Pyruvate Kinase Deficiency Flashcards
A subtype of anemia which results in increased destruction of erythrocytes
Hemolytic Anemia
Hemolytic anemia is coupled with an increase in RBC production because there is a decreased oxygen carrying capacity with loss of functional red blood cells which triggers
Erythropoetin (EPO) Production
Refers defects in the erythrocytes themselves
Intrinsic hemolysis
These are often hereditary and include the hemoglobinopathies, membrane deficiencies such as hereditary spherocytosis and elliptocytosis, enzyme deficiencies, and paroxysmal nocturnal hemoglobinuria.
Intrinsic hemolysis
Refers to factors outside of the red blood cell that cause hemolysis
Extrinsic hemolysis
These are almost always acquired and include causes such as infections, toxins, hypersplenism, microangiopathic hemolysis, liver disease and autoimmune hemolytic anemia
Extrinsic hemolysis
The features of extravascular hemolysis are
Anemia, splenomegaly, and jaundice
In hemolytic anemia, erythrocytes are most often
Normochromic and normocytic (MCV 80-100)
In G6PD deficiency, the shape of RBCs is described as
Heinz bodies
Helmet cells signifying destruction
Schisocytes
An enzyme that catalyzes the last reaction of the glycolytic pathway
PYruvate Kinase
Catalyzes the transfer of the high-energy phosphate bond from phosphoenolpyruvate (PEP) to ADP in an irreversible step producing ATP and pyruvate
PYruvate kinase (PK)
In mammals, there are four
PK isoforms
Encodes PKL, expressed in the liver and some cells of the pancreas, intestine, and kidney
PKLR gene
Also encodes PKR expressed in erythrocytes
PKLR gene
Encodes PKM1 and PKM2 through alternative splicing
PKM gene
Clinical PK deficiency with hemolytic anemia is limited to mutations of the
LR gene
In affected individuals, activity of erythrocytic PK is
-Whereas PK activity in white cells, platelets, and
other tissues is normal
Markedly reduced
Devoid of a nucleus, mitochondria, ribosomes, and other organelles and thus has no capacity for cell replication, protein synthesis, or oxidative phosphorylation
Mature eryhtrocytes
The glycolytic production of ATP is the only source of energy production for the
Mature RBC
A deficiency in the functionality of pyruvate kinase causes decreased production of
ATP
Low ATP levels are responsible for erythrocyte concentration disruption, due to failure of the energy driven
Na+/K+ ATPase
A consequence of this is cellular distortion, rigidity, and dehydration which leads to premature erythrocyte destruction driven mostly by the
Spleen and liver
Additionally, the conversion of glucose to glucose-6-
phosphate requires
ATP
An intermediate of the hexose monophosphate pathway and the de-novo glutathione synthesis from glycine, glutamate, and cysteine
G-6-P
Made from HMP and glutathione are essential in protecting the erythrocyte against free radical production
NADPH
Therefore pyruvate kinase deficiency leaves RBCs susceptible to intracellular
Oxidative stress
An autosomal recessive disorder with an estimated prevalence of 1 In 300,000 live births
Pyruvate Kinase Deficiency
Affects both genders equally and occurs in all races with highest incidences occuring in the Amish population and internationally in Northern Europe and Japan
PKD
Which mutations are common in European patients with PK deficiency?
G1529 → A and the C1456 → T
Which mutation is common in Japanese patients with PK deficiency?
C1151 → T
Individuals affected by PKD are either homozygous for a single mutation
Compound heterozygous (2 different mutations)
Have intermediate enzyme levels that usually do not produce clinical disease
PKD heterozygotes
Can be acquired as a result of blood disorders such as leukemia, preleukemia, and refractory sideroblastic anemia
PKD
Since RBCs lack mitochondria, the conversion of pyruvate to lactate regenerates
NAD+ from NADH
The only method of ATP generation in RBCs
Glycolysis
Physiologically, the hemoglobin of affected individuals has an increased capacity to release oxygen into the tissues due to a stalling at the level of pyruvate kinase causing
PEP accumulation
PEP is converted back to 3-phosphoglycerate, leading to increased
2,3-BPG
Interestingly, for a comparative hemoglobin and hematocrit level individuals with PKD have more efficient
Oxygen delivery
Individuals with PKD are more resistant to
P. Falciparum
The clinical severity of this disorder varies and can range from
Mile compensated anemia to severe anemia
Variable clinical severity is explained, at least in part, by the existence of numerous mutant forms of the enzyme whose differing properties result in variable degrees of
Hemolysis
Symptoms include jaundice, icteric sclera, and hepatosplenomegaly due to hemolysis
Severe PK Deficiency
Can also result due to increased levels of bilirubin (byproduct of erythrocyte destruction) in the biliary ducts
Pigmented Gallstones
Fatigue and lethargy are common in PKDs due to impaired oxygen delivery given decreased amounts of
RBCs
In very severe cases of PKDs, heart failure can result from extensive anemia in newborns-- this is called
Hydrops Fatalis
One thing to workout when you suspect PKD is
LDH (Lactate Dehydrogenase)
Decreased haptoglobin levels are a marker for
Intravascular Hemolysis
Bilirubin is the byproduct of the breakdown of red blood cells. Increased bilirubin levels signify
Hemolysis
Young erythrocytes that are produced by the bone marrow in times of increased red blood cell destruction
Reticulocytes
High levels of reticulocytes signify
Hemolytic Anemia
NADH fluorescence under ultraviolet light is a commonly used screening test for
PK Deficiency
Loss of fluorescence of NADH under ultraviolet light in this test is observed as evidence of the presence of
PKD
Show echinocytes (RBC with thorny projections) which have deformed shapes due to the disrupted cell membrane that occurs because of lack of energy requirements to run the Na/K ATPase pump
Peripheral Blood Smear
What is the treatment for PKD?
Transfusions and Vitamin supplementation (folic acid and B Vitamins)
Only indicated in severe cases due to increased risk of serious bacterial infections
Splenectomy
