N-acetylcysteine for non-paracetamol (acetaminophen)-related acute liver failure

Acute liver failure is a rare and serious disease. Acute liver failure may be paracetamol-induced or non-paracetamol-induced. Acute liver failure not caused by paracetamol (acetaminophen) has a poor prognosis with limited treatment options. N-acetylcysteine has been successful in treating paracetamol-induced acute liver failure and reduces the risk of needing to undergo liver transplantation. Recent randomised clinical trials have explored whether the benefit can be extrapolated to treat non-paracetamol-related acute liver failure. The American Association for the Study of Liver Diseases (AASLD) 2011 guideline suggested that N-acetylcysteine could improve spontaneous survival when given during early encephalopathy stages for patients with non-paracetamol-related acute liver failure.

To assess the benefits and harms of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, in people with non-paracetamol-related acute liver failure.

We searched the Cochrane Hepato-Biliary Group Controlled Trials Register (searched 25 June 2020), Cochrane Central Register of Controlled Trials (CENTRAL; 2020, Issue 6) in The Cochrane Library, MEDLINE Ovid (1946 to 25 June 2020), Embase Ovid (1974 to 25 June 2020), Latin American and Caribbean Health Science Information database (LILACS) (1982 to 25 June 2020), Science Citation Index Expanded (1900 to 25 June 2020), and Conference Proceedings Citation Index - Science (1990 to 25 June 2020).

We included randomised clinical trials that compared N-acetylcysteine at any dose or route with placebo or no intervention in participants with non-paracetamol-induced acute liver failure.

We used standard methodological procedures as described in the Cochrane Handbook for Systematic Reviews of Interventions. We conducted meta-analyses and presented results using risk ratios (RR) with 95% confidence intervals (CIs). We quantified statistical heterogeneity by calculating I². We assessed bias using the Cochrane risk of bias tool and determined the certainty of the evidence using the GRADE approach.

We included two randomised clinical trials: one with 183 adults and one with 174 children (birth through age 17 years). We classified both trials at overall high risk of bias. One unregistered study in adults is awaiting classification while we are awaiting responses from study authors for details on trial methodology (e.g. randomisation processes). We did not meta-analyse all-cause mortality because of significant clinical heterogeneity in the two trials. For all-cause mortality at 21 days between adults receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (N-acetylcysteine 24/81 (29.6%) versus placebo 31/92 (33.7%); RR 0.88, 95% CI 0.57 to 1.37; low certainty evidence). The certainty of the evidence was low due to risk of bias and imprecision. Similarly, for all-cause mortality at one year between children receiving N-acetylcysteine versus placebo, there was inconclusive evidence of effect (25/92 (27.2%) versus 17/92 (18.5%); RR 1.47, 95% CI 0.85 to 2.53; low certainty evidence). We downgraded the certainty of evidence due to very serious imprecision.  We did not meta-analyse serious adverse events and liver transplantation at one year due to incomplete reporting and clinical heterogeneity. For liver transplantation at 21 days in the trial with adults, there was inconclusive evidence of effect (RR 0.72, 95% CI 0.49 to 1.06; low certainty evidence). We downgraded the certainty of the evidence due to serious risk of bias and imprecision. For liver transplantation at one year in the trial with children, there was inconclusive evidence of effect (RR 1.23, 95% CI 0.84 to 1.81; low certainty of evidence). We downgraded the certainty of the evidence due to very serious imprecision.   There was inconclusive evidence of effect on serious adverse events in the trial with children (RR 1.25, 95% CI 0.35 to 4.51; low certainty evidence). We downgraded the certainty of the evidence due to very serious imprecision.  We did not meta-analyse non-serious adverse events due to clinical heterogeneity. There was inconclusive evidence of effect on non-serious adverse events in adults (RR 1.07, 95% CI 0.79 to 1.45; 173 participants; low certainty of evidence) and children (RR 1.19, 95% CI 0.62 to 2.16; 184 participants; low certainty of evidence). None of the trials reported outcomes of proportion of participants with resolution of encephalopathy and coagulopathy or health-related quality of life. The National Institute of Health in the United States funded both trials through grants. One of the trials received additional funding from two hospital foundations' grants. Pharmaceutical companies provided the study drug and matching placebo, but they did not have input into study design nor involvement in analysis.

The available evidence is inconclusive regarding the effect of N-acetylcysteine compared with placebo or no N-acetylcysteine, as an adjunct to usual care, on mortality or transplant rate in non-paracetamol-induced acute liver failure. Current evidence does not support the guideline suggestion to use N-acetylcysteine in adults with non-paracetamol-related acute liver failure, nor the rising use observed in clinical practice. The uncertainty based on current scanty evidence warrants additional randomised clinical trials with non-paracetamol-related acute liver failure evaluating N-acetylcysteine versus placebo, as well as investigations to identify predictors of response and the optimal N-acetylcysteine dose and duration.