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

Abstract

Keywords acetaminophen hepatotoxicity, drug induced liver damage, liver injury, paracetamol hepatotoxicity, repeated supratherapeutic acetaminophen ingestion, repeated supratherapeutic paracetamol ingestion AIMSTo 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). METHODSSystematic literature review with collation and analysis of individual-level data from reported cases of RSPI associated with liver damage. RESULTSIn 199 cases meeting the selection criteria, severe liver damage (ALT/AST ≥1000 IU l À1 , 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 À1 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. CONCLUSIONSSevere liver damage is reported after RSPI in adults and children, sometimes involving reported doses below current thresholds for intervention. Paracetamol concentrations <20 mg l À1 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. British Journal of Clinical PharmacologyBr J Clin Pharmacol (2016) 82 923-931 923

Updated guidelines for the management of paracetamol poisoning in Australia and New Zealand

“…Patients who meet the criteria for supratherapeutic ingestion (Box 1) should have the paracetamol concentration and ALT measured. There is evidence that the combination of a low paracetamol concentration and normal ALT at any time indicates there is minimal risk of subsequent hepatotoxicity . If the paracetamol concentration is greater than 20 mg/L (132 μmol/L) or ALT is greater than 50 U/L, then acetylcysteine is commenced, and pathology repeated 8 hours after the initial sampling.…”

Suspected paracetamol overdose in Monrovia, Liberia: a matched case–control study

“…Among the cases with measured plasma paracetamol concentration, we note that there is debate over the most appropriate thresholds (10 or 20 μg/ml) [27,32]. Among cases with a sample collected on the day of admission, almost all exceeded 10 μg/mL and concurrently had elevated transaminases consistent with paracetamol intoxication.…”

Risk Factors for Hepatotoxicity Due to Paracetamol Overdose in Adults

“…For a more detailed assessment of the risk factors for hepatotoxicity, and in view of the fact that a considerable proportion of patients presented with a moderate increase in plasma aminotransferase levels (over the normal range but below 1000 IU/L), we divided the study population into three groups, as described above. In the available literature, there are numerous studies that have discussed new risk factors for hepatotoxicity [ 9 , 10 , 11 , 15 , 16 , 19 , 20 , 21 , 22 , 23 , 24 ], including parameters related to the patient’s medical history, acetaminophen dose, biochemical findings, or a combination thereof. Quantitative and qualitative medical variables, which might serve as such risk factors in the studied population, are presented in Table 1 and Table 2 .…”