Page 729 - Hematology_ Basic Principles and Practice ( PDFDrive )

C H A P T E R 44

RED BLOOD CELL ENZYMOPATHIES

Xylina T. Gregg and Josef T. Prchal

Reticulocytes are already enucleated when released from the bone thus these immense oxidative stresses must be countered by antioxi-
marrow and in the process of maturation into red blood cells (RBCs) dant enzymes and other antioxidant protective mechanisms such as
they also lose their mitochondria and ribosomes. Unable to carry out the active efflux of oxidized glutathione for the RBC to survive.
oxidative phosphorylation and protein synthesis, RBCs still have to
sustain an active metabolism to maintain viability and to preserve
hemoglobin in its functional form to ensure adequate oxygen delivery ENZYMOPATHIES ASSOCIATED WITH
to tissues. HEMOLYTIC ANEMIA
RBC enzymes allow RBCs to accomplish these tasks by support-
ing glycolysis and the pentose shunt and by providing protection Deficiencies in three enzymes account for most of cases of hemolytic
against oxidants by maintaining a high ratio of reduced glutathione anemia. The most common is glucose-6-phosphate dehydrogenase
(GSH) to oxidized glutathione (GSSG). Other RBC enzymes par- (G6PD), which is an enzyme essential for glutathione metabolism,
ticipate in nucleotide degradation and salvage to remove toxic followed by an enzyme defect in the glycolytic pathway, pyruvate
nucleotides from erythrocytes. Glycolytic enzymes also have diverse, kinase, (PK) and lastly pyrimidine 5′ nucleotidase-1 (P5′N1), which
nonenzymatic functions, including stimulation of cell movement, is essential for removal of toxic nucleotide precursors. Deficiencies of
control of apoptosis and modulation of oncogene regulation. These other enzymes are rarer and have highly variable clinical phenotypes
other roles of glycolytic enzymes may explain some of the nonery- that appear to be specific for each enzymatic defect.
throid effects of mutations of the glycolytic enzyme genes. In Enzyme disorders affecting glutathione metabolism can cause
addition, RBCs contain enzymes, such as glutamine-oxaloacetic either chronic or acute intermittent hemolysis and Heinz bodies
transaminase, with no obvious physiologic function; these may be (precipitated denatured hemoglobin) may be seen in RBCs during
remnants of its nucleated past. an acute hemolytic episode. The glycolytic enzyme deficiencies result
The activities of some RBC enzymes rapidly decrease with aging, in chronic hemolysis by a poorly understood mechanism. These
but the activities of others decrease slowly or not at all. Clinically patients are not subject to hemolytic crises after exposure to oxidants
significant abnormalities of RBC enzymes cause various hematologic and their RBCs do not have any characteristic morphologic abnor-
phenotypes, principally acute and chronic hemolytic anemia, polycy- malities. The chronic hemolytic anemia that occurs in enzyme defi-
themia, and methemoglobinemia. Disorders of some RBC enzymes ciencies is termed hereditary nonspherocytic hemolytic anemia.
have no RBC phenotype but their dysfunction in nonerythroid
tissues causes systemic disorders such as galactosemia and glycogen
storage disorders. Thus the presence of these enzymes in easily acces- Glucose-6-Phosphate Dehydrogenase Deficiency
sible RBCs serves as a convenient approach for the diagnosis of these
disorders. Deficiencies or abnormalities of other RBC enzymes, such Introduction
as erythrocyte lactate dehydrogenase (LDH), have no apparent disease
phenotype. G6PD deficiency was the first described and is the most common
and best-studied RBC enzyme deficiency. G6PD deficiency is more
common where Plasmodium falciparum malaria is or has been
METABOLIC PATHWAYS endemic. It was discovered in the 1950s as a result of investigations
into a self-limited hemolysis that occurred after administration of the
Glucose is used in two different pathways: glycolysis (Fig. 44.1), antimalarial drug primaquine, most commonly in individuals of
which provides two molecules of adenosine triphosphate (ATP), and African or Mediterranean ethnic origin. These early studies also
the pentose shunt (see Fig. 44.1), which generates five and seven determined that G6PD deficiency is X-linked and subsequent studies
carbon carbohydrates and reduces nicotinamide adenine dinucleo- in carrier females led to the discovery of X-inactivation, a phenom-
tide phosphate (NADP to NADPH), the sole source of NADPH enon that has been exploited to study the hierarchy of hematopoiesis
in red cells. Under physiologic conditions, approximately 90% of and the clonality of malignant neoplasms.
glucose is consumed in the glycolytic pathway and about 10% is
used in the pentose shunt. In conditions of increased oxidant stress,
however, the contribution of the pentose shunt may be significantly Epidemiology
increased. In the glycolytic pathway, the generation of one molecule
of ATP could be bypassed by the Rapoport-Luebering shunt (see G6PD deficiency is the most prevalent human enzyme deficiency in
Fig. 44.1), which generates an important glycolytic intermediate, the world, affecting an estimated 500 million people, although the
2,3 biphosphoglycerate (BPG), that facilitates hemoglobin oxygen vast majority of affected individuals are not symptomatic. Although
delivery. most prevalent in individuals of African, Mediterranean, and Asian
In addition, RBCs have an active glutathione metabolism com- ethnic origins, it has been found in almost every population. The
prised of its synthesis and reduction (Fig. 44.2). Maintaining a high highest prevalence is in the tropical belt of sub-Saharan Africa (>32%)
ratio of GSH to its oxidized form (GSSG) is the principal antioxidant and the Arabian Peninsula. In other populations, its prevalence ranges
protective mechanism for RBCs. The release of oxygen from hemo- from less than 1 in 1000 among northern European populations to
globin generates reactive oxygen species (ROS). Another source of 50% of the males in Kurdish Jews. The distribution across Asia is
endogenous ROS in RBCs is NADPH oxidase and, in reticulocytes, heterogeneous. Nearly 20% of males in Thailand are affected by one
mitochondrial derived ROS. Excessive ROS is detrimental to RBCs of the five prevalent variants. It is common in southern China (~5%
by affecting membrane deformability and hemoglobin solubility, and in Hong Kong) and rare in other parts of China, while in India the

616