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Acetaminophen is a widely used analgesic for pain management, especially useful in chronic diseases, such as rheumatoid arthritis. However, easy access to this medicine has increased the occurrence of episodes of poisoning. Patients often develop severe liver damage, which may quickly lead to death. Consequently, numerous studies have been conducted to identify new biomarkers that allow the prediction of the degree of acetaminophen intoxication and thus intervene in a timely manner to save patients’ lives. This review highlights the main mechanisms of the induction and progression of liver damage arising from acetaminophen poisoning. In addition, we have discussed the possibility of using new clinical biomarkers for detecting acetaminophen poisoning.

Acetaminophen (APAP) administration at therapeutic doses is safe, however overdosing produces hepatocellular injury via a multifactorial mechanism(s) that involves generation of reactive oxygen species (ROS), being the most common cause of acute liver failure (ALF) in the northern hemisphere. Brain alterations induced by APAP intoxication are usually considered secondary to hepatic encephalopathy development due to ALF. Although APAP is primarily metabolized in the liver, it is also distributed and metabolized homogeneously in the brain, affecting brain redox status. Nevertheless, comprehensive studies on the potential of APAP intoxication to produce brain toxicity are scarce. The aim of this study was to characterize the direct toxic effects of APAP in different regions of the brain and on behavior in rats where the magnitude of hepatotoxicity produced is not associated with ALF. The present work demonstrates that APAP intoxication producing hepatotoxicity, but not ALF in rats, is associated with marked hypolocomotion. Our studies also suggest that selective downregulation in dopamine levels in brain areas that regulate motor activity may be responsible, in part, for the decreased locomotion observed with APAP treatment. Furthermore, we observed that the brain histoarchitecture is conserved and that edema is not present. However, an increase in oxidative stress, reactive astrogliosis and a decrease in neuron processes are the main features observed in APAP-intoxicated animals. These effects might be partly due to direct toxic effects of APAP in brain, since the same reactive astrogliosis observed in rats was also observed in rat primary astrocyte cultures exposed to APAP.

Introduction Amanita phalloides and paracetamol intoxications are responsible for the majority of acute liver failures. Aim To assess survival outcomes and to analyse risk factors affecting survival in the studied group. Material and methods Of 1369 liver transplantations performed in the Department of General, Transplant, and Liver Surgery, Medical University of Warsaw before December 2013, 20 (1.46%) patients with Amanita phalloides (n = 13, 0.95%) and paracetamol (n = 7, 0.51%) intoxication were selected for this retrospective study. Overall and graft survival at 5 years were set as primary outcome measures. Results Five-year overall survival after liver transplantation in the studied group was 53.57% and 53.85% in patients with paracetamol and Amanita phalloides poisoning, respectively (p = 0.816). Five-year graft survival was 26.79% for patients with paracetamol and 38.46% with Amanita phalloides intoxication (p = 0.737). Risk factors affecting patient survival were: pre-transplant bilirubin concentration (p = 0.023) and higher number of red blood cells (p = 0.013) and fresh frozen plasma (p = 0.004) transfused intraoperatively. Likewise, higher number of red blood cells (p = 0.012) and fresh frozen plasma (p = 0.007) transfused were risk factors affecting 5-year graft survival. Surprisingly, donor and recipient blood type incompatibility was neither the risk factor for 5-year overall survival (p = 0.939) nor the risk factor for 5-year graft survival (p = 0.189). Conclusions In selected intoxicated patients urgent liver transplantation is the only successful modality of treatment. Risk factors affecting survival are in correspondence with the patient's pre-transplant status (bilirubin level in serum) and intraoperative status (number of red blood cells and fresh frozen plasma transfused).

Rationale: Procalcitonin (PCT) is used as a biomarker for identifying the occurrence of sepsis. Previous studies have reported high levels of PCT with acetaminophen intoxication without evidence of infection. Here, we report two patients with acetaminophen intoxication with high levels of PCT without showing any symptoms of bacterial infection. Patient concerns: This case study examined two unrelated patients with acetaminophen intoxication admitted to emergency at different times. The first patient was admitted to the emergency department after ingesting approximately 8000 mg (153.8 mg/kg) of acetaminophen. On admission, C-reactive protein (CRP), glutamic oxaloacetic transaminase (GOT), and glutamic pyruvic transaminase (GPT) were normal. PCT and acetaminophen levels were 31.89 ng/mL and below 0.5 μg/mL, respectively. The second patient was admitted to the emergency department 8 h after ingesting ∼23,600 mg (280.6 mg/kg) of acetaminophen. By the second day of admission, GOT and GPT increased to 2508 and 1473 IU/L, respectively. PCT was 45.66 ng/mL with acetaminophen level at 116.9 μg/mL. Both patients were clear of symptoms associated with bacterial infection. Diagnosis: Acetaminophen intoxication. Interventions: N-acetylcysteine was given intravenously to both patients for 20 h per protocol. Outcomes: Both patients were discharged without complications. Lessons: Observations suggests that elevated levels of PCT in patients intoxicated with acetaminophen may be associated with involvement of other organs impacted by cytokine stimuli from sterile inflammation resulting from hepatic damage rather than PCT secretion directly caused by hepatic cell damage.

Objective: To evaluate the demographic and clinical features associated with acetaminophen overdose and to identify the clinical use of IV (intravenous) N- Acetylcysteine (NAC) treatment in children. Methods: This prospective study was conducted in Kanuni Sultan Suleyman Training and Research Hospital between August 2016 and August 2017. A total of 59 patients with overdose acetaminophen ingestion were included in this study. The toxic dose for acute acetaminophen intake was defined as greater than 150 mg/kg. Rumack-Matthew nomogram was used to evaluate the risk of acute intoxication and to determine the decision of using antidote. Results: The mean age of the patients was 8.5 +/- 6.4 y and 34 of them (58%) were female. The mean time from ingestion to admission was 4.3 +/- 4.7 h. The mean ingested acetaminophen dose was 142.1 +/- 80 mg/kg. Twenty four patients (41%) received NAC and there were significant differences in terms of acetaminophen dose, creatinine and INR between antidote and decontamination therapy groups at admission time (p= 0.00, p= 0.03, p= 0.02, respectively). The complication due to antidote therapy was observed in only 1 patient. Conclusions: This study confirms that the side effects due to IV NAC therapy are uncommon and it is generally well tolerated in children.

The aim of this study was to evaluate the accuracy of procalcitonin (PCT) in predicting bacterial infection and survival without transplantation upon admission in the ICU for acute liver failure (ALF).From January 2009 until October 2015, all cases of ALF patients admitted in our ICU were retrospectively reviewed and included in the study if the PCT level upon admission was available. Patients with pre-existing liver pathology or ALF in a context of already advanced multiorgan failure were excluded. The main clinical and biological characteristics of patients were recorded, as well as the etiology of ALF, diagnosis of bacterial infection (bacteriologically documented or suspected), and outcome.35 patients were included: 46% men, mean age 42 years, initial prothrombin ratio 31%, PCT 9.8 mg/l (0.7-49), and PCT more than 2 mg/l in 54% of cases. Etiology was acetaminophen intoxication in 18/35 (51%) cases. Sepsis was diagnosed in 9/35 (26%) cases, most frequently pneumonia with 4/9 cases. Survival without liver transplantation (LT) was observed in 28 (80%) cases. The median PCT was not different in patients with or without bacterial infection [6.3 mg/l (0.6-16) vs. 1.2 mg/l (0.8-9.7), P=0.8]. The median PCT was not different in patients who survived without LT [7.1 mg/l (0.9-16.1) vs. 0.75 mg/l (7.7-11.5), P=0.06]. In patients with ALF unrelated to acetaminophen intoxication, the median PCT was higher in patients with bacterial infection [1.1 mg/l (0.9-4) vs. 0.5 mg/l (0.3-0.8), P=0.01], but was similar in patients who did not survive without LT [0.7 mg/l (0.4-1.1) vs. 0.8 mg/l (0.4-2.2), P=0.6]. In the overall cohort, the median C-reactive protein (CRP) and leukocyte count were higher in patients who developed bacterial infection [40 mg/l (19-60) vs. 16 mg/l (6-34), P=0.04; 11.9 G/l (8.3-19) vs. 7.9 G/l (6-12.6), P=0.05]. The median CRP and leukocyte count were not significantly different in survivors versus nonsurvivors without LT.PCT was an accurate predictor for the diagnosis of bacterial infection only in patients with ALF unrelated to acetaminophen intoxication. CRP was higher in patients who developed infection and could also be an interesting tool in ALF patients.

This study investigates the comparative hepatoprotective activity of crude ethanol extracts ofCuscuta australisagainst acetaminophen (APAP) intoxication. Thirty-six rats were randomly divided into six groups of 6 replicates: Group 1 which served as control received water. Group 2 was orally administered 835 mg/kg body wt. of paracetamol on day 8. Groups 3 and 4 were orally administered ethanolic extracts of the seed ofCuscuta australisin doses of 125 mg/kg and 250 mg/kg, respectively, for 7 days and then intoxicated as in Group 2 on the 8th day. Groups 5 and 6 received similar oral doses ofCuscuta australisstem extracts for 7 days and then intoxicated as in Groups 3 and 4. Group 2 rats showed severe periportal hepatic necrosis, significantly elevated serum hepatic injury markers, markedly increased lipid peroxidation, and decreased hepatic antioxidant enzymes activities. Remarkably,Cuscuta australis(seed and stem) extract pretreatments in Groups 3, 4, 5, and 6, most especially, the stem extract pretreatment in Groups 5 and 6, improved better the hepatic histoarchitecture, the hepatocellular, and the oxidative stress injury markers in a dose-dependent manner. Conclusively, ethanol extractions ofCuscuta australisstem appear to protect the liver from acetaminophen intoxication better than the seed counterpart.

This study aims to investigate the acute protective effect of montelukast sodium in hepatic injury secondary to acetaminophen (APAP) intoxication. This study used 60 rats. The rats were grouped into 6 groups. The control group was administered oral distilled water 10 ml/kg, the APAP group oral APAP 1 g/kg, the montelukast sodium (MK) group oral MK 30 mg/kg, the acetaminophen+N-acetylcysteine (APAP+NAC) group oral APAP 1 g/kg, followed by a single dose of intraperitoneal NAC 1.5 g/kg three hours later, the acetaminophen+montelukast sodium (APAP+MK) group oral APAP 1 g/kg, followed by oral MK 30 mg/kg 3 h later, the acetaminophen+N-acetylcysteine+montelukast sodium (APAP+NAC+MK) group oral APAP 1 g/kg, followed by a single intraperitoneal NAC 1.5 g/kg plus oral MK 30 mg/kg 3 h later. Blood and liver tissue samples were taken 24h after drug administration. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), and total bilirubin were studied from the blood samples. Liver tissue samples were used for histopathological examination. Compared with the control group, serum AST and ALT activities were higher in the APAP and APAP+NAC groups. APAP+NAC, APAP+MK, and APAP+NAC+MK groups had reduced serum ALT and AST activities than the group administered APAP alone. APAP+MK and APAP+NAC+MK groups had a lower serum ALP activity than the control group. Histopathologically, there was a difference between the group administered APAP alone and the APAP+MK and APAP+NAC+MK groups. MK is as protective as NAC in liver tissue in APAP intoxication in rats.

AIM To investigate the changes of hemodynamic and laboratory parameters during the course of acute liver failure following acetaminophen overdose. METHODS Eight pigs underwent a midline laparotomy following jejunal catheter placement for further acetaminophen intoxication and positioning of a portal vein Doppler flow-probe. Acute liver failure was realized by intrajejunal acetaminophen administration in six animals, two animals were sham operated. All animals were invasively monitored and received standardized intensive care support throughout the study. Portal blood flow, hemodynamic and ventilation parameters were continuously recorded. Laboratory parameters were analysed every eight hours. Liver biopsies were sampled every 24 h following intoxication and upon autopsy. RESULTS Acute liver failure (ALF) occurred after 28 ± 5 h resulted in multiple organ failure and death despite maximal support after further 21 ± 1 h (study end). Portal blood flow (baseline 1100 ± 156 mL/min) increased to a maximum flow of 1873 ± 175 mL/min at manifestation of ALF, which was significantly elevated (P < 0.01). Immediately after peaking, portal flow declined rapidly to 283 ± 135 mL/min at study end. Thrombocyte values (baseline 307 × 103/µL ± 34 × 103/µL) of intoxicated animals declined slowly to values of 145 × 103/µL ± 46 × 103/µL when liver failure occurred. Subsequent appearance of severe thrombocytopenia in liver failure resulted in values of 11 × 103/µL ± 3 × 103/µL preceding fatality within few hours which was significant (P > 0.01). CONCLUSION Declining portal blood flow and subsequent severe thrombocytopenia after acetaminophen intoxication precede fatality in a porcine acute liver failure model.

The United Kingdom has recently changed the indications for N-acetylcysteine treatment for acetaminophen intoxication. Any ingestion over 75 mg/kg is now referred to the hospital. A model based on pharmacokinetic parameters was developed to predict 4-h acetaminophen concentration for this and other ingested doses.EMBASE and Medline were searched to obtain values for volume of distribution, absorption, and elimination constants and bioavailability for acetaminophen. Four-hour concentrations were calculated for ingestion doses currently recommended for hospital referral in different countries. Calculated plasma concentrations at 4 h for several doses were plotted against the Rumack-Matthew and the United Kingdom treatment lines.Six articles were used for the calculations (4 adult and 2 pediatric). In order to achieve a 4-h acetaminophen concentration of 100 mg/L, doses (mg/kg ± 99.9CI) of 180.5 ± 43.2 for adults and 396.1 ± 115.5 for children were calculated.A dose of 75 mg/kg would likely yield a 4-h acetaminophen concentrations well below 100 mg/L. Medical toxicologists and poison information specialists are left without evidence-based guidance for which patients or which ingestion history would now warrant referral to hospital for acetaminophen concentration measurement. Larger toxicokinetic studies in acetaminophen overdose are needed to define ingestion dose for referral to hospital.

Background: Acetaminophen is at present one of the most commonly used analgesics and antipyretics. Recent evidence has suggested that oxidative stress is involved in the mechanism of acetaminophen intoxication. Paraoxonase-1 (PON1) plays an important role as an endogenous free-radical scavenging molecule. The aim of this study was to evaluate the influence of serum PON1 activity and oxidative stress in patients with acetaminophen intoxication. Methods: A total of 20 patients with acetaminophen intoxication and 25 healthy controls were enrolled. Serum total antioxidant capacity (TAC), lipid hydroperoxide (LOOH) levels, and paraoxonase and arylesterase activities were measured spectrophotometrically. Results: The serum TAC levels and the paraoxonase and arylesterase activities were significantly lower in patients with acetaminophen intoxication compared with controls (all, p < 0.001), while the serum LOOH levels were significantly higher ( p < 0.001). Conclusions: Our results suggest that decreased PON1 activity seems to be associated with increased oxidative stress in patients with acetaminophen intoxication. Measuring serum PON1 activity may be useful in assessing the development of toxicity risk in acetaminophen toxicity. It would be useful to recommend vitamins with antioxidant effects such as vitamins C and E along with medical treatments.

Background and Aims: Severe intoxication following acetaminophen overdose is the most common cause of acute liver failure (ALF) in many Western European and North American countries. A reproducible large animal model of acetaminophen intoxication has not been successfully evaluated previously. Methods: Eight male pigs underwent acetaminophen intoxication receiving an initial enteric bolus of 250 mg/kg body weight acetaminophen followed by an acetaminophen plasma level (300–450 mg/l) adapted enteric maintenance dose of 1,000–3,000 mg/h to the onset of ALF (prothrombin time value Results: All animals developed ALF after 25 ± 3 h, which was confirmed by laboratory values, the clinical course and histological examinations. All animals died due to ALF after a further 21 ± 5 h, precipitated by cerebral edema. Conclusions: Using an initial enteric acetaminophen bolus, followed by body weight-adapted acetaminophen plasma level intoxication, it was possible to establish a reproducible, clinically relevant porcine model which may be used for the investigation of novel therapeutic approaches in this life-threatening condition.

Cell death is known to play a crucial role in liver diseases. We compared the clinical courses of two cases of liver failure of different origins correlated with the extent of cell death (apoptosis and/or necrosis), measured in the patient's blood. Patient 1 was admitted with acute liver failure following acetaminophen intoxication. Intravenous therapy with acetylcysteine was performed. The percentage of apoptotic cell death measured by M30 was three times higher than normal and the overall cell death measured by M65 was more than 30 × higher than normal. High levels of aminotransferases were detected, indicating high rates of necrosis. M30 and M65 values rapidly returned to normal levels, while the liver function test (LFT) levels decreased with latency. Patient 2 was admitted with acute-on-chronic liver failure with known liver fibrosis. M30 values were 16 × higher than normal. In contrast, M65 values were lower than in the first case. This time, no movement in M30 levels was seen until the M30 levels rapidly increased indicating the inevitable death of the patient, while LFTs did not change. These results indicate the role of M30 and M65 immunoexpression as markers for functioning liver cell mass, capacity for recovery and therefore as predictive markers in acute liver failure.

For over two decades, pediatricians have been made aware of the potential risk associated with the acute ingestion of large single and/or multiple doses of acetaminophen (APAP). Clearly, APAP-induced hepatotoxicity remains as a recognized medical emergency which, when treated promptly with appropriate gastrointestinal decontamination and when indicated, with the antidote N-acetylcysteine, has a uniformly good clinical outcome. Recently, the hepatotoxic potential associated with “therapeutic” APAP administration has been brought to the attention of the pediatric community. This review explores the issue of APAP toxicity with therapeutic intent by examining both the clinical literature and also, relevant information concerning the basic pharmacology and toxicology of this old and widely used nonprescription drug. A “risk profile” is developed with regard to factors that may predispose infants and children to this iatrogenic form of toxicity so that the awareness of physicians and other caregivers (including parents) can be heightened and preventative education administered. As is true for most all potentially beneficial medicines used in pediatrics, awareness of the actual amount of drug received from all sources and caution to not exceed the age-appropriate dosing guidelines (i.e., both amount and duration) contained in the approved labeling for all products containing APAP will insure safe and effective therapy.

To test the accuracy of a newly developed meter that determines serum acetaminophen concentration after a 30-second analysis of one drop of whole blood.Sixty-six blood samples from patients with known or suspected drug overdose were analyzed for the presence of acetaminophen. In all cases determination of serum acetaminophen concentration was performed simultaneously with the meter and by a reference laboratory.Eligible patients were those who presented during a nine-month period to the emergency departments of two tertiary care hospitals (including a pediatric hospital).Thirty-one specimens had a laboratory-confirmed detectable acetaminophen concentration. The meter identified these toxic specimens in all cases; there were no false-negatives (sensitivity, 100%). Among the 35 specimens not containing acetaminophen, the meter invariably confirmed a nondetectable serum acetaminophen concentration (specificity, 100%). Acetaminophen measurements by the meter correlated strongly with laboratory determinations (r = .985, P less than .001). Repeated testing of one specimen documented the precision and reproducibility of the meter's analysis; mean coefficient of variation was .08 in measuring toxic acetaminophen concentrations. Drug coingestion had no significant effect on the accuracy of the meter. Instrument accuracy was maintained after more than 100 uses without recalibration.This meter identifies the possibility of rapid and accurate determinations of serum acetaminophen concentration. The instrument is ideally suited for patients with acetaminophen poisoning in whom expeditious and appropriate administration of antidotal therapy is desired.

To prove the function of isolated transplanted hepatocytes in acute liver failure we tried to establish a hepatic failure model in pigs which correlates to a clinical situation. In 12 pigs we administered 500-2000 mg acetaminophen/kg b.wt. after enzyme induction with pentobarbital. Seven animals receiving 500-1000 mg/kg survived the intoxication. Five animals receiving 1000-2000 mg/kg acetaminophen died within 6.5 h after intoxication because of methemoglobinemia. A close correlation between administered dosage of the drug, acetaminophen blood levels, and methemoglobinemia was found. Histology of surviving animals showed a dosage-dependent cell necrosis. A standardized hepatic failure model could not be established in pigs by acetaminophen intoxication because dosages of less than 1000 mg/kg were survived. In dosages higher than 1000 mg/kg a side-effect of the acetaminophen intoxication, i.e., methemoglobinemia, limited the life of the animals. Therefore, acetaminophen cannot be used to induce acute hepatic failure in pigs.

Acetaminophen is a readily available, widely used drug which has been thought safer than aspirin. Overdosage which may result in fatal hepatic necrosis is commonly seen in the United Kingdom but is rarely reported in the United States. In a two-month period, three patients were admitted to a general hospital because of acetaminophen overdose, suggesting that this problem may occur more commonly than expected. They were successfully treated with N-acetylcysteine. Our experience in management of these three patients is presented and the pertinent literature concerning diagnosis and treatment of acute acetaminophen intoxication in briefly reviewed. Language: en

To the Editor.— The incidence of acute acetaminophen intoxication in the United States appears to be increasing as this drug finds wider use as a nonprescription analgesic and antipyretic. In England, where acetaminophen has been popular for some time, a substantial number of poisonings have been encountered.1,2Most severely intoxicated patients (ingested dose > 15 gm in adults) develop liver damage; some also show renal injury.1-3The maximum necrotic effect appears two to four days after drug ingestion; death can occur any time between two to seven days after the intoxication. No form of therapy has proven effective in reducing or preventing hepatic necrosis due to acetaminophen poisoning.2It is, therefore, particularly important to employ measures for reducing the absorption of the ingested drug. We are presently evaluating the efficacy of activated charcoal as an inhibitor of acetaminophen absorption in man. These studies are still in progress