Why are pyruvate and lactate levels elevated in individuals with pyruvate dehydrogenase deficiency?

The elevation of pyruvate and lactate levels in individuals with pyruvate dehydrogenase deficiency occurs primarily because pyruvate cannot enter the citric acid cycle. Under normal circumstances, the enzyme pyruvate dehydrogenase catalyzes the conversion of pyruvate into acetyl-CoA, which then enters the citric acid cycle for further processing and energy production.

When there is a deficiency in this enzyme, pyruvate accumulates because it cannot be effectively converted to acetyl-CoA. As a result of the excess pyruvate, the body may also convert pyruvate to lactate through anaerobic fermentation, particularly in tissues that cannot fully utilize aerobic respiration due to the lack of sufficient acetyl-CoA. This shift towards lactate production is especially common in conditions where aerobic metabolism is impaired, leading to increased lactate levels, a condition known as lactic acidosis.

Thus, the inability to enter the citric acid cycle due to a deficiency in pyruvate dehydrogenase is the key reason for the elevated levels of both pyruvate and lactate in these individuals.