Intestinal injury in paracetamol overdose (ATOM-8).

Abstract

Paracetamol, a widely used medication, is known for its delayed hepatotoxicity in cases of overdose. However, the potential for intestinal toxicity resulting from very high paracetamol concentrations during absorption is not well explored. This study aims to investigate the presence of intestinal toxicity and its correlation with observations in early and late paracetamol toxicity. Serial samples of 30 patients with acute paracetamol overdose (>10g or 200mg/kg) were prospectively tested. Markers of enterocyte damage, including plasma intestinal fatty acid binding protein (IFABP) and selected gut-related microRNAs (miR-21, miR-122, miR-194, and miR-215), were analyzed. Sub-analysis was performed on patients presenting with hyperlactatemia defined as a lactate greater than 2mmol/L within 12h post ingestion. In paracetamol overdose patients, median plasma IFABP was significantly elevated compared with healthy controls (720μg/L [interquartile range, IQR, 533-1644] vs 270μg/L [IQR 153-558], P<0.001). Four patients had early hyperlactatemia and had significantly higher median plasma IFABP compared with those without early hyperlactatemia (3028μg/L [IQR 1399-3556] vs 574μg/L [IQR 526-943], P=0.007). Furthermore, two microRNAs (miR-122 and miR-215) were downregulated in early hyperlactatemia (P=0.019 and P=0.006, respectively). Plasma IFABP concentrations correlated with paracetamol concentration (Spearman's r=0.55) and lactate (r=0.60). Paracetamol overdose causes concentration-related intestinal toxicity, and this is a possible explanation for the early hyperlactatemia syndrome. Intestinal toxicity has potential impacts on pharmacokinetics of other agents ingested and on the evolution of hepatotoxicity. Further studies are required to explore the mechanisms and prognostic implications of intestinal toxicity.