Page 733 - Hematology_ Basic Principles and Practice ( PDFDrive )

620 Part V Red Blood Cells

deficiency, the vast majority of patients with G6PD deficiency never splenic erythroid progenitors. Following splenectomy, despite
suffer a hemolytic episode, while PK deficiency exhibits a high pen- decreased hemolysis and improved anemia, patients paradoxically
etrance of the hemolytic phenotype. have a higher number of reticulocytes; this phenomenon is as yet
unexplained.
Epidemiology
Tolerance of Anemia
PK deficiency is distributed worldwide but is more common among
people of northern European extraction. The population prevalence The anemia of PK deficiency is better tolerated than a comparable
of PK deficiency among whites is approximately 50 cases per 1 level of anemia seen in patients with hexokinase deficiency, since the
million. PK deficiency is an autosomal recessive disease, and affected block in glycolysis occurs after the Rapoport-Leubering shunt (see
patients are typically double heterozygotes, or, less commonly, homo- Fig. 44.1); (see section on 2,3-BPG deficiency). The resultant accu-
zygous for the same mutation. Homozygous mutations are usually mulation of 2,3-BPG shifts the oxyhemoglobin dissociation curve to
seen in groups with marked consanguinity, and homozygous PK the right, leading to better oxygen delivery to the tissue and improved
deficiency has been well described in the Amish populations of tolerance of anemia.
Pennsylvania and Ohio. Common mutations have well-defined
geographic associations. Mutation 1529A is the most common muta-
tion in the United States, northern and central Europe, 1456T in Clinical and Laboratory Manifestations
southern Europe, and 1468T in Asia.
PK deficiency does not localize to geographic areas of malarial The severity of hemolysis in PK-deficient patients is highly variable,
endemicity. However, there is in vitro evidence that PK deficiency ranging from a mild, fully compensated chronic hemolytic process
provides protection against infection and replication of Plasmodium without anemia, to life-threatening transfusion-requiring hemolytic
falciparum in human RBCs, an effect possibly mediated by reduced anemia present at birth, to rare hydrops fetalis because of homozygos-
ATP levels in PK-deficient RBCs. PK deficiency was also shown to ity for PK null mutations. The disease severity is typically similar
be protective in a mouse model of infection with Plasmodium among siblings of a given family. In most cases the degree of hemolysis
chabaudi. declines after infancy, by a not fully understood pathophysiologic
mechanism. Splenomegaly is often but not invariably present. Patients
with severe hemolysis may be chronically jaundiced and may develop
Pathobiology the clinical complications of chronic hemolytic states, including
gallstones, transient aplastic anemia crises (caused by parvovirus
PK catalyzes the irreversible transfer of phosphate from phosphoenol- infection), folate deficiency, extramedullary hematopoiesis and
pyruvate to adenosine diphosphate (ADP) yielding one molecule of infrequently, skin ulcers. Pregnancy may precipitate hemolysis. Iron
pyruvate and one molecule of ATP (see Fig. 44.1). Two genes encode overload has been reported in both nontransfused and transfusion-
four PK isoenzymes with different tissue expression. PK-R (unique dependent patients and may be severe; in some cases iron overload
to RBCs) and PK-L (in liver) are products transcribed from two has been attributed to coinheritance of mutations in HFE, the gene
different, tissue-specific promoters of the PKLR gene on chromosome associated with hereditary hemochromatosis. Neonatal icterus may
1q21. Other undefined regulatory elements are also involved in PKLR occur and is augmented by coincidental heterozygosity or homozy-
gene expression. PK-M1 (in skeletal muscle) and PK-M2 (in leuko- gosity for the UGT1A1 polymorphism.
cytes, kidney, adipose tissue, lungs and fetal RBCs) are formed from Hemolysis is mainly extravascular with a variable intravascular
the PKM2 gene by alternative splicing. PK-M2 in fetal erythropoiesis component; thus, increased LDH, hyperbilirubinemia and low
is replaced by the PK-R isoform after birth. PK-R is a heterotetramer haptoglobin levels may be present. The reticulocyte count invariably
whose enzymatic activity is allosterically augmented by fructose increases after splenectomy.
1,6-diphosphate.
More than 230 mutations in the PKLR gene have been identified,
most of which are missense mutations. Mutations affecting the active Diagnosis
site or protein stability are associated with more severe hemolytic
anemia. However, the phenotypic expression of identical mutations There are no characteristic RBC morphologic findings in PK defi-
can be strikingly different. Since most PK-deficient patients are ciency. A screening test using crude hemolysate with a single concen-
compound heterozygous for two different mutations, rather than tration substrate has been used for the detection of pyruvate deficiency
homozygous for one, several different tetrameric forms of PK may be but occasionally misses some PK variants. Specialized laboratories can
present, each with distinct structural and kinetic properties. This perform quantitative PK enzyme analysis and further analyze the
complicates genotype-to-phenotype correlations in these individuals, mutant enzyme by comprehensive kinetic studies. In these assays,
as it is difficult to infer which mutation is primarily responsible for leukocytes and platelets must be carefully removed as their presence
deficient enzyme function and the clinical phenotype. There are even can obscure a deficiency in the red cells. Molecular studies for prenatal
cases in which the activity of PK as measured in vitro is higher than diagnosis can be used if the mutation is known.
normal, but a kinetically abnormal enzyme is responsible for the
hemolytic anemia.
PK deficiency may be also caused by mutations not directly Therapy
involving PKLR gene. Combined heterozygosity for the common
1529A PK mutation and a unique promoter mutation on the other Many patients do not require therapy. Some require RBC transfu-
allele that markedly reduced its allelic transcription resulted in a sions only in transient settings of increased stress, such as the periop-
severe hemolytic variant. Mutations in the key erythroid transcription erative period, coexistent infections, or pregnancies. However, others
factor KLF1 caused severe congenital hemolytic anemia because of a require chronic transfusions. Iron chelation may be required in
deficiency of PK. chronic transfusion programs and also in some patients who have
The mechanism of hemolysis in PK deficiency is not clear. The never been transfused.
defect in ATP generation is unlikely to be the cause as ATP deficiency Splenectomy has documented benefit in severe cases; the degree
is difficult to demonstrate in many patients and other disorders with of hemolysis and anemia is ameliorated and the transfusion require-
more severe ATP deficiency are not associated with significant hemo- ment is generally abolished or markedly decreased. The increase in
lysis. Increased apoptosis and ineffective erythropoiesis may also be a hemoglobin concentration in nontransfusion requiring patients after
feature of PK deficiency, although this has only been studied in splenectomy ranges from 1–3 g/dL. It is recommended to delay