Determinants of hepatotoxicity after repeated supratherapeutic paracetamol ingestion: systematic review of reported cases

Abstract

Aims: To evaluate the role of reported daily dose, age and other risk factors, and to assess the value of quantifying serum transaminase activity and paracetamol (acetaminophen) concentration at initial assessment for identifying patients at risk of hepatotoxicity following repeated supratherapeutic paracetamol ingestion (RSPI).

Methods: Systematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage.

Results: In 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l(-1) , liver failure or death) was reported in 186 (93%) cases including 77/78 (99%) children aged ≤6 years. Liver failure occurred in 127 (64%) cases; of these 49 (39%) died. Maximum ingested daily paracetamol doses were above UK recommendations in 143 (72%) patients. US-Australasian thresholds for repeated supratherapeutic ingestions requiring intervention were not met in 71 (36%) cases; of these 35 (49%) developed liver failure and 10 (14%) died. No cases developing liver damage had paracetamol concentration < 20 mg l(-1) and a normal ALT/AST on initial presentation or when RSPI was first suspected, but both of these values were only available for 79 (40%) cases.

Conclusions: Severe liver damage is reported after RSPI in adults and children, sometimes involving reported doses below current thresholds for intervention. Paracetamol concentrations <20 mg l(-1) with normal serum ALT/AST activity on initial assessment suggests a low risk of subsequent liver damage. These findings are, however, limited by low patient numbers, publication bias and the accuracy of the histories in reported cases.

Keywords: acetaminophen hepatotoxicity; drug induced liver damage; liver injury; paracetamol hepatotoxicity; repeated supratherapeutic acetaminophen ingestion; repeated supratherapeutic paracetamol ingestion.

Figure 1

Flow diagram for publication review and article selection

Figure 2

Liver outcome (hepatic injury ▲, hepatotoxicity +, liver failure ◊, death ■) relative to timed serum paracetamol concentrations with illustration of the UK () and US (− −) treatment lines for acute paracetamol ingestion

Figure 3

Liver outcome (hepatic injury ▲, hepatotoxicity +, liver failure ◊ and death ■) relative to serum paracetamol concentration and initial ALT or AST activity. AST: aspartate aminotransferase; ALT: alanine aminotransferase