What’s in a name?

What is pyruvate kinase (PK)?

a
An enzyme
b
A structural protein
c
A cofactor
d
A membrane protein
e
A transcription factor

Pyruvate kinase is necessary for generating:

a
NADH
b
ATP
Correct. See next slide.
c
NADPH
d
Spectrin
e
Glucose

Pyruvate kinase (PK) catalyzes the conversion of phosphoenolpyruvate to pyruvate in the glycolytic pathway, resulting in ATP production. ATP is necessary for maintaining the structural and functional integrity of red blood cells during their lifespan of 100 to 120 days.

Abnormal or deficient PK enzyme activity results in inadequate ATP production with consequent:

  • Loss of membrane plasticity
  • Cellular dehydration
  • Premature destruction of red blood cells in the spleen or liver

The following schematics show the glycolytic pathway under normal conditions and in the setting of pyruvate kinase (PK) deficiency.

In glycolysis, glucose is metabolized to pyruvate (proximal steps are schematically indicated by unlabeled arrows). When mitochondria and oxygen are present, pyruvate enters the Kreb’s cycle where its oxidation generates >30 molecules of ATP. Red cells do not have mitochondria, so they depend solely on glycolysis to meet their energy needs. In this case, each molecule of glucose yields only 2 molecules of ATP. Pyruvate kinase (PK) is responsible for generating one of these 2 molecules. Thus, loss of PK results in 50% loss of ATP generation. 2,3-DPG is a byproduct in one of the proximal steps in glycolysis. PK deficiency results in build up of 2,3-DPG levels.

Levels of 2,3-DPG are elevated in patients with PK deficiency. Which way does the oxygen dissociation curve shift?

a
To the left
b
To the right
Correct. See next slide.

Increased G6PD causes the oxygen dissociation (OCD) curve to shift to the right:

Which of the following statement best describes the shift of the OCD curve to the right?

a
Hb has lower oxygen affinity, offloads less oxygen to tissues
b
Hb has lower oxygen affinity, offloads more oxygen to tissues
c
Hb has higher oxygen affinity, offloads less oxygen to tissues
d
Hb has higher oxygen affinity, offloads more oxygen to tissues

As a result of the increased 2,3 DPG levels, patients are:

a
More tolerant of anemia
b
Less tolerant of anemia

OCD, oxygen dissociation curve

MT EVEREST

Which way does the OCD curve shift when you climb Mt. Everest?

Click for Answer

Also to the right, though this is probably maladaptive when considering that animal species that have evolved at high altitude have a left-shifted curve!

We will discuss pyruvate kinase (PK) deficiency in more detail in About the Condition, but several principles are worth mentioning now as they relate to our patient:

  • As in our case, splenectomy is often performed in patients with PK deficiency.
  • Splenectomy in patients with PK deficiency is associated with an improvement in anemia, but a paradoxical increase in reticulocyte count. This may explain our patient’s profound reticulocytosis.
  • Transfusions are common in children with PK deficiency (87% of patients younger than 18 years of age having received at least one transfusion in their lifetime), and therefore patients are at risk for iron overload (approximately 50% of children younger than 18 years of age have iron overload). This explains why our patient was treated with iron chelation therapy.
  • Evidence of hemolysis and risk of gallstones often persist after splenectomy, as shown in our patient.
  • Splenectomy is associated with infectious and thrombotic risks. These risks persist lifelong after splenectomy, and this is an important reason to follow our patient throughout adulthood.

In the next section, we will consider post-splenectomy complications in more detail.

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