Paracetamol Hepatotoxicity After Therapeutic Doses: Susceptibility Factors and Early Detection Biomarkers

Paracetamol (acetaminophen, APAP) is a ubiquitous painkiller and antipyretic available worldwide in numerous over-the-counter and prescription medications. At supra-therapeutic doses, APAP is a well described hepatotoxic agent and a significant public health concern since 30'000 hospitalizations are estimated to be related to APAP drug induced liver injury (DILI) each year in the US. APAP is indeed the commonest cause of acute liver failure (ALF) in the US and Europe with an estimated overall mortality of 28%. Half APAP overdoses are unintentional and the poor ability of patients to identify products with APAP has been documented. In hospitals, 1% all drug prescriptions have contained an overdosed APAP prescription highlighting the need for increased awareness on unintentional APAP overdose.

At the recommended therapeutic dose of 4g/d, APAP is usually considered safe. However, associations between APAP therapeutic dosing and alanine aminotransferase (ALT) elevations have been demonstrated. Indeed, up to 1/3 healthy volunteers treated with therapeutic doses of APAP experienced 3x ALT elevation (up to 14x) after 3 days of treatment for up to 11 days. These results were confirmed in non-drinker patients. The multinational case-population SALT study reported 81 cases of ALF (49 in France) leading to transplantation after non-overdose APAP exposure in a 3 year follow-up and non-overdose APAP was associated with a 2x higher rate of ALF than NSAIDs. In the US, 17% of APAP induced ALF over a 41 month period were reported with an APAP dose inferior to 4g/day.

Malnutrition as a risk factor Some authors have suggested that therapeutic doses of APAP may be hepatotoxic in the presence of malnutrition and low body weight as well as chronic alcohol consumption and drugs inducing cytochromes P450 (CYPs). As glutathione (GSH) is synthesized from 3 amino-acids (aa)(Cys, Glu and Gly), protein or aa deficiency may result in GSH depletion. In rats, fasting was associated with increased APAP hepatotoxicity as a consequence of hepatic GSH decrease, and a 16h fasting period was sufficient to deplete GSH stores. GSH levels have been shown to be reduced in anorexic female patients as compared to controls and a positive correlation between GSH levels and BMI was observed. A small retrospective study (n=10) showed that severe hepatotoxicity after moderate APAP dose (4 to 10g/day) was preceded in 80% of cases by malnutrition. Several case reports of severe hepatotoxicity (some fatal) after therapeutic APAP doses in malnourished adults have been published. In the pediatric population, ALF cases were reported after therapeutic APAP doses after viral infection and low nutrition status. However, no well conducted study has aimed to prospectively assess the impact of malnutrition on the toxicity to therapeutic doses of APAP.

FDA experts pointed out that APAP is frequently used in cachexia patients. Cachexia is a complex syndrome characterized by several homeostatic perturbations including progressive involuntary weight loss, accompanied by wasting, early satiety, weakness and anorexia. A broad spectrum of clinical disease is associated with cachexia. The prevalence of malnutrition has been observed in 20-29% of hospitalized patients in Europe, and 33% in surgical wards. Pickering et al. demonstrated that APAP metabolism shifts toward the toxic oxidative pathways after major aortic surgery suggesting that those patients may be particularly susceptible. Drug consumption data also indicates that APAP utilization is high is post-operative settings. The British National Formulary has recommended a maximal dose of 60mg/kg IV APAP for use in adults whose weight is less than 50kg and 3g/day IV in chronic malnutrition or dehydration. Surprisingly, no such recommendation is available for oral APAP and which is commonly prescribed independently of the nutritional status. It is likely that cases of liver damage secondary to normal recommended dose are under-represented as the dose is not perceived as excessive and not described as such in international guidelines for pain management. Considering the widespread use of APAP and the prevalence of malnutrition in surgery wards, it is of crucial clinical importance to clarify whether malnutrition predispose to APAP induced hepatotoxicity at the recommended dosage of 4g/day.

Biomarker of APAP hepatotoxicity: