Can N-Acetylcysteine be Used in Non-Acetaminophen Induced Acute Liver Failure?

May 20, 2016

800px-Extra_Strength_Tylenol_and_Tylenol_PMBy David Pineles, MD

Peer Reviewed

In the early 1970’s, scientists discovered in animal models that a minor metabolite of acetaminophen, N-acetyl-p-benzoquinone imine (NAPQI), accumulates in the body after ingestion. This metabolite is normally conjugated by glutathione, but when acetaminophen is taken in excess, the body’s glutathione reserves are inadequate to inactivate all of the toxic NAPQI. This metabolite is then free to cause direct damage to hepatocytes. If present in high enough concentrations, the liver damage can be so extensive that it results in liver failure. As a corollary to that observation, use of measures to increase hepatic glutathione were found to abrogate the toxic effects of NAPQI [1,2]. Two medications that were known to increase hepatic glutathione concentration, methionine and cysteamine, were reported to prevent acetaminophen-induced hepatic injury [3,4]. However, these two agents caused severe side effects including flushing, vomiting, and “misery” [3].

A third agent, since found, N-acetylcysteine (NAC) replenishes hepatic stores of glutathione without causing major side effects. Multiple large trials have proven the efficacy of NAC for the treatment of acetaminophen overdose, the largest of which was performed by Smilkstein et al. and published in the New England Journal of Medicine in 1988. In this study, 2,540 patients suspected of acetaminophen overdose were given oral N-acetylcysteine therapy. The study demonstrated that AST or ALT concentrations rose above 1000 IU per liter, indicative of severe liver injury, in only 6.1% of patients who were treated with NAC within 10 hours after ingestion and in 26.4% of those treated between 10 and 24 hours after ingestion. The authors noted that these rates were lower than that of historical controls, and concluded that NAC treatment should be initiated within 8 hours of an acetaminophen overdose [5]. Two additional smaller studies demonstrated the efficacy of intravenous N-acetylcysteine therapy in patients in whom acetaminophen-induced hepatic failure had already developed [5,6]. In the first study published in the Lancet in 1990, Harrison et al. retrospectively analyzed 98 patients and highlighted that those treated with intravenous NAC had a 21% reduction in mortality [6]. A later randomized, placebo-controlled trial that included 50 patients treated with intravenous NAC showed a 28% reduction in mortality as well as a significantly lower incidence of cerebral edema and hypotension requiring inotropic support [7]. Due to the resounding evidence in its favor, NAC has become the universally accepted antidote for acetaminophen poisoning.

Given its efficacy in acetaminophen-induced acute liver failure, the use of NAC in non-acetaminophen-induced acute liver failure has been questioned. While acetaminophen is responsible for approximately 50% of all acute liver failure cases in the United States, idiosyncratic drugs constitute 12%, hepatitis B 7%, autoimmune hepatitis 5% and hepatitis A 3% of cases. Approximately 15% of cases of acute liver failure remain indeterminate [8]. Non-acetaminophen induced acute liver failure carries substantial morbidity and mortality.

In addition to its ability to replenish hepatic stores of glutathione, NAC has also been shown to have anti-inflammatory, antioxidant, inotropic, and vasodilating effects which improve microcirculatory blood flow and oxygen delivery to vital organs [10,11]. In a prospective study published in Hepatology in 2009, 47 patients with non-acetaminophen induced acute liver failure were treated with oral NAC at a dose of 140 mg/kg, followed by 70 mg/kg, for a total of 17 doses, 4 hours apart and within 6 hours of admission. Compared to historical controls, the patients who received oral NAC had a slight, though significantly reduced overall mortality compared to those who did not receive NAC (53.2% versus 72.7%, p=0.05) [12]. The study is intrinsically flawed by use of historical controls who were not necessarily treated at the same time point as the study subjects.

In a prospective, double-blind trial of 173 patients with non-acetaminophen-induced acute liver failure, patients were randomized to receive an infusion of either 5% dextrose (placebo) or 5% dextrose with N-acetylcysteine at a loading dose of 150 mg/kg/hour over one hour followed by 12.5 mg/kg/hour for 4 hours, then continuous infusions of 6.25 mg/kg for the remaining 67 hours. The intravenous NAC group had a significantly higher transplant-free survival as compared to the placebo group (40% versus 27%, p=0.043). Of note, sub-group analysis revealed that the benefits of transplant-free survival were restricted to West Haven encephalopathy coma grade I-II patients who received NAC, rather than those with more severe neurologic defects (West Haven coma grade III-IV patients) [13]. While this may be interpreted to mean that initiation of NAC will only benefit those at early stages of disease, it is possible to interpret these findings to mean that the patients with coma grade I-II were less sick, overall, than those with coma grade III-IV and therefore would have had an improved prognosis regardless of NAC treatment. In 2013, Singh et al. analyzed that same study cohort of 173 patients with non-acetaminophen induced acute liver failure, stratified by coma grade (I-II vs. III-IV) to examine the effect of NAC on hepatic serological biomarkers rather than overall mortality. They found that those patients with coma grade I-II treated with intravenous NAC showed a significant improvement in bilirubin and ALT levels when compared to those that received placebo with the similar coma grade (p<0.02) [14]. These findings support the hypothesis that individuals with coma grade I-II appear to benefit most from NAC treatment. However, the study is limited by the fact that there were a small number of patients with coma grade III-IV encephalopathy at time of randomization.

Unfortunately, the above studies are all limited by their smaller sample sizes with a lack of power, and so their generalizability is restricted. A recent meta-analysis assessed the efficacy and safety of NAC in non-acetaminophen induced acute liver failure. The authors studied four clinical trials in their meta-analysis that included a total of 331 patients who received NAC treatment and 285 control patients. (Two of these studies were discussed earlier [12,13]). No statistical difference was identified between the NAC group and the control group with regard to overall survival [71% versus 67%; 95% CI, 1.16 (0.81-1.67); p=0.42]. However, there was a significant difference in survival with native liver [41% versus 30%; 95% CI, 1.61 (1.11-2.34); p=0.01] and in post-transplantation survival [85.7% versus 71.4%; 95% CI, 2.44 (1.11-5.37); p=0.03]. Lastly, the authors found that the side effects of NAC therapy were mainly nausea, vomiting, and diarrhea and constipation [15]. One limitation of this meta-analysis is that the authors did not stratify the patients by coma grade, which may have biased the study towards results demonstrating no benefit of NAC therapy. Based on these results, it would appear that although overall survival is not improved, the benefit of NAC therapy in those with non-acetaminophen induced acute liver failure outweighs the risk.

Based on the available data, The American Association for the Study of Liver Diseases (AASLD) recommends (with level III evidence) that NAC be used in cases of acute liver failure in which acetaminophen ingestion is possible or when knowledge of circumstances surrounding admission is inadequate but aminotransferases suggest acetaminophen poisoning. In addition, the AASLD recommends (with level I evidence) that NAC may be beneficial for acute liver failure due to drug-induced liver injury [16].

Despite the marginal benefit from NAC therapy with coma grade I-II, the routine use of NAC in non-acetaminophen-induced-acute liver failure patients is not strongly promoted. However, given the available data and the relatively safe side effect profile of NAC, practitioners should strongly consider early administration of NAC in patients with non-acetaminophen-induced-acute liver failure, especially those with coma grade I-II, in non-transplant centers while awaiting referral or when transplantation is not an option.

Dr. David Pineles is an internal medicine resident at NYU Langone Medical Center

Peer Reviewed by Michael Poles, MD Associate Professor of Medicine, Division of Gastroenterology, NYU Langone Medical Center

Image courtesy of Wikimedia Commons


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