Page 737 - Williams Hematology ( PDFDrive )

712 Part VI: The Erythrocyte Chapter 47: Erythrocyte Enzyme Disorders 713

clinically to be corrected. There are patients with PK deficiency who nonspherocytic hemolytic anemia resulting from G6PD deficiency, gall-
need to be transfused continually. Chronic transfusion therapy usu- stones may occur. During periods of infections or drug administra-
637
ally requires iron chelation if of sufficient iron load. Patients with TPI tion, anemia may increase in severity. Otherwise, the hemoglobin level
deficiency generally die as children, not because of the severity of the of affected subjects remains relatively stable.
anemia but because of the severe neuromuscular effects of the enzyme Nearly all patients with drug- or infection-induced hemolysis
deficiency. It has been proposed that the exogenous replacement of TPI recover uneventfully. Favism must be considered, by comparison, a rel-
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might be useful for the treatment of this deficiency, but no clinical atively dangerous disease. The most serious complication of G6PD defi-
627
trials have been carried out. PK deficiency and PGK deficiency have ciency is neonatal icterus. If not recognized early and properly treated,
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been treated successfully by stem cell transplantation, but this is still it can lead to kernicterus (see “Clinical Features” above).
only very rarely done. Studies are underway to improve gene therapy in In one large population study, a decreasing incidence of G6PD defi-
638
PK deficiency. 305,307,308 In PK deficiency, erythroid cells have been treated ciency was noted with increasing age of the population, but no such
22
ex vivo with glycolytic intermediates to correct for metabolic dysfunc- change was observed in another. Although age stratification might rep-
tion. Preliminary evidence indicates that small molecule activation of resent evidence of a shorter life span for individuals with the A– defi-
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mutant PK may be able to restore glycolytic pathway activity and nor- ciency, other factors are more likely explanations. Examination of the
malize red cell metabolism in PK deficiency. The jaundice of glucose- health records of more than 65,000 U.S. Veterans Administration males
629
phosphate isomerase deficiency has been treated by the administration failed to reveal any higher frequency of any illness in G6PD-deficient
639
of phenobarbital. 630 compared to nondeficient subjects. Furthermore, it appears that there
The principal decision that the physician must make regarding are no indications that G6PD-deficient individuals should systemat-
patients with hereditary nonspherocytic hemolytic anemia is whether ically be excluded from serving as blood donors, or hematopoietic
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or not they require a splenectomy. This decision is not made easily as stem cell donor. In view of the benign nature of the common types of
the response is unpredictable, and some patients who fail to respond G6PD deficiency, community-based population screening is not recom-
may develop serious thrombotic complications, resulting thrombocy- mended. However, screening for G6PD deficiency of all patients admit-
tosis is often exaggerated when splenectomy does not ameliorate the ted to the hospital may be useful in anticipating hemolytic reactions and
hemolysis. The recommendation that is made should be based upon the in understanding them if they occur; however, this recommendation has
following considerations: (1) severity of the disease, (2) family history not been submitted to rigorous analysis and is controversial because of
of response to splenectomy, (3) the underlying defect, and (4) perhaps low likelihood of any preventable hemolysis. This is particularly prudent
the need for cholecystectomy. Because it is unusual to obtain more than if a drug such as dapsone or rasburicase, known to cause hemolysis in
a partial response to splenectomy, this procedure should probably be G6PD-deficient individuals, is to be given. 483,642 Study of family members
reserved for patients whose quality of life is impaired by their anemia. of patients with this X chromosome-linked enzyme deficiency can be
The operation needs to be particularly considered for patients who need helpful in providing appropriate counseling to affected individuals.
frequent transfusion and for those who require gallbladder surgery, The diagnosis of hereditary nonspherocytic hemolytic anemia has
202
in which splenectomy might be carried out as part of the same proce- been made as late as the seventh decade, and the disease can be fatal
dure. The best guide to the likely efficacy of splenectomy is probably in the first few years of life. TPI deficiency appears to have the worst
the response to splenectomy of other affected family members. Unfor- prognosis of all of the known defects that cause this disorder. With few
tunately, such information is only occasionally available. The physician exceptions, patients with this deficiency have died by the fifth or sixth
must therefore rely upon the experience of other patients with heredi- year of life, usually of cardiopulmonary failure. PK deficiency, too, can
tary nonspherocytic hemolytic anemia of similar etiology to serve as a be fatal in early childhood; the PK mutation prevalent among the Amish
guide. However, even as the large group of patients with hereditary non- of Pennsylvania produces particularly severe disease. Unless the
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spherocytic hemolytic anemia represents a heterogeneous population, affected homozygous children have their spleens removed, the disor-
so individuals with a single enzymatic lesion, such as PK deficiency, der is commonly lethal. In PK deficiency, compound heterozygotes and
are heterogeneous. Each family is likely to be afflicted with a distinct homozygotes can suffer of major side effects as a result of the chronic
mutant enzyme, and the various mutants may differ both with respect hemolysis and the burden of repeated transfusions and iron chelation.
to clinical manifestations and with respect to response to splenectomy. In general, however, hereditary nonspherocytic hemolytic anemia is a
Some of the available information regarding response to splenectomy relatively mild disease and most affected individuals lead a relatively
of patients with hereditary nonspherocytic hemolytic anemia has been normal life, apparently without much compromise of life span.
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reviewed and is summarized in Table 47–2.
Glucocorticoids are of no known value in this group of disorders. REFERENCES
Folic acid is often given, as in other patients with increased marrow
activity, but without proven hematologic benefit. In the absence of 1. Beutler E: G6PD deficiency. Blood 84:3613–3636, 1994.
2. Beutler E: Glucose-6-phosphate dehydrogenase deficiency: A historical perspective.
iron deficiency, iron is contraindicated. Iron overload is a complication Blood 111:16–24, 2008.
in this group of disorders, particularly in connection with PK deficie 3. Luzzatto L, Seneca E: G6PD deficiency: A classic example of pharmacogenetics with
on-going clinical implications. Br J Haematol 164:469–480, 2014.
ncy, 289,571,631,632 even in nontransfused patients. The iron overload is 4. Crosby WH: Hereditary nonspherocytic hemolytic anemia. Blood 5:233–253, 1950.
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probably multifactorial (Chap. 43), involving chronic hemolysis, inef- 5. Dacie JV: The congenital anaemias, in The Haemolytic Anaemias, p 171. Grune & Strat-
fective erythropoiesis, splenectomy, coinheritance of hereditary hemo- ton, New York, 1960.
chromatosis gene (HFE) mutations, growth differentiation factor-15, 6. Selwyn JG, Dacie JV: Autohemolysis and other changes resulting from the incubation
and hepcidin levels. 571,634,635 in vitro of red cells from patients with congenital hemolytic anemia. Blood 9:414–438,
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7. Robinson MA, Loder PB, DeGruchy GC: Red-cell metabolism in non-spherocytic con-
genital haemolytic anaemia. Br J Haematol 7:327–339, 1961.
COURSE AND PROGNOSIS 8. Valentine WN, Tanaka KR, Miwa S: A specific erythrocyte glycolytic enzyme defect
(pyruvate kinase) in three subjects with congenital non-spherocytic hemolytic anemia.
Hemolytic episodes in the A– type of deficiency are usually self-limited, Trans Assoc Am Physicians 74:100–110, 1961.
even if drug administration is continued. This is not the case in the more 9. Howes RE, Piel FB, Patil AP, et al: G6PD deficiency prevalence and estimates of affected
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severe Mediterranean type of deficiency. In patients with hereditary Med 9:e1001339, 2012.

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