Outcomes of patients with acetaminophen-associated toxic hepatitis at a far east poison center

Acetaminophen is one of the best-selling analgesics in Taiwan and one of the most popular drugs in the world. Although it is safe at therapeutic doses, overdoses of acetaminophen can cause severe liver injury. Although the first case of acetaminophen-related hepatic necrosis due to overdose was documented in 1966 (Davidson and Eastham, 1966), it is still the leading agent of liver failure due to poisoning (Lee, 2004).

Acetaminophen is ingested orally. The daily maximum dose is 4 g for an adult and 80 mg/kg for a child. After ingestion, the concentration peaks around 2 h. Dosages that induce toxic hepatitis are greater than 12 g per day in adults and 250 mg/kg over 24 h in children (Makin et al., 1995). After ingestion, around 90% of the acetaminophen is metabolized to sulfate and glucuronide, which is conjugated in the liver and then excreted into the urine. Eight percent of the remaining acetaminophen is metabolized by cytochrome p450 into the more toxic form of N-acetyl-p-benzoquinoneimine (NAPQI) when the glutathione (GSH) is depleted (Bessems and Vermeulen, 2001). NAPQI then binds to the cysteine group in the hepatocyte, and oxidative injury and hepatocellular centrilobular necrosis is then induced (Jollow et al., 1973). However, N-acetylcysteine limits the toxicity of acetaminophen by increasing the GSH stores, binding with NAPQI as a substitute for GSH, and enhancing sulfate conjugation (Lee, 2004).

There is an overall paucity of data regarding the outcomes of patients with acetaminophen poisoning in Taiwan. In the only original research study, Tsai et al. (Tsai et al., 2004) have reported that age and the time to presentation were the independent risk factors for hepatotoxicity (P = 0.033 and P = 0.002, respectively) after acetaminophen intoxication. However, due to their low sample size, the certainty of the conclusions may be limited.

Therefore, the purpose of this study was to recruit a larger number of patients and to examine the clinical features, the degrees of toxic hepatitis, the physiological markers, and the clinical outcomes after intentional acetaminophen poisoning, and to determine what association, if any, might exist between these findings.

At the end of the analysis, 1 patient with toxic hepatitis died of liver failure (Table 4). Nevertheless, there was no significant difference in mortality between patients with and without hepatitis (P = 0.051).

Acetaminophen is a well-known agent that causes dose-dependent toxic hepatitis. It was revealed in this study that although patients with toxic hepatitis suffered higher serum acetaminophen levels than patients without toxic hepatitis, a univariate logistic regression analysis failed to identify serum acetaminophen level as a significant risk factor for toxic hepatitis complication after ingestion, possibly due to small sample size and short follow up duration (Table 5). Theoretically, the toxic metabolite NAPQI is formed by cytochrome p450 and then detoxified by conjugating with GSH (Nelson, 1990), and oversaturated NAPQI makes the hepatocytes more vulnerable to injury (Potter et al., 1973). Nevertheless, the amount of acetaminophen in patients without toxic hepatitis in was 36.5 ± 25.1 tablets (or 17.8 ± 12.6 g), which was much higher than 4 g, the maximum recommended dose for adult (Table 1). Mitochondria injury may be the major determinant for this because previous animal studies have demonstrated that NADQI binds to mitochondria and leads to oxidative stress (Jaeschke, 1990). NADQI induced mitochondria permeability transition pore opening and mitochondrial permeability changes (Bajt et al., 2006). Endonuclease G and the apoptosis-inducing factor are released by mitochondria, and DNA fragmentation occurs with the release of these enzymes (Kon et al., 2004). Although oversaturation is the major mechanism in acetaminophen-related toxic hepatitis, mitochondria-related cytotoxic damage may be the reason for the heterogeneity of the phenotypes after the ingestion of large amounts of acetaminophen.

In this study, 1 patient with toxic hepatitis died of liver failure, and the overall mortality rate was 0.5% (Table 4). Evidently, the favorable outcomes depended on a prompt diagnosis of acetaminophen poisoning and the immediate institution of detoxification protocols. In US reports on acetaminophen-related acute hepatitis and liver failure, the mortality rate has been reported to be around 19–30% (Lee, 2008; Schiodt et al., 1997). Larson et al. (Larson et al., 2005) have reported that 27% of US patients with acetaminophen-induced acute liver failure died in 3 weeks. Therefore, our mortality rate was much lower than the data from the US Poison Centers. In terms of metabolism (Patel et al., 1992), acetaminophen is extensively conjugated with glucuronic acid and sulfate prior to renal excretion. A minor metabolic route involves the microsomal oxidation of acetaminophen to a hepatotoxic reactive intermediate, which subsequently undergoes GSH conjugation, yielding cysteine and mercapturate conjugates, both of which are excreted in the urine. In a previous pharmacogenetic study (Patel et al., 1992), it has been reported that the mean fractional excretion of cysteine metabolites differed between Caucasians and Orientals (P < 0.005). Therefore, it is unclear whether the low mortality rate in our study can be explained by ethnic differences in enzymatic metabolism between Orientals and Caucasian.

The prevalence of hepatitis B virus carrier in Taiwan is around 15–20%, which is higher than in the Europe or US (Ott et al., 2012; Lee et al., 2013). The percentage of the hepatitis B virus carrier in our study was 5.3% (Table 1), which was much lower than national Taiwanese registry (Lee et al., 2013). Nevertheless, the prevalence of hepatitis B virus carrier was higher in patients with than patients without toxic hepatitis (Table 1). Although the presence of hepatitis B carrier was not longer a significant predictor for toxic hepatitis after logistic regression analysis (Table 5), it was the authors’ thought that the viral carrier status might make hepatocytes more vulnerable to toxic injury. Literature data on the influence of acetaminophen intake on acute viral hepatitis is scarce. It was disclosed in a small clinical study (Yaghi et al., 2006) that the use of acetaminophen at therapeutic doses was associated with greater alterations of surrogate markers of the severity of acute viral hepatitis. On the other hand, susceptibility to acetaminophen toxicity was unexpectedly decreased during acute viral hepatitis in mice (Getachew et al., 2010). Therefore, further studies should be considered to confirm if infected hepatocytes are more vulnerable to acetaminophen toxicity.

It was revealed in this study that the onset of toxic hepatitis was within hours after acetaminophen exposure (Table 3), which was in sharp contrast to our previous experience with paraquat-induced toxic hepatitis (Yang et al., 2012). In paraquat patients, the symptoms of toxic hepatitis usually developed within 6.7 ± 6.3 days of exposure, peaked at 9.5 ± 8.8 days, and were resolved in 17.3 ± 9.8 days. It was hypothesized by Mullick et al. (Mullick et al., 1981) that paraquat injury to the liver is biphasic; it is initially hepatocellular but becomes cholangiocellular after the first 2 days. However, only hepatocellular damage mechanisms have been implicated following acetaminophen intoxication (Larson, 2007). Therefore, it is unclear whether the faster onset of toxic hepatitis in cases of acetaminophen poisoning can be explained by different liver injury mechanisms.

In this study, patients with toxic hepatitis received lesser proportion of gastric lavage and active charcoal than patients without toxic hepatitis (Table 4). This could be due to longer time elapse between acetaminophen ingestion and hospital arrival in patients with than without toxic hepatitis (Table 1). Similarly, the time elapse was not a significant risk factor for mortality after logistic regression analysis (Table 5). In a study that was conducted in Hong Kong (Chan et al., 1996), it was found that the time that elapsed between acetaminophen ingestion and treatment was the most important prognostic factor for liver toxicity. However, the N-acetylcysteine antidote was only used in 50% of the patients (Chan et al., 1996), but the proportion of patients that received N-acetylcysteine treatment was as high as 78.6% in our study (Table 4). Therefore, it is unclear whether the difference in the use of the N-acetylcysteine antidote could influence predictions of time elapses for toxic hepatitis.

The analytical results showed that patients with toxic hepatitis showed higher incidences of acute respiratory failure than those shown by the patients who did not have hepatitis (Table 2). The results of a laboratory study (Ilic et al., 2010) have also indicated that a high hepatotoxic dose of paracetamol (5 g per kg intraperitoneally) produced hepatic encephalopathy with generalized convulsions in rats. Hepatic coma by liver failure may be possible cause inducing respiratory failure or high anion gap metabolic acidosis (Mendoza et al., 2006).

In summary, the analytical data revealed that toxic hepatitis was not uncommon (15/187 or 8.0%) after acetaminophen overdose. Nevertheless, this study failed to identify any significant risk factors for mortality, possibly due to low sample size and short follow up duration. Further studies are warranted.