Overdose pattern and outcome in paracetamol‐induced acute severe hepatotoxicity

Abstract

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Paracetamol hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. • Conflicting data exist regarding the impact of overdose pattern upon subsequent mortality or need for emergency liver transplantation. WHAT THIS STUDY ADDS • Unintentional paracetamol overdose is independently associated with reduced survival compared with intentional overdose. • Unintentional paracetamol overdoses should be treated as high‐risk for the development of multiorgan failure, and should be considered for N‐acetyl cysteine treatment irrespective of admission serum paracetamol concentrations. • The King's College poor prognostic criteria have reduced sensitivity in unintentional overdose patients and alternative prognostic criteria may be required. AIMS Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol‐induced ALF resulting from different overdose patterns are reported. METHODS Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit. RESULTS Between 1992 and 2008, 663 patients were admitted with paracetamol‐induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King's College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P= 0.032). CONCLUSIONS Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses.

Role of endoplasmic reticulum stress in drug‐induced toxicity

“…Although APAP is usually deemed as a safe drug, APAP intoxication after an overdose can lead to massive hepatocellular necrosis and acute liver failure (Craig et al. 2011). Moreover, there is evidence that the maximum recommended dose (i.e., 4 g/day) can induce mild to moderate hepatic cytolysis, even in healthy individuals (Watkins et al.…”

Differences in Early Acetaminophen Hepatotoxicity between Obeseob/obanddb/dbMice

“…Although APAP is usually deemed a safe drug, APAP intoxication is relatively common, in particular in the context of unintentional overdosage (Larson et al, 2005;Craig et al, 2011). Several predisposing factors could enhance the risk and the severity of APAP-induced acute liver failure, including malnutrition, alcoholic liver disease, hepatitis C virus infection, and nonalcoholic fatty liver disease (NAFLD), which is often associated with obesity and type 2 diabetes (Nguyen et al, 2008;Myers and Shaheen, 2009).…”

Acetylcholinesterase Inhibitors for Alzheimer’s Disease Treatment Ameliorate Acetaminophen-Induced Liver Injury in Mice via Central Cholinergic System Regulation

“…The liver injury induced by APAP overdose is a critical issue, as it is the most frequent cause of acute liver injury in different regions of the world (Gow et al, 2004;Larson et al, 2005;Wei et al, 2007;Craig et al, 2011;Li and Martin, 2011;Lee, 2012). Patients with the most severe symptoms may develop hepatic encephalopathy and require liver transplantation (Ostapowicz et al, 2002;Russo et al, 2004;Lee, 2012).…”