A 54-year-old man with a history of cirrhosis is brought to the emergency department by his wife, who found him agitated and confused. She reports that he was nauseous and vomited bright red blood several times yesterday. His cirrhosis is secondary to chronic hepatitis C infection, and he has received treatment for esophageal varices in the past. Physical examination reveals abdominal distension, decreased liver span, and testicular atrophy. A jerky, irregular flexion-extension tremor involving his hands is seen with wrist extension. Which of the following is most likely to be elevated in this patient's astrocytes?
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This patient has hepatic encephalopathy, likely due to his recent gastrointestinal bleeding causing a corresponding increase in nitrogen absorption by the gut. The pathogenesis of hepatic encephalopathy is related to increased circulatory levels of ammonia and other neurotoxins due to failure of the liver to metabolize waste products.
Under normal conditions, astrocytes regulate neurotransmission by taking up glutamate present in the synapse, preventing excessive neuronal excitation. Through the action of glutamine synthetase, glutamate undergoes a condensation reaction with ammonia to form glutamine (a non-neuroactive compound). Glutamine is then released by the astrocytes and taken up by neurons, where it is converted back to glutamate for use as a neurotransmitter (glutamate-glutamine cycle).
When excess ammonia is present in the blood, it crosses the blood-brain barrier and is taken up by astrocytes, increasing glutamine production. The presence of excess glutamine within astrocytes leads to increased intracellular osmolarity, causing astrocyte swelling and impaired glutamine release. Hyperammonemia consequently decreases the amount of glutamine available for conversion to glutamate in neurons, resulting in disruption of excitatory neurotransmission.
(Choice A) α-ketoglutarate functions as a key intermediate in the TCA cycle and as a nitrogen transporter in metabolic reactions. In the setting of hyperammonemia, ammonia is detoxified to glutamate via glutamate dehydrogenase, depleting α-ketoglutarate and impairing energy metabolism in the brain.
(Choice B) Alanine is an amino group transporter in the glucose-alanine cycle in liver and muscle tissue. This process allows tissues that use amino acids for fuel to shunt excess nitrogen back to the liver.
(Choice C) Aspartate is a nonessential amino acid that functions as a substrate in the urea cycle and as part of the malate-aspartate shuttle that transfers cytosolic-reducing equivalents into the mitochondrial matrix.
(Choice D) Carbamoyl phosphate is a urea cycle intermediate synthesized by carbamoyl phosphate synthetase I, which transfers an ammonia molecule from glutamine or glutamate to a phosphorylated bicarbonate. Carbamoyl phosphate production is decreased in patients with advanced liver disease.
Educational objective:
Hyperammonemia in advanced liver failure occurs as a direct result of the cirrhotic liver's inability to metabolize nitrogenous waste products. Ammonia crosses the blood-brain barrier and causes excess glutamine to accumulate within astrocytes. This decreases the amount of glutamine available for conversion to glutamate in the neurons, resulting in disruption of excitatory neurotransmission.