Paracetamol, alcohol and the liver

Abstract

It is claimed that chronic alcoholics are at increased risk of paracetamol (acetaminophen) hepatotoxicity not only following overdosage but also with its therapeutic use. Increased susceptibility is supposed to be due to induction of liver microsomal enzymes by ethanol with increased formation of the toxic metabolite of paracetamol. However, the clinical evidence in support of these claims is anecdotal and the same liver damage after overdosage occurs in patients who are not chronic alcoholics. Many alcoholic patients reported to have liver damage after taking paracetamol with`therapeutic intent' had clearly taken substantial overdoses. No proper clinical studies have been carried out to investigate the alleged paracetamol± alcohol interaction and acute liver damage has never been produced by therapeutic doses of paracetamol given as a challenge to a chronic alcoholic.The paracetamol±alcohol interaction is complex; acute and chronic ethanol have opposite effects. In animals, chronic ethanol causes induction of hepatic microsomal enzymes and increases paracetamol hepatotoxicity as expected (ethanol primarily induces CYP2E1 and this isoform is important in the oxidative metabolism of paracetamol). However, in man, chronic alcohol ingestion causes only modest (about twofold) and short-lived induction of CYP2E1, and there is no corresponding increase (as claimed) in the toxic metabolic activation of paracetamol. The paracetamol±ethanol interaction is not speci®c for any one isoform of cytochrome P450, and it seems that isoenzymes other than CYP2E1 are primarily responsible for the oxidative metabolism of paracetamol in man. Acute ethanol inhibits the microsomal oxidation of paracetamol both in animals and man. This protects against liver damage in animals and there is evidence that it also does so in man. The protective effect disappears when ethanol is eliminated and the relative timing of ethanol and paracetamol intake is critical.In many of the reports where it is alleged that paracetamol hepatotoxicity was enhanced in chronic alcoholics, the reverse should have been the case because alcohol was actually taken at the same time as the paracetamol. Chronic alcoholics are likely to be most vulnerable to the toxic effects of paracetamol during the ®rst few days of withdrawal but maximum therapeutic doses given at this time have no adverse effect on liver function tests. Although the possibility remains that chronic consumption of alcohol does increase the risk of paracetamol hepatotoxicity in man (perhaps by impairing glutathione synthesis), there is insuf®cient evidence to support the alleged major toxic interaction. It is astonishing that clinicians and others have unquestioningly accepted this supposed interaction in man for so long with such scant regard for scienti®c objectivity.

Acetaminophen‐induced acute liver failure

“…Because the subjects with ALF reporting use of Յ4 g acetaminophen per day were often alcohol abusers (65%) and the amount of daily alcohol consumed was greater than that reported by patients who admitted to taking Ͼ4 g acetaminophen per day (data not shown), ethanol may still serve as an important co-factor in these lower-dose subjects. 4,6,13,24,[34][35][36] The overall transplant-free survival rate of 65% in acetaminophen subjects is comparable to that of prior studies and continues to be more favorable than that observed for most other ALF causes. 13,37,38,39 The use of the King's criteria at admission to predict outcome was inaccurate, and use of the APACHE II provided a more accurate of assessment outcome.…”

Staggered overdose pattern and delay to hospital presentation are associated with adverse outcomes following paracetamol‐induced hepatotoxicity

“…A third explanation is that staggered overdoses act as a surrogate marker for other risk factors for adverse outcomes following paracetamol overdose, such as older age and chronic alcohol abuse [22,24], both of which were more common in the staggered overdose group. Whilst acute alcohol consumption has an inhibitory effect on the oxidative metabolism of paracetamol and may be hepatoprotective [25], this protective effect is probably lost in the context of chronic alcohol abuse or where there is a delay between alcohol and paracetamol intake [26], perhaps explaining why staggered overdose patients had worse clinical outcomes despite the increased incidence of acute alcohol consumption at the time of overdose (54% vs. 39%) in this subgroup.…”

Acute Ethanol Coingestion Confers a Lower Risk of Hepatotoxicity after Deliberate Acetaminophen Overdose

“…16,[20][21][22] However, there is some uncertainty about the significance of chronic ethanol consumption as an independent risk factor, because the association is confounded by delayed presentation to hospital and initiation of NAC. [23][24][25][26] Exclusion of patients who presented more than 24 hours after ingestion does not allow us to address whether chronic ethanol excess might influence the development of hepatotoxicity in patients who present late. Induction of cytochrome 2E1 requires chronic exposure to ethanol concentrations >250 mg ⁄ dL, which might be encountered only in patients with extremely heavy drinking patterns.…”