This is the most common enzyme defect. It results in
hereditary, nonspherocytic hemolytic anemia.
Pyruvate Kinase Deficiency of Erythrocytes; Pyruvate
Kinase Liver type Deficiency.
First described in 1952 by J.V. Dacies et al. in patients with
congenital hemolytic anemia who presented with hereditary spherocytosis. However, in the more
recently described anemia, it is shown that the osmotic fragility is normal and
spherocytes not encountered.
The prevalence rate of a heterozygous carrier is
approximately 1 to 3% and the prevalence of confirmed cases has been
estimated at about 1:300,000 live births. Pyruvate kinase deficiency (PKD)
affects both genders equally and occurs in all races (a high incidence has
been reported in Amish people from Pennsylvania). Internationally, PKD has been reported
in Northern Europe and Japan. The prevalance in Germany is reported at 1% and Hong Kong
3%. In the United Kingdom, the prevalence is 3.2 cases per million population.
Autosomal recessive. It is caused by mutations
in the PKLR gene (pyruvate kinase expressed in liver and red blood cells (RBCs), which has
been mapped to 1q21 and encodes the L (liver) and R (red cells) pyruvate
The mature erythrocytes have neither a nucleus nor
mitochondria, and therefore depend entirely on anaerobic glycolysis as a
source of energy. Pyruvate kinase (PK) catalyzes the conversion of
phosphoenolpyruvate to pyruvate and is one of three rate-limiting kinases
(together with hexokinase and phosphofructokinase) in the Embden-Meyerhof
pathway, which is responsible for adenosine triphosphate (ATP) production by anaerobic glycolysis. On
the one hand, this defect results in accumulation of intermediate and
various glycolytic metabolites in the erythrocyte upstream of the enzymatic
block; on the other hand, these RBCs lack the products downstream in the
pathway (lactate and ATP). ATP is required to maintain erythrocyte
transmembranous electrolyte concentration gradients (mainly potassium)
across the cellular membrane, hydration, and flexibility of the RBC.
Consequently, the lack of ATP results in loss of potassium, dehydration, and
rigidity of the cellular membrane, and, finally, in premature destruction of
the erythrocytes in spleen and liver. A shunt in the glycolytic pathway
unique to the erythrocyte (Rapoport-Luebering shunt) is responsible for the
twoto threefold increase in intracellular 2,3-DPG concentration, and hence
a marked right shift in the oxygen dissociation curve of hemoglobin with
decreased affinity of hemoglobin for oxygen. Two different PK genes (PKLR
and PKM) encode for four PK isozymes: L in liver, R in RBCs, M1 in muscles,
and M2 in leukocytes and platelets.
In the absence of blood loss, a chronic normochromic,
normocytic, or macrocytic anemia (usually with hemoglobin concentrations
between 60 and 120 g/L) in combination with marked reticulocytosis (5 to
15%) is suggestive of hemolysis. Enzyme assays (with residual PK activity
of 5 to 25% in homozygotes and approximately 50% [wide range] in
heterozygous carriers) and polymerase chain reaction for DNA analysis are
available to confirm not only the diagnosis, but also a carrier status. ...