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chapter 15
Carbohydrate Metabolism II: Gluconeogenesis, Glycogen Synthesis and Breakdown, and Alternative Pathways
Peroxide inactivation is catalyzed by glutathione perox-
idase, a selenium-containing enzyme, in the following
reactions:
2GSH + ROOH
GSSG + H20 + ROH
and
2GSH + H20 2 -> GSSG + 2HzO
The concentrations of substrates for glutathione reductase
and peroxidase determine the rate at which the pentose
phosphate pathway operates in erythrocytes.
Genetically determined deficiencies of
y
-glutamyl-
cysteine synthase and glutathione synthase can cause
hemolytic anemia (Chapter 17). Abnormalities of glu-
tathione metabolism can also result from nutritional de-
ficiencies of riboflavin or selenium. Glutathione reductase
is an FAD enzyme that requires riboflavin for activity, and
riboflavin deficiency can cause hemolytic anemia. An in-
herited lack of glutathione reductase apoenzyme has been
described. Selenium deficiency diminishes activity of glu-
tathione peroxidase and can lead to peroxidative damage.
This can be partially ameliorated by vitamin E, an antiox-
idant (Chapters 37 and 38).
Glucose-6-Phosphate Dehydrogenase Deficiency
G6PD deficiency is the most common inherited enzyme
deficiency known to cause human disease, occurring in
about 100 million people. Most clinical manifestations are
related to hemolysis, which results from impaired ability
to produce cytosolic NADPH. Over 150 variants of the
G6PD structural gene are known, many of which show
either abnormal kinetics or instability of the enzyme. The
erythrocytes are most severely affected because of their
long half-lives and inability to carry out protein synthesis.
Since persons with G6PD deficiency can usually make an
adequate supply of NADPH under normal conditions, the
defect may not become apparent until the patient takes a
drug, such as primaquine, that greatly increases the de-
mand for NADPH. The severity of the reaction depends,
in part, on the particular inherited mutation.
In most persons with G6PD deficiency, hemolysis is ob-
served as an acute phenomenon only after severe oxidative
stress, leading to loss of perhaps 30-50% of the circulating
red cells. The urine may turn dark, even black, from the
high concentration of hemoglobin, and a high urine flow
must be maintained to prevent damage to the renal tubules
by the high-protein load. Because G6PD activity is highest
in reticulocytes and decreases as the cell ages, the older
erythrocytes (more than 70 days old) are destroyed. For
this reason, measurement of red cell G6PD activity follow-
ing a hemolytic crisis can lead to a spuriously high value,
TABLE 15-2
Partial List o f Drugs and Chemicals That Cause Acute
Hemolytic Anemia in Persons with G6PD Deficiency
8-Aminoquinoline
Phenylhydrazine
derivatives (pamaquine,
pentaquine, primaquine)
Sulfonamides and
Methylene blue
sulfones (dapsone,
sulfacetamide,
Nalidixic acid
sulfamethoxazole,
sulfanilamide,
Naphthalene
sulfapyridine,
salicylazosulfa-
Neoarsphenamine
pyridine,
thiazolesulfone)
Niridazole
Toluidine blue
Nitrofurantoin
Trinitrotoluene
even within the normal range. If the patient survives the
initial crisis, with or without transfusions, recovery usually
occurs as the reticulocyte count increases.
The characteristics of the disorder were elucidated
during
investigations
into
the
hemolytic
crises
ob-
served in some patients following administration of
8-aminoquinoline derivatives, such as primaquine and pa-
maquine, used for prophylaxis and treatment of malaria.
The relatively high frequency of such crises in some ge-
ographic areas is due to the extensive overlap in the dis-
tributions of endemic malaria and G6PD deficiency. The
geographic distribution of G6PD variants, like that of
sickle cell trait (Chapter 28), suggests that heterozygosity
for G6PD deficiency may confer some protection against
falciparum malaria.
A number of other drugs (Table 15-2)
also cause hemolytic crises.
Oxidation of glutathione by these drugs beyond the
capacity of the cell to generate NADPH for GSSG re-
duction causes the acute crisis. Since these drugs do not
cause hemolysis
in vitro,
additional steps must take place
in vivo.
Following administration of a drug known to
promote hemolysis, Heinz bodies are seen in erythro-
cytes in the peripheral blood. These also occur in some
thalassemias
and consist of oxidized and denatured forms
of hemoglobin known as
hemichromes
(Chapter 28).
Heinz bodies impair movement of the cells through the
splenic pulp and probably are excised there, presumably
together with the adjacent piece of plasma membrane,
leaving a red cell that is more susceptible to destruc-
tion by the reticuloendothelial system. Infection and di-
abetic ketoacidosis can also cause hemolysis in persons
