Extrahepatic toxicity of acetaminophen: critical evaluation of the evidence and proposed mechanisms

Abstract

Research on acetaminophen (APAP) toxicity over the last several decades has focused on the pathophysiology of liver injury, but increasing attention is being paid to other known and possible adverse effects. It has been known for decades that APAP causes acute kidney injury, but confusion exists regarding prevalence, and the mechanisms have not been well investigated. More recently, a number of experimental, clinical and epidemiological studies have reported evidence for pulmonary, endocrine, neurological and neurodevelopmental toxicity, but the quality of evidence from those studies varies. It is important to consider these data due to implications for regulation and clinical practice. Here, we review the evidence and proposed mechanisms for extrahepatic adverse effects of APAP and weigh weaknesses and strengths in the data. We consider results from clinical, epidemiological and experimental research. Our goal is to determine the strength of claims regarding extrahepatic toxicity of APAP and to identify areas of need for future research. It is especially important to view claims of developmental effects of antenatal APAP exposure with a critical eye because APAP is currently the only over-the-counter medication recommended for pregnant women to self-treat pain and fever.

Acetaminophen Intoxication Rapidly Induces Apoptosis of Intestinal Crypt Stem Cells and Enhances Intestinal Permeability

“…Our observations highlight the fact that APAP toxicity is a whole‐body issue with pathological effects beyond liver injury. Previous reports have indicated APAP induces inflammation and injury of the kidney, lung, and brain . For this study, we focused on the gut due to the critical role the intestinal physiology and the microbiome play in regulating chronic conditions of the liver and potentially other organs .…”

“…Previous reports have indicated APAP induces inflammation and injury of the kidney, lung, and brain. (6)(7)(8) For this study, we focused on the gut due to the critical role the intestinal physiology and the microbiome play in regulating chronic conditions of the liver (9) and potentially other organs. (10) Currently, the role that intestinal barrier function and intestinal microbiota play in APAP-induced liver injury is somewhat unclear.…”

“…Thus, there are likely overlooked pathological effects of APAP overdose on target organs other than the liver that potentially contribute to the increased morbidity and mortality observed in APAP‐induced ALF transplant recipients. For example, a few studies have highlighted this possibility by identifying injury and inflammation in the brain, lung, and kidney following APAP overdose . The intestine is an organ with a particularly important role in both regulating and itself being modulated by liver disease due to the close physiological connections through portal circulation and hepatic biliary output .…”

“…For example, a few studies have highlighted this possibility by identifying injury and inflammation in the brain, lung, and kidney following APAP overdose. (6)(7)(8) The intestine is an organ with a particularly important role in both regulating and itself being modulated by liver disease due to the close physiological connections through portal circulation and hepatic biliary output. (9) Critically, the intestine must maintain a tightly regulated and efficient barrier to entry for the countless species of bacteria, fungi, and viruses that comprise the gut microbiome.…”

Preexisting diabetes mellitus had no effect on the no-observed-adverse-effect-level of acetaminophen in rats

“…APAP interferes with the formation of mitochondrial respiratory supercomplexes, and leads to decreased ATP generation and increased reactive oxygen species production (Barbier-Torres et al, 2017). In addition to liver injury, APAP induces renal toxicity via protein binding, oxidative stress, γ-glutamyl cycling, or GSH depletion in humans and rodents (Kennon-McGill and McGill, 2017).…”