of kernicterus relative to the ent. Gallstones are common. As in other forms of chronic hemolytic
frequency of in the background population, also in countries with a low anemia, ankle ulcers may be present. 552,553 Pregnancy has been thought
overall frequency of G6PD deficiency. Thus, G6PD deficiency is a pre- to precipitate hemolysis in patients with PK deficiency, perhaps even in
472
ventable cause of mental retardation, 514–516 and this aspect of the disor- heterozygotes. 554–556 In PK deficiency, the increased 2,3-BPG levels may
der has considerable public health significance. Neonatal screening for ameliorate the anemia by lowering the oxygen-affinity of hemoglobin.
G6PD deficiency has been associated with a decrease in the number of Some PK-deficient patients present with hydrops fetalis. 557
cases of kernicterus. 472 In the case of some enzyme defects, characteristic nonhematologic
systemic manifestations may be present, and these may be the only sign
Nonspherocytic Hemolytic Anemia of the enzyme deficiency. For example, patients with PFK deficiency
As described, the anemia in G6PD deficiency is usually episodic and may have type VII muscle glycogen storage disease. In some patients
acute, but some sporadic variants of G6PD may cause nonspherocytic with this defect, hemolysis is present without muscle manifestations,
congenital hemolytic disease, exacerbated by oxidative stress. Affected but in others both muscle abnormalities and hemolysis occur. Glu-
558
individuals have a history of severe neonatal jaundice, and features of tathione synthetase deficiency may be associated with 5-oxoprolinuria
chronic hemolysis (see “Variants Producing Hereditary Nonspherocytic and neuromuscular disturbances, and such abnormalities may occur
262
559
Hemolytic Anemia” above). The hemolysis is mainly extravascular. either with or without hematologic abnormalities. On the other
hand, some patients with GS deficiency manifest only the hematologic
Effects on Other Tissues abnormalities. Spinocerebellar degeneration was documented in the
382
In the common variants of G6PD, such as G6PD A– and Mediterra- first case of glutamate cysteine synthetase described, 381,384 but was not
nean, and even in most of the severely deficient variants, there is usually present in subsequently investigated patients. 382,383 Patients with TPI
no demonstrated defect in leukocyte number or function. However, deficiency nearly always manifest serious neuromuscular disease, and
517
there have been reports of isolated instances of leukocyte dysfunction most of the patients who inherit this abnormality die in the first decade
associated with rare, severely deficient variants of G6PD. 280,281,518–522 of life, 560,561 but there are exceptions, as only one of two brothers with
Patients with G6PD deficiency do not have a bleeding tendency, and the same genotype manifested neurologic disease (see “Genetic Mod-
studies of platelet function have yielded conflicting results. 523,524 Occa- ifiers of the Phenotypes” below). 562,563 Neurologic symptoms have also
sionally, cataracts have been observed in patients with variants of G6PD been noted in patients with deficiencies of glucosephosphate isomerase

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