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Increased activity of alcohol dehydrogenase
7%
17/238
Decreased activity of pyruvate dehydrogenase
55%
130/238
Decreased activity of lactate dehydrogenase
17%
41/238
Increased activity of isocitrate dehydrogenase
4%
9/238
Increased flux through the electron transport chain
11%
27/238
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Septic shock leads to ischemia-induced metabolic derangement and anaerobic metabolism. Flux through the pyruvate dehydrogenase (PDH) complex is decreased in this setting as the metabolic products of glucose are diverted to lactate production. This post-operative patient with fever, tachycardia, hypotension, tachypnea, hypocarbia, leukocytosis, and bacteremia has an anion gap acidosis secondary to lactate accumulation and septic shock. Due to a lack of or inability to use available oxygen to serve as the final electron acceptor in the electron transport chain, NADH builds up and inhibits the PDH complex. Pyruvate is subsequently diverted to lactate production through the action of lactate dehydrogenase. Gauer discusses the early recognition and management of sepsis. He notes that mortality rates for septic shock (as in this patient) are extremely high--between 40-70%. He discusses the importance of early goal-directed therapy to treat sepsis within 6 hours of its identification. Thomas et al. investigated the dysregulation of the pyruvate dehydrogenase complex upon in vitro exposure to bacterial toxins. They hypothesized that given the association of lactic acidosis with bacterial sepsis, there might be an additional factor inhibiting the PDH complex beyond simple ischemia; their experimental findings bore out this hypothesis, suggesting cell wall components and insulin may also contribute. Illustration A shows a schematic of glycolysis and the TCA cycle, showing the divergent fates of pyruvate in aerobic metabolism (TCA cycle through PDH complex) and anaerobic metabolism (lactate through lactate dehydrogenase). Incorrect Answer: 1: Alcohol dehydrogenase activity is induced by the presence of substrates such as ethanol, ethylene glycol, and methanol. This patient's anion gap is much more likely to be the result of a lactic acidosis than any of these alcohol dehydrogenase substrates. 3: Lactate dehydrogenase activity is increased in the setting of anaerobic metabolism, as this enzyme is needed to convert pyruvate that is unable to enter the citric acid cycle into lactate. This is the cause of the patient's lactic acidosis. 4: Flux through isocitrate dehydrogenase, a component of the citric acid cycle, would be decreased in the setting of anaerobic metabolism. 5: Flux through the electron transport chain is decreased in the setting of ischemia due to lack of oxygen to serve as the final electron acceptor.
4.1
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