April 11, 2025: What major organ system besides the liver may be injured after an acute acetaminophen poisoning?

April 11, 2025

Acetaminophen (APAP) is known as the most frequent cause of xenobiotic induced liver failure in the United States.1 Another major organ system that can be injured is the kidneys. For decades, acute kidney injury (AKI) and acute kidney failure has been reported in all age groups of patients who have ingested an overdose of APAP. This renal toxicity is independent of the hepatotoxicity and is not a result of a hepatorenal syndrome. A retrospective study performed at Vanderbilt University Medical Center demonstrated that AKI might be more common in acetaminophen poisoned patients who have high modified Models for End-Stage Liver Disease (m-MELD) scores; however, 26% of patients with low m-MELD scores also developed AKI.2

While the exact mechanisms of the nephrotoxicity are unclear, the P450 Cyp2E1 enzyme is highly suspect. Cyp2E1 is expressed in the proximal tubular cells. 4-methypyrazole (fomepizole), which inhibits Cyp2E1, attenuates apoptotic cell death in mouse and human kidney cells in an in vitro model of APAP poisoning.3 Unfortunately, historical experience and recent data would suggest that N-acetylcysteine (NAC) does not prevent the nephrotoxicity of APAP.3 This would suggest that while Cyp2E1 is a culprit enzyme for both the hepatotoxicity and nephrotoxicity, the downstream effects causing the apoptosis in each of the organs are different. Fascinating.

Saralyn R. Williams, MD, Professor of Emergency Medicine, Medicine, and Pediatrics

  1. Reuben A, Tillman H, Fontana RJ, et al. Outcomes of adults with acute liver failure between 1998-2013. Ann Int Med 2016;164:724-32.
  2. Stollings JL, Wheeler AP, Rice TW. Incidence and characterization of acute kidney injury after acetaminophen overdose. J Crit Care 2016;35:191-4.
  3. Akakpo JY, Ramachandran A, et al. Lack of mitochondrial Cyp2E1 drives acetaminophen-induced ER stress-mediated apoptosis in mouse and human kidneys: Inhibition by 4-methylpyrazole but not N-acetylcysteine. Toxicology 2023; 500:153692.

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