WBR0860

Author	[[PageAuthor::Serge Korjian M.D. (Reviewed by Serge Korjian)]]
Exam Type	ExamType::USMLE Step 1
Main Category	MainCategory::Biochemistry, MainCategory::Pharmacology
Sub Category	SubCategory::General Principles
Prompt	[[Prompt::A 16-year-old girl is brought to the emergency department by EMS after her father found her lying on the bathroom floor gasping for air. On admission, the patient is tachycardic and tachypneic with a temperature of 39.8 ˚C (103.6 ˚F). ABGs show good oxygen saturation with significant respiratory alkalosis. After initial stabilization, the patient admits that she had ingested half a tube of methyl salicylate cream a few hours back after she found out she was pregnant. What is the mechanism behind the associated fever in this patient?]]
Answer A	AnswerA::Direct inhibition of the electron transport chain
Answer A Explanation	AnswerAExp::Direct inhibition of the ETC occurs by disrupting electron transport. It is usually seen with agents like carbon monoxide and cyanide. Inhibition of the ETC does not lead to fever since energy production decreases.
Answer B	AnswerB::Inhibition of the mitochondrial ATP synthase
Answer B Explanation	AnswerBExp::Oligomycin is the typical agent that inhibits the mitochondrial ATP synthase. With inhibition of ATP synthase, fever is usually not present since the excess energy is not released as heat.
Answer C	AnswerC::Release and accumulation of pyrogenic cytokines
Answer C Explanation	AnswerCExp::Release of pyrogenic cytokines, especially IL-1 and IL-6, is responsible for the febrile reaction to infectious processes.
Answer D	AnswerD::Increase permeability of the inner mitochondrial membrane
Answer D Explanation	AnswerDExp::Salicylates like aspirin, and methyl salicylate (oil of wintergreen) are uncoupling agents that increase the permeability of the inner mitochondrial membrane leading to loss of energy as heat and decrease in ATP production.
Answer E	AnswerE::Increase in proton gradient across electron transport chain
Answer E Explanation	AnswerEExp::An increase in proton gradient across electron transport chain can be seen with agents that inhibit ATP synthase. Inhibition of ATP synthase is usually not associated with fever.
Right Answer	RightAnswer::D
Explanation	[[Explanation::Salicylates are agents with analgesic and anti-inflammatory properties found in many OTC drugs and preparations. Since these agents are so ubiquitous, salicylate toxicity is an important cause of mortality. Patients usually present with tachycardia and tachypnea. Arterial blood gases would initially show significant respiratory alkalosis that progresses eventually into a combined disturbance of respiratory alkalosis and metabolic acidosis. Tinnitus is usually a common symptom of salicylate toxicity as well. Almost all patients with significant toxicity have fever on presentation. The mechanism behind the development of fever is the "uncoupling" nature of salicylates that increases the permeability of the inner mitochondrial membrane. This uncouples electron transport from ATP synthesis leading instead to a dissipation of energy as heat. Other examples of uncoupling agents include other salicylates like aspirin as well as thermogenin found in brown adipose tissue of infants, and 2,4-dinitrophenol. Educational Objective: Salicylates like methyl salicylate (oil of wintergreen) are uncoupling agents that increase the permeability of the inner mitochondrial membrane leading to loss of energy as heat and decrease in ATP production. References: Gutknecht J. Salicylates and proton transport through lipid bilayer membranes: a model for salicylate-induced uncoupling and swelling in mitochondria. J Membr Biol. 1990;115(3):253-60.]]
Approved	Approved::Yes
Keyword	WBRKeyword::Electron transport chain, WBRKeyword::Oxidative phosphorylation, WBRKeyword::Aspirin toxicity, WBRKeyword::Salicylate toxicity, WBRKeyword::Uncoupling agents
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