N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review protocol

Chughlay et al. Systematic Reviews (2015) 4:84 DOI 10.1186/s13643-015-0075-6 PROTOCOL Open Access N-acetylcysteine for non-paracetamol drug-induced liver injury: a systematic review protocol Mohamed Farouk Chughlay1*, Nicole Kramer2, Mahmoud Werfalli3, Wendy Spearman4, Mark Emmanuel Engel5 and Karen Cohen1 Abstract Background: Drug-induced liver injury (DILI) refers to acute or chronic liver injury that may occur as a consequence of using drugs and herbal or dietary supplements. Specific therapies for DILI are limited. There is considerable evidence for efficacy and safety of N-acetylcysteine (NAC) in management of paracetamol-induced liver injury. More recently, research has explored the use of NAC in non-paracetamol drug-induced liver injury. It is important to summarise the evidence of NAC for non-paracetamol DILI to determine if NAC may be considered a therapeutic option in this condition. Methods/design: We will conduct a systematic review of the benefit and harm of NAC in non-paracetamol druginduced liver injury. Primary and secondary outcomes of interest are pre-specified. Primary outcomes include all-cause mortality, mortality due to DILI, time to normalisation of liver biochemistry (e.g. return of alanine transaminase to <100 U/l and/or international normalized ratio (INR) <1.5) and adverse events. Secondary outcomes include transplantation rate, time to transplantation, transplant-free survival and duration of hospitalisation. We will include randomized controlled trials (RCTs) and prospective cohort studies. RCTs will contribute to the evaluation of safety and efficacy of NAC, whereas, the cohort studies will contribute exclusively to the evaluation of safety. We will search several bibliographic databases (including PubMed, Scopus, CINAHL, CENTRAL), grey literature sources, conference proceedings and ongoing trials. Following data extraction and assessment of the risk of bias, we will conduct a meta-analysis if feasible, as well as subgroup analyses. We will assess and explore clinical and statistical heterogeneity. Discussion: The aim of this review is to provide evidence on the effectiveness and safety of NAC in non-paracetamol DILI. We anticipate that the results could aid health care practitioners, researchers and policymakers in the decisionmaking regarding the use of NAC in patients with non-paracetamol DILI. Systematic review registration: PROSPERO CRD42014008771 Keywords: N-acetylcysteine, Acetylcysteine, Drug-induced, Hepatitis, Liver, Liver failure, Non-paracetamol, Non-acetaminophen Background Drug-induced liver injury (DILI) refers to acute or chronic liver injury that may occur as a consequence of using drugs and herbal or dietary supplements [1, 2]. According to recent estimates, the yearly incidence of DILI is estimated to be between 14–19 cases per 100,000 [3, 4]. * Correspondence: 1 Division of Clinical Pharmacology, Department of Medicine, Faculty of Health Sciences, University of Cape Town, Anzio Road, Observatory 7925 Cape Town, South Africa Full list of author information is available at the end of the article While this may suggest that the condition is uncommon, there is still a considerable potential for harm. In the USA, it is the most common cause of acute liver failure, with 11 % of cases due to idiosyncratic DILI [5]. Moreover, the true incidence of DILI may be underestimated due to diagnostic difficulty as well as underreporting [2]. A number of risk factors are thought to be associated with the development of DILI. In general, older age is a risk factor, with DILI occurring more commonly in adults compared with children [6]. While there seems to be a biological basis for age as a risk factor, it may also © 2015 Chughlay et al. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http:// creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Chughlay et al. Systematic Reviews (2015) 4:84 reflect that adults are more frequently exposed to potential hepatotoxins compared with children. However, age as a risk factor does not always hold true, such that for certain drugs, the risk is greater in children e.g. DILI caused by valproic acid is more common in children. Females appear to be at a greater risk compared to their male counterparts [7]. Certain genetic variations place individuals at risk of DILI due to specific drugs e.g. isoniazid DILI and N-acetyltransferase 2 gene polymorphism as well as the HLA-*B5701 genotype and flucloxacillin [8]. While these genetic variations have been shown to increase the risk for the development of DILI, they do not predict severity of injury. Pre-existing liver disease is a further independent risk factor, with this being observed in patients coinfected with viral hepatitis and tuberculosis who develop DILI in response to antiviral and antituberculous drugs [9, 10]. Furthermore, alcohol abuse and malnutrition are also risk factors associated with the development of DILI [2]. The general management of DILI consists of the discontinuation of the offending drug in combination with supportive treatment [2]. Patients often require prolonged hospital stays which may be costly to both patient and health service. Therapeutic re-challenge with the offending drug is generally not recommended but may be attempted in certain instances after a thorough consideration of the risks and potential benefits. There are specific therapies available for DILI caused by certain drugs. However, these are limited to carnitine for valproic acid and N-acetylcysteine (NAC) for paracetamol overdose [11, 12]. This limited availability highlights the need for further research into therapies for DILI. NAC was first used as a treatment for paracetamol overdose in 1979 [13]. Since then, it has been firmly established as an effective and safe treatment for this condition [12]. NAC has also been shown to be safe and effective outside of paracetamol overdose. NAC has been evaluated as a treatment option for non-paracetamol acute liver failure in adults and paediatric patients. In a randomised clinical trial comparing NAC with placebo in adults with non-paracetamol acute liver failure, NAC was associated with an improvement in transplant-free survival in a subgroup of patients with grade 1 and grade 2 encephalopathy [14]. In a prospective study conducted in adults with non-paracetamol acute liver failure at a centre without the facility for transplantation, the use of NAC was associated with a mortality benefit [15]. In a retrospective study in paediatric patients with non-paracetamol acute liver failure, NAC was associated with a shorter hospital stay and improved survival posttranspla (...truncated)