A 44-year-old man is brought to the emergency department after police officers found him agitated and confused. During transport to the hospital, he is started on intravenous fluids with dextrose. On arrival, the patient is disoriented but cooperative. Physical examination shows bruises on the forehead, forearms, and shins. Extraocular findings include bilateral horizontal nystagmus and impaired lateral eye movements; however, the ambulance personnel state that the patient's extraocular movements were normal when they arrived on the scene. The patient also has an unsteady gait with widely spaced legs and short steps. Review of the medical record shows that he has been admitted to the hospital with alcohol intoxication several times before. This patient's neurologic findings are most likely related to deficiency of a cofactor required for which of the following reactions?
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This patient's multiple previous hospitalizations for alcohol intoxication and easy bruising are indicative of chronic alcohol use. Patients with this condition are frequently deficient in thiamine, a necessary cofactor for several enzymes involved in glucose metabolism, including pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase, and transketolase (Choices A, B, E, F, and G).
The administration of glucose to thiamine-deficient patients can rapidly deplete the small amount of circulating thiamine. This can result in neuronal injury within highly metabolic brain regions, leading to the classic triad of acute Wernicke encephalopathy seen in this patient:
(Choices C and H) The metabolism of ethanol by alcohol dehydrogenase and aldehyde dehydrogenase consumes NAD+ and increases the NADH/NAD+ ratio. This skewed ratio inhibits enzymatic pathways requiring NAD+ (eg, alpha-ketoglutarate dehydrogenase, isocitrate dehydrogenase, malate dehydrogenase), and as a result, the entire citric acid cycle is typically impaired in intoxicated patients. However, this patient has the classic findings of Wernicke encephalopathy, which is caused by thiamine (not NAD+) depletion; the only thiamine-dependent enzyme in the citric acid cycle is alpha-ketoglutarate dehydrogenase.
Educational objective:
Several enzymes involved in glucose metabolism (eg, pyruvate dehydrogenase, alpha-ketoglutarate dehydrogenase) require thiamine as a cofactor. The administration of glucose to thiamine-deficient patients (eg, chronic alcohol use) can precipitate Wernicke encephalopathy (eg, acute confusion, ophthalmoplegia, ataxia) due to rapid thiamine consumption.