WBR0860

Author	[[PageAuthor::Rim Halaby, M.D. [1] (Reviewed by Alison Leibowitz)]]
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 ER by EMS after her father finds her lying on the bathroom floor gasping for air. On admission, the patient is tachycardic and tachypneic with a temperature of 39.8˚C. ABGs show normal oxygen saturation with significant respiratory alkalosis. After initial stabilization, the patient discloses that she had ingested half a tube of methyl salicylate cream 2 hours prior to hospitalization after she found out she was pregnant. Which of the following options is the most likely 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 often occurs with the presence of agents such as carbon monoxide, cyanide, rotenone, and antimycin A. Inhibition of the ETC does not lead to fever because energy is not dissipated as heat, due to the inhibition of oxidative phosphorylation.]]
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 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 are uncoupling agents that increase the permeability of the inner mitochondrial membrane, disallowing for a proton gradient, which is necessary for ATP synthesis. Because energy is no longer generated through ATP synthesis, it instead dissipates as heat.]]
Answer E	AnswerE::Increase in proton gradient across electron transport chain
Answer E Explanation	[[AnswerEExp::An increase in the 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, because the mitochondrial matrix lacks the protons necessary for oxidation, the process responsible for generating heat.]]
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 may be fatal. Patients often present with tachycardia, tachypnea, and tinnitus. Arterial blood gases initially show significant respiratory alkalosis, which progress into a combined disturbance of respiratory alkalosis and metabolic acidosis. Patients with salicylate toxicity often have fever on presentation. Fever develops as a result of salicylates, a type of uncoupling agent, which increase the permeability of the inner mitochondrial membrane. This increased permeability disallows for the proton gradient, which is necessary for ATP synthesis, leading instead to a dissipation of energy as heat. Other examples of uncoupling agents include aspirin as well as thermogenin (found in brown adipose tissue of infants), other salicylates, and 2,4-dinitrophenol. Educational Objective: Salicylates are uncoupling agents that increase the permeability of the inner mitochondrial membrane, disallowing for a proton gradient, which is necessary for ATP synthesis. Because energy is no longer generated through ATP synthesis, it instead dissipates as heat. 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
Linked Question	Linked::
Order in Linked Questions	LinkedOrder::