![]() Overall, APAP overdose is responsible for 46% of all cases of ALF in the US and has now grown to be a significant public health problem 6. ![]() Thus, APAP hepatotoxicity contributes to around 70,000 hospitalizations each year in the US 5. While a number of APAP overdose cases are due to suicide attempts, the availability of combination products, where the presence of APAP may not be easily recognized, has led to an increase in unintentional and chronic APAP overdose, accounting for over 50% of cases of APAP-related ALF 4. Because of the ubiquitous nature and broad availability of the drug, this has resulted in APAP hepatotoxicity being the most frequent cause of acute liver failure (ALF) in the US 2 and other Western countries 3. Though the drug is safe and effective at therapeutic doses, the therapeutic window is narrow, and an overdose is highly hepatotoxic. In spite of these new insights into the mechanisms of liver injury, significant controversy still exists on the role of innate immunity in APAP-induced hepatotoxicity.Īcetaminophen (APAP) is one of the most common analgesic and antipyretic drugs in use globally 1. In addition, the discovery of the role of mitochondrial dynamics and autophagy in APAP-induced liver injury provides additional insight into the elaborate cell signaling mechanisms involved in the pathogenesis of this important clinical problem. The identification of specific mediators of necrotic cell death further establishes the regulated nature of APAP-induced hepatocyte cell death. ![]() Thus, it is now established that mitochondrial oxidative and nitrosative stress is a key mechanistic feature involved in downstream signaling after APAP overdose. More recent investigations into APAP hepatotoxicity have established the critical role of mitochondrial dysfunction in mediating liver injury as well as clarified mechanisms of APAP-induced hepatocyte cell death. However, the narrow therapeutic window of this intervention necessitates a better understanding of the intricacies of APAP-induced liver injury for the development of additional therapeutic approaches that can benefit late-presenting patients. Acetaminophen (APAP) overdose is the most common cause of acute liver failure in the US, and decades of intense study of its pathogenesis resulted in the development of the antidote N-acetylcysteine, which facilitates scavenging of the reactive metabolite and is the only treatment in clinical use. ![]()
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