Lee WM, Hynan LS, Rossaro L, Fontana RJ, Stravitz RT, Larson AM, et al.; Acute Liver Failure Study Group. Intravenous N-acetylcysteine improves transplant-free survival in early stage non-acetaminophen acute liver failure. Gastroenterology 2009;137:856–886. (Reprinted with permission.)
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BACKGROUND & AIMS: N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. METHODS: In a prospective, double-blind trial, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were stratified by site and coma grade and assigned randomly to groups that were given NAC or placebo (dextrose) infusion for 72 hours. The primary outcome was overall survival at 3 weeks. Secondary outcomes included transplant-free survival and rate of transplantation. RESULTS: A total of 173 patients received NAC (n = 81) or placebo (n = 92). Overall survival at 3 weeks was 70% for patients given NAC and 66% for patients given placebo (1-sided P = .283). Transplant-free survival was significantly better for NAC patients (40%) than for those given placebo (27%; 1-sided P = .043). The benefits of transplant-free survival were confined to the 114 patients with coma grades I-II who received NAC (52% compared with 30% for placebo; 1-sided P = .010); transplant-free survival for the 59 patients with coma grades III-IV was 9% in those given NAC and 22% in those given placebo (1-sided P = .912). The transplantation rate was lower in the NAC group but was not significantly different between groups (32% vs 45%; P = .093). Intravenous NAC generally was well tolerated; only nausea and vomiting occurred significantly more frequently in the NAC group (14% vs 4%; P = .031). CONCLUSIONS: Intravenous NAC improves transplant-free survival in patients with early stage non-acetaminophen-related acute liver failure. Patients with advanced coma grades do not benefit from NAC and typically require emergency liver transplantation.
Acute liver failure (ALF) is characterized by loss of liver function without pre-existing chronic liver disease. The grade of hepatic encephalophathy and the international normalized ratio (INR) have been identified as the main prognostic indicators in this disease. The clinical course in severe ALF may be characterized by the rapid development of multiorgan failure, extended intensive care, and liver transplantation may be needed.
The definition of ALF has not been clearly established. The clinical presentation of coagulopathy and encephalopathy suggests the diagnosis. However, ALF with less severe liver injury can present with coagulopathy but without encephalopathy. The historical classification of ALF into fulminant or hyperacute, acute and subacute liver failure depending on the duration of clinical symptoms has no prognostic relevance.1 Causes of ALF with unfavorable prognosis include Wilson's disease, Budd-Chiari syndrome, and non-A hepatitis B or C.
In the United States, approximately 2000 cases of ALF are recorded annually and cause 6% of liver-related deaths overall.2 The most common etiologies of ALF are drug-induced injury, viral hepatitis, and indeterminate causes. Acetaminophen (AAF) toxicity accounts for 39% of the cases of ALF in the United States and Europe.3 Recovery from ALF is determined by the metabolic consequences of reduced liver cell mass, the release of toxic substrates from hepatocytes, and the capability of hepatocyte regeneration.
In AAF-induced ALF, formation of the toxic metabolite N-acetyl-p-benzoquinone imine (NAPQI) is essential to trigger liver injury. N-acetylcysteine (NAC), as a gluthatione precursor and substitute, has specific effects on the detoxification of NAPQI and thus can limit or prevent liver damage. To test if NAC could also have beneficial effects in other forms of ALF, Lee et al. performed a prospective, randomized, double-blind, placebo-controlled trial using NAC doses, as known in AAF-induced ALF (Table 1), to investigate the impact of NAC in patients with non-AAF induced ALF including 24 centers in the United States from 1998–2006.4 Eligible candidates for this trial were adult patients (18–70 years old) with ALF as defined by any degree of encephalopathy and coexistent coagulopathy (international normalized ratio [INR] ≥ 1.5), and duration of clinical symptoms of less than 24 weeks. Patients were excluded with known or suspected AAF overdose, liver failure due to ischemia, pregnancy or cancer, and refractory hypertension, concomitant septic shock, and instantly inevitable transplantation. A total of 173 patients were enrolled.
|Application of N-acetylcysteine|
|1.||150 mg/kg/h||1 hour|
|2.||12.5 mg/kg/h||4 hours|
|3.||6.25 mg/kg/h||67 hours|
The treatment groups where categorized by grade of hepatic encephalopathy (I-II versus III-IV) and received either placebo (92 patients) or NAC (81 patients) intravenously over a period of 72 hours (Table 1). The primary endpoint was overall survival at 3 weeks; secondary endpoints were transplant-free survival and transplantion rate. The four main causes for ALF in this trial were: drug-induced liver injury (DILI; 45 patients), autoimmune hepatitis (26 patients), hepatitis B virus (37 patients), and indeterminate cause (41 patients). To exclude AAF toxicity in indeterminate cases, a specific assay for acetaminophen adducts in serum was performed and six patients with evident high-dose acetaminophen ingestion could be identified.5 In the placebo arm 63% and in the NAC arm 59% of the patients completed 72 hours of therapy, and the majority of patients (80%) received at least 24 hours hours of therapy. Side effects of NAC therapy were negligible.
The results of the study demonstrated an overall survival rate at 3 weeks of 70% for NAC-treated and of 66% for placebo-treated patients, which was not statistically significant. However, a statistically significant higher transplant-free survival in the treatment group as compared with the placebo group was observed (40% versus 27%, P = 0.043). In regard to the grade of hepatic encephalopathy the most evident effect of NAC therapy was observed in patients with lower grades of encephalopathy (52% versus 30%; P = 0.01). The odds ratio for transplant-free survival comparing treatment groups with coma grade I-II versus coma grade III-IV was calculated to be 2.46.
In secondary endpoint assessment, a significantly longer transplant-free survival time was seen in the treatment group with coma grade I-II as compared to the other groups (largest P = 0.017). Furthermore, patients in the treatment group with coma grades I-II showed a longer time to transplantation than patients in the other study arms (largest P = 0.032). Comparing overall and transplant-free survival in the different etiological groups, ALF caused by DILI or hepatitis B virus infection seemed to have the highest benefit of NAC therapy. Due to the small number of patients, statistical subgroup analysis was not reasonable and therefore was not performed.
Advances in intensive care medicine and supportive therapy have improved the overall outcome of ALF. However, liver transplantation remains the ultimate therapy in those patients who fail to restore functional liver mass. In the present study, 40% of the patients required liver transplantation. The authors demonstrate that organ availability and quality are essential factors determining short-term outcomes of transplantation. In patients with early-stage non–AAF-induced liver failure, they could demonstrate an improved transplant-free survival using NAC. These results indicate that patients with non–AAF-induced ALF could benefit from early NAC therapy.
Due to the complexity of ALF and the requirement of vigorous intensive-care therapy, it has been unlikely that a given drug will be the “magic bullet” in improving the outcome of non–AAF-induced ALV. However, because NAC has already been studied before in vitro and in vivo it may give a link to a better understanding of ALV pathophysiology.
Treatment with NAC also has some beneficial effects after late administration in AAF toxicity, which indicates additional mechanisms of cellular protection. Recent data from mouse models imply hepatoprotective effects independent of gluthatione replenishment but rather based on changes in intracellular energy metabolism due to NAC.6 NAC especially favors the formation of hypotaurin (Htau) from its cysteine residue, which has been shown protective in cell injury by acting as radical scavenger.7 However, the hepatoprotective potential of Htau is not completely understood. Moreover, NAC increases flux through pyruvate dehydrogenase, a key enzyme for mitochondrial energy metabolism by providing acetyl-coenzyme A for the mitochondrial tricarboxylic acid cycle. These metabolic actions seem interesting because they potentially stabilize the mitochondrial function in these patients. Additionally, NAC has been shown to influence cytokine synthesis and is a free-radical scavenger, hence, it has anti-inflammatory and antioxidant effects and may positively affect liver regeneration.8 Moreover, NAC has inotropic and vasodilatatory effects, which might improve microcirculation and oxygen delivery in multiorgan failure due to ALF of all etiologies.9
In summary, the findings of this study are very relevant not only for the novelty of the results, but also that they provide an additional therapeutic option in selected patients with ALF. Building upon earlier experimental studies with NAC in vivo and in vitro, this study also gives a potential link for developing future, more-specific therapeutic strategies. In summary, this study demonstrates that NAC is a safe and inexpensive therapy and should be considered in patients with early stages of non–acetaminophen induced liver failure.