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Acetaminophen is a commonly used analgesic and antipyretic drug, which has experienced an increase in its consumption in recent years in our environment. There has also been an increase in the number of accidental and intentional overdoses that were treated by the health system. Its toxicity is dose-dependent and can cause fulminant liver failure, becoming one of the main reasons for liver transplantation in English-speaking countries. The case of a 28-year-old woman with a history of major depression and five previous suicide attempts, who deliberately ingested a significant amount of paracetamol tablets, is here presented. She developed fulminant liver failure and metabolic acidosis, for which she underwent an emergency liver transplant due to the severity of her condition, from which she evolved favorably. The decision to perform a liver transplant in serious cases like this and under a condition of severe psychiatric vulnerability is challenging and must be carefully considered. This particular case illustrates the importance of multidisciplinary care including psychiatric evaluation in patients with acetaminophen poisoning.

Objective: It is well known that local complications, such as avascular necrosis and arthrosis can develop after surgery for developmental dysplasia of the hip (DDH). Thus far, systemic complications that may develop in such cases have not been identified in the literature. This study is the first case series to evaluate acute liver failure (ALF) development after DDH surgery in pediatric patients., Patients and Methods: Six patients, five female and one male, who underwent DDH surgery were selected for this study. Perioperative fasting time, laboratory values, treatments, histopathological evaluations, and prognoses after ALF in these patients were evaluated retrospectively., Results: All the patients were administered paracetamol and sevoflurane in therapeutic doses. The patients were referred postoperatively to our pediatric emergency department after 5 ± 1.67 days (range = 3-7 days) on average. The average perioperative fasting time was 9.3 ± 0.82 hours (range = 8-10 hours). Due to the very high aminotransferases and use of paracetamol, intravenous N-acetylcysteine was administered alongside supportive treatments to all the patients. After liver transplantation, two of three patients with grade 3 encephalopathy, died in the early postoperative period. Histopathological evaluations of the three patients' explants were compatible with toxic hepatitis due to paracetamol., Conclusions: Paracetamol is a commonly used analgesic after pediatric surgery. The therapeutic dose of paracetamol remains uncertain in children who have been fasting for a long time and have been exposed to hepatotoxic drugs due to previous surgery. In conclusion, caution should be exercised in the use of paracetamol in children with DDH who will undergo surgery, and careful perioperative clinical and laboratory monitoring for ALF is essential.

Liver regenerates following surgical removal and after drug-induced liver injury (DILI). However, most of the mechanisms of liver regeneration were identified using partial hepatectomy (PHX) model rather than using DILI models. We compared mechanisms of liver regeneration following PHX and after acetaminophen (APAP) overdose, a DILI model, using transcriptomic approach. Kinetics of hepatocyte proliferation and global gene expression profiles were studied in male C57BL/6J mice either subjected to PHX or following APAP overdose. Liver regeneration was much more synchronized after PHX as compared to APAP overdose. Transcriptomics analysis revealed activation of common upstream regulators in both models including growth factors HGF, EGF and VEGF; and cytokines IL6 and TNFα. However, magnitude of activation and temporality was significantly differed between the two models. HGF and VEGF showed similar activation between PHX and APAP but activation of EGF was significantly stronger in the APAP model. Activation of IL6 and TNFα transcriptional programs was delayed but remarkably higher in APAP. These dissimilarities could be attributed to inherent differences in the two models including significant injury and inflammation exclusively in the APAP model. This study highlights need to study mechanisms of liver regeneration after DILI separately from the mechanisms of regeneration PHX., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Objective: Acute liver failure (ALF) leads to severe illness and usually requires admission to the intensive care unit (ICU). Despite its importance, little is known about patients with ALF in Australia and New Zealand., Design: Binational observational study to evaluate the aetiology, baseline characteristics, patterns of illness, management, and outcomes for patients with ALF admitted to Australian and New Zealand ICUs., Setting: All six Australian and New Zealand ICUs in liver transplant centres submitted de-identified data for ten or more consecutive patients with ALF. Data were obtained from the clinical record and included baseline characteristics, aetiology, mode of presentation, illness severity, markers of liver failure, critical care interventions, utilisation of transplantation, and hospital outcome., Results: We studied 62 patients with ALF. Paracetamol overdose (POD) was the underlying cause of ALF in 53% of patients (33/62), with staggered ingestion in 42% of patients (14/33). Among patients with POD, 70% (23/33) were young women, most had psychiatric diagnoses, and most presented relatively early with overt liver failure. This group were transplanted in only 6% of cases (2/33) and had an overall mortality of 24% (8/33). The remaining patients with ALF had less common conditions, such as hepatitis B and non-paracetamol drug-induced ALF. These patients presented later and exhibited less extreme evidence of acute hepatic necrosis. Transplantation was performed in 38% of patients (11/29) in this subgroup. The mortality of nontransplanted non-POD patients was 56% (10/18). Illness severity at ICU admission, initial requirement for organ support therapies and length of hospital stay were similar between patients with POD and non-POD ALF., Conclusion: POD is the major cause of ALF in Australian and New Zealand liver transplant centres and is a unique and separate form of ALF. It has a much lower associated mortality and treatment with liver transplantation than non-POD ALF. Non-POD patients have a poor prognosis in the absence of transplantation.

Background & Aims: Acute liver failure patients who meet poor prognostic criteria have high early mortality without emergency liver transplantation. A recent study however, reported that patients that survive spontaneously have a poorer outcome compared with patients undergoing transplantation. In this single centre study, we aimed to confirm or refute this observation., Methods: Early survivors (acute liver failure patients who survived 90 days after the ICU admission) were assessed for long-term outcomes in four distinctive cohorts, incorporating aetiology (Acetaminophen overdose or non-Acetaminophen overdose), and management strategy (conservative or liver transplantation). Chi Squared or Fisher test were used to compare outcomes among the four cohorts (P < 0.05) and Kaplan-Meier curve (Log Rank test) to represent cumulative survival., Results: Two hundred consecutive acute liver failure patients between 1990 and 2014 were included; mean age 38.3, ±12.8, male 70, 35%. 124/200 (62%) early survivors were identified; 13/124 (10.5%) acetaminophen patients underwent transplantation and 48/124 (38.7%) survived spontaneously; 36/124 (29.0%) non-acetaminophen underwent transplantation and 27/124 (21.8%) survived spontaneously. A total of 11/124 (8.9%) died subsequently (median survival 5.3± IQR 9.1), three spontaneous survivors and eight transplanted patients (P = 0.025); of the eight transplanted patients, six died of transplant related complications and two of suicide., Conclusion: The results of this study suggest that although liver transplantation is a life-saving procedure for acute liver failure patients, they have a worse long-term outcome compared with spontaneous survivors. Novel therapies to increase the percentage of spontaneous survivors are urgently needed., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Objective: To determine overall long-term patient and graft survival rates among the recipients liver transplanted due to acute liver failure (ALF). Secondary aims included assessment of whether diagnosis, donor-recipient blood group compatibility and time-era of transplantation affected the outcome, and whether prescription-free availability of acetaminophen increased the need for liver transplantation (LTx)., Materials and Methods: A Retrospective cohort study of 78 patients who underwent LTx for ALF at Karolinska University Hospital 1984-2014. Patients were divided into two cohorts according to two 15-year periods: early cohort transplanted 1984-1999 (n = 40) and late cohort transplanted 2000-2014 (n = 38). Survival rates were established using Kaplan-Meier analyses., Results: ALF patient survival rates for 1-year, 5-years, 10-years and 20-years were 71%, 63%, 52% and 40%, respectively. Survival for the late cohort at 1, 5 and 10 years was 82%, 76% and 71%, respectively. A high early mortality rate was noted during the first three months after transplantation when compared to LTx patients with chronic disease. Long-term survival rates were comparable between patients with ALF and chronic liver disease. Prescription-free access to acetaminophen did not increase the need for LTx. There was a strong trend towards improved survival in blood group identical donor-recipient pairs and blood group O recipients may have benefitted from this., Conclusions: The high early mortality rate most likely reflects the critical pre-transplant condition in these patients and the urgent need to sometimes accept a marginal donor liver. Long-term survival improved significantly over time and variation in patient access to acetaminophen did not influence the rate of LTx in our region.

Background: Paracetamol (acetaminophen) is the most widely used non-prescription analgesic in the world. Paracetamol is commonly taken in overdose either deliberately or unintentionally. In high-income countries, paracetamol toxicity is a common cause of acute liver injury. There are various interventions to treat paracetamol poisoning, depending on the clinical status of the person. These interventions include inhibiting the absorption of paracetamol from the gastrointestinal tract (decontamination), removal of paracetamol from the vascular system, and antidotes to prevent the formation of, or to detoxify, metabolites., Objectives: To assess the benefits and harms of interventions for paracetamol overdosage irrespective of the cause of the overdose., Search Methods: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (January 2017), CENTRAL (2016, Issue 11), MEDLINE (1946 to January 2017), Embase (1974 to January 2017), and Science Citation Index Expanded (1900 to January 2017). We also searched the World Health Organization International Clinical Trials Registry Platform and ClinicalTrials.gov database (US National Institute of Health) for any ongoing or completed trials (January 2017). We examined the reference lists of relevant papers identified by the search and other published reviews., Selection Criteria: Randomised clinical trials assessing benefits and harms of interventions in people who have ingested a paracetamol overdose. The interventions could have been gastric lavage, ipecacuanha, or activated charcoal, or various extracorporeal treatments, or antidotes. The interventions could have been compared with placebo, no intervention, or to each other in differing regimens., Data Collection and Analysis: Two review authors independently extracted data from the included trials. We used fixed-effect and random-effects Peto odds ratios (OR) with 95% confidence intervals (CI) for analysis of the review outcomes. We used the Cochrane 'Risk of bias' tool to assess the risks of bias (i.e. systematic errors leading to overestimation of benefits and underestimation of harms). We used Trial Sequential Analysis to control risks of random errors (i.e. play of chance) and GRADE to assess the quality of the evidence and constructed 'Summary of findings' tables using GRADE software., Main Results: We identified 11 randomised clinical trials (of which one acetylcysteine trial was abandoned due to low numbers recruited), assessing several different interventions in 700 participants. The variety of interventions studied included decontamination, extracorporeal measures, and antidotes to detoxify paracetamol's toxic metabolite; which included methionine, cysteamine, dimercaprol, or acetylcysteine. There were no randomised clinical trials of agents that inhibit cytochrome P-450 to decrease the activation of the toxic metabolite N-acetyl-p-benzoquinone imine.Of the 11 trials, only two had two common outcomes, and hence, we could only meta-analyse two comparisons. Each of the remaining comparisons included outcome data from one trial only and hence their results are presented as described in the trials. All trial analyses lack power to access efficacy. Furthermore, all the trials were at high risk of bias. Accordingly, the quality of evidence was low or very low for all comparisons. Interventions that prevent absorption, such as gastric lavage, ipecacuanha, or activated charcoal were compared with placebo or no intervention and with each other in one four-armed randomised clinical trial involving 60 participants with an uncertain randomisation procedure and hence very low quality. The trial presented results on lowering plasma paracetamol levels. Activated charcoal seemed to reduce the absorption of paracetamol, but the clinical benefits were unclear. Activated charcoal seemed to have the best risk:benefit ratio among gastric lavage, ipecacuanha, or supportive treatment if given within four hours of ingestion. There seemed to be no difference between gastric lavage and ipecacuanha, but gastric lavage and ipecacuanha seemed more effective than no treatment (very low quality of evidence). Extracorporeal interventions included charcoal haemoperfusion compared with conventional treatment (supportive care including gastric lavage, intravenous fluids, and fresh frozen plasma) in one trial with 16 participants. The mean cumulative amount of paracetamol removed was 1.4 g. One participant from the haemoperfusion group who had ingested 135 g of paracetamol, died. There were no deaths in the conventional treatment group. Accordingly, we found no benefit of charcoal haemoperfusion (very low quality of evidence). Acetylcysteine appeared superior to placebo and had fewer adverse effects when compared with dimercaprol or cysteamine. Acetylcysteine superiority to methionine was unproven. One small trial (low quality evidence) found that acetylcysteine may reduce mortality in people with fulminant hepatic failure (Peto OR 0.29, 95% CI 0.09 to 0.94). The most recent randomised clinical trials studied different acetylcysteine regimens, with the primary outcome being adverse events. It was unclear which acetylcysteine treatment protocol offered the best efficacy, as most trials were underpowered to look at this outcome. One trial showed that a modified 12-hour acetylcysteine regimen with a two-hour acetylcysteine 100 mg/kg bodyweight loading dose was associated with significantly fewer adverse reactions compared with the traditional three-bag 20.25-hour regimen (low quality of evidence). All Trial Sequential Analyses showed lack of sufficient power. Children were not included in the majority of trials. Hence, the evidence pertains only to adults., Authors' Conclusions: These results highlight the paucity of randomised clinical trials comparing different interventions for paracetamol overdose and their routes of administration and the low or very low level quality of the evidence that is available. Evidence from a single trial found activated charcoal seemed the best choice to reduce absorption of paracetamol. Acetylcysteine should be given to people at risk of toxicity including people presenting with liver failure. Further randomised clinical trials with low risk of bias and adequate number of participants are required to determine which regimen results in the fewest adverse effects with the best efficacy. Current management of paracetamol poisoning worldwide involves the administration of intravenous or oral acetylcysteine which is based mainly on observational studies. Results from these observational studies indicate that treatment with acetylcysteine seems to result in a decrease in morbidity and mortality, However, further evidence from randomised clinical trials comparing different treatments are needed.

Analyses of outcomes after acute liver failure (ALF) have typically included all ALF patients regardless of whether they were listed for liver transplantation (LT). We hypothesized that limiting analysis to listed patients might provide novel insights into factors associated with outcome, focusing attention on disease evolution after listing. Listed adult ALF patients enrolled in the US Acute Liver Failure Study Group registry between 2000 and 2013 were analyzed to determine baseline factors associated with 21-day outcomes after listing. We classified 617 patients (36% of overall ALF group) by 3-week outcome after study admission: 117 were spontaneous survivors (SSs; survival without LT), 108 died without LT, and 392 underwent LT. Only 22% of N-acetyl-p-aminophenol (APAP) ALF patients were listed; however, this group of 173 patients demonstrated greater illness severity: higher coma grades and more patients requiring ventilator, vasopressor, or renal replacement therapy support. Only 62/173 (36%) of APAP patients received a graft versus 66% for drug-induced liver injury patients, 86% for autoimmune-related ALF, and 71% for hepatitis B-related ALF. APAP patients were more likely to die than non-APAP patients (24% versus 17%), and the median time to death was sooner (2 versus 4.5 days). Despite greater severity of illness, the listed APAP group still had a SS rate of 40% versus 11% for non-APAP causes (P < 0.001). APAP outcomes evolve rapidly, mainly to SS or death. Patients with APAP ALF listed for LT had the highest death rate of any etiology, whereas more slowly evolving etiologies yielded higher LT rates and, consequently, fewer deaths. Decisions to list and transplant must be made early in all ALF patients, particularly in those with APAP ALF., (© 2015 American Association for the Study of Liver Diseases.)

Background & Aims: The long-term clinical outcomes in initial survivors with acute liver failure (ALF) are not well known. The aim of this study was to provide an overview of the 2-year clinical outcomes among initial survivors and liver transplant (LT) recipients that were alive 3 weeks after enrolment in the Acute Liver Failure Study Group (ALFSG)., Methods: Outcomes in adult ALFSG patients that were enrolled between 1998 and 2010 were reviewed., Results: Two-year patient survival was significantly higher in the 262 LT recipients (92.4%) compared to the 306 acetaminophen (APAP) spontaneous survivors (SS) (89.5%) and 200 non-APAP SS (75.5%) (P < 0.0001). The causes of death were similar in the three groups but the time to death was significantly longer in the LT recipients (P < 0.0001). Independent predictors of 2-year mortality in the APAP group were a high serum phosphate level and patient age (c-statistic = 0.65 (0.54, 0.76)), patient age and days from jaundice to ALF onset in the non-APAP group (c-statistic = 0.69 (0.60, 0.78)), and patient age, days from jaundice, and higher coma grade in the LT recipients (c-statistic = 0.74 (0.61, 0.87)). The LT recipients were significantly more likely to be employed and have a higher educational level (P < 0.05)., Conclusions: Two-year outcomes in initial survivors of ALF are generally good but non-APAP patients have a significantly lower survival which may relate to pre-existing medical comorbidities. Spontaneous survivors with APAP overdose experience substantial morbidity during follow-up from ongoing psychiatric and substance abuse issues., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: The widespread availability of medication without prescription, so-called over the counter (OTC), and the rapid development of health consciousness of Poles is associated with broad access to medical information in the mass media. This causes patients to recognize their own disease, cancel doctor's appointments, and begin self-treatment. This time and money-saving behavior, often signaled by pain, usually leads to the treatment of symptoms alone, without seeking the cause of the disease.The aim of the study was to present life-threatening paracetamol poisoning, and the treatment of acute liver failure., Material and Methods: In 2002-2014, 35 patients were hospitalized due to acute paracetamol poisoning: 17 female and 18 male patients aged between 17-59 (mean 32.3 years). Patients were treated in the surgical intensive care unit, where their parameters of liver and renal function were continuously monitored. If there was no improvement in the liver function, patients underwent albumin dialysis with the Prometheus system and were qualified for liver transplantation (LTx)., Results: 26 patients were treated pharmacologically and 7 out of 9 patients who underwent LTx were dialyzed. Overall, 11 patients had 26 albumin dialysis in total; 4 patients died - 1 post-transplant and 3 pre-transplant., Conclusions: Paracetamol is the cause of many poisonings resulting from the lack of public awareness about toxic interactions with alcohol, and suicide attempts. Acetaminophen-induced acute liver failure concerns a small percentage of patients but can be successfully treated with albumin dialysis, and in extreme cases by liver transplantation.

Background: The innate immune system is profoundly dysregulated in paracetamol (acetaminophen)-induced liver injury. The neutrophil-lymphocyte ratio (NLR) is a simple bedside index with prognostic value in a number of inflammatory conditions., Aim: To evaluate the prognostic accuracy of the NLR in patients with significant liver injury following single time-point and staggered paracetamol overdoses., Patients and Methods: Time-course analysis of 100 single time-point and 50 staggered paracetamol overdoses admitted to a tertiary liver centre. Timed laboratory samples were correlated with time elapsed after overdose or admission, respectively, and the NLR was calculated., Results: A total of 49/100 single time-point patients developed hepatic encephalopathy (HE). Median NLRs were higher at both 72 (P=0.0047) and 96 h after overdose (P=0.0041) in single time-point patients who died or were transplanted. Maximum NLR values by 96 h were associated with increasing HE grade (P=0.0005). An NLR of more than 16.7 during the first 96 h following overdose was independently associated with the development of HE [odds ratio 5.65 (95% confidence interval 1.67-19.13), P=0.005]. Maximum NLR values by 96 h were strongly associated with the requirement for intracranial pressure monitoring (P<0.0001), renal replacement therapy (P=0.0002) and inotropic support (P=0.0005). In contrast, in the staggered overdose cohort, the NLR was not associated with adverse outcomes or death/transplantation either at admission or subsequently., Conclusion: The NLR is a simple test which is strongly associated with adverse outcomes following single time-point, but not staggered, paracetamol overdoses. Future studies should assess the value of incorporating the NLR into existing prognostic and triage indices of single time-point paracetamol overdose.

Purpose of Review: Fulminant hepatic failure (FHF) is one of the more dramatic and challenging syndromes in clinical medicine. Time constraints and the scarcity of organs complicate the evaluation process in the case of patients presenting with FHF, raising ethical questions related to fairness and justice. The challenges are compounded by an absence of standardized guidelines., Recent Findings: Acetaminophen overdose, often occurring in patients with histories of psychiatric illness and substance dependence, has emerged as the most common cause of FHF. The weak correlations between psychosocial factors and nonadherence, as per some studies, suggest that adherence may be influenced by systematic factors. Most research suggests that applying rigid ethical parameters in these patients, rather than allowing for case-dependent flexibility, can be problematic., Summary: The decision to transplant in patients with FHF has to be made in a very narrow window of time. The time-constrained process is fraught with uncertainties and limitations, given the absence of patient interview, fluctuating medical eligibility, and limited data. Although standardized scales exist, their benefit in such settings appears limited. Predicting compliance with posttransplant medical regimens is difficult to assess and raises the question of prospective studies to monitor compliance.

Background: An acetominophen overdose (AOD) is the leading cause of acute liver failure (ALF) in the UK and USA. For patients who meet the King's College Hospital criteria, (mortality risk > 85%), an emergency orthotopic liver transplantation (OLT) is conventionally performed with subsequent life-long immunosuppression. A new technique was developed in 1998 for AOD-induced ALF where a subtotal hepatectomy (right hepatic trisectionectomy) and whole graft auxiliary liver transplant (WGALT) was performed with complete withdrawal of immunosupression during the first year post-operatively., Results: During 1998-2010, 68 patients were listed for an emergency transplantation for AOD ALF at our institution: 28 died waiting, 16 underwent OLT and 24 a subtotal hepatectomy with WGALT. Eight OLT (50%) and 16 WGALT remain alive (67%); actuarial survival at 5 years OLT 50%, WGALT 63%, P = 0.37. All patients who had successful WGALT are off immunosuppression. Poor prognostic factors in the WGALT group included higher donor age (40.4 versus 53.9, P = 0.043), requirements for a blood transfusion (4.3 versus 7.6, P = 0.0043) and recipient weight (63.1 versus 54 kg, P = 0.036)., Conclusion: Although OLT remains standard practice for AOD-induced ALF, life-long immunosuppression is required. A favourable survival rate using a subtotal hepatectomy and WGALT has been demonstrated, and importantly, all successful patients have undergone complete immunosuppression withdrawal. This technique is advocated for patients who have acetominophen hepatotoxicity requiring liver transplantation., (© 2013 International Hepato-Pancreato-Biliary Association.)

Context: An elevated troponin I (TnI) is associated with a poorer prognosis during critical illness., Objective: Our aims were to determine whether significant paracetamol-induced hepatotoxicity was associated with an elevated TnI; if this elevation was persistent and was associated with worse clinical outcomes., Materials and Methods: In this retrospective cohort study, the requirement for orthotopic liver transplantation (OLT) or death and/or the development of multiorgan failure (MOF) was evaluated for 48 consecutive patients admitted to the Royal Infirmary of Edinburgh (a university tertiary referral centre) with acute liver injury or acute liver failure secondary to paracetamol overdose., Results: TnI was elevated (≥ 0.05 ng/L) in 13/48 patients (27%). This appeared to be sustained for at least 6 days which has not been shown previously in the context of Acute Liver Injury (ALI). Elevated TnI was strongly associated with MOF, with the requirement for inotropic support being the strongest predictor (p = 0.003, OR 9.00, 95% CI 2.13-37.98). TnI elevations also correlated strongly with Acute Physiology and Chronic Health Evaluation (APACHE) II scores (p = 0.0006, r = 0.482, 95% CI 0.22-0.68) and with interleukin 6 (IL-6) levels (p = 0.0001, r = 0.55, 95% CI 0.29-0.73). Although a raised TnI was associated with a markedly increased risk of death or orthotopic liver transplant (p = 0.005, OR 7.73, 95% CI 1.87-32.05) on univariate analysis, this was primarily seen in the context of MOF (SOFA score p = 0.003, OR 1.23, 95% CI 1.07-1.41) and was not an independent predictor of death. There was no correlation between TnI or outcome with other cardiac biomarkers and markers of cardiovascular risk., Discussion and Conclusion: An elevated TnI in the context of acute liver injury or liver failure following paracetamol overdose is associated with a significantly worse patient outcome but it is not an independent prognostic factor. Further studies should be undertaken to investigate the mechanism behind this elevated troponin association.

Objectives: Pentraxin 3 (PTX3) is a long pentraxin with diverse humoral innate immune functions. The aims of this study were to measure levels of PTX3 and C-reactive protein (CRP), a hepatocyte-derived short pentraxin, in patients after acute liver injury., Methods: PTX3 and CRP levels were measured in a total of 60 patients [48 paracetamol overdose (POD), 12 non-POD]. PTX3 expression was assessed by immunohistochemical analysis in explanted liver tissue., Results: Admission PTX3 levels were significantly higher in POD acute liver failure (ALF) patients compared with POD non-ALF patients (P=0.0005) and non-POD patients (P=0.004). PTX3 levels in POD patients who died or required orthotopic liver transplantation (OLT, n=14) were significantly higher compared with those in spontaneous survivors (n=34, P=0.0011). The area under the receiver operator characteristic for PTX3 for death/OLT in POD patients was 0.80 (95% confidence interval 0.67-0.93). PTX3 levels were significantly higher in those POD patients who developed the systemic inflammatory response syndrome (P=0.001). Conversely, admission CRP levels were significantly lower in POD compared with non-POD patients (P=0.011), with no significant differences between survivors and nonsurvivors. After emergency OLT, PTX3 levels fell markedly; in contrast, CRP levels rapidly increased. Immunohistochemical analysis showed PTX3 expression in sinusoidal lining cells of a normal liver, infiltrating inflammatory cells in patients with ALF, and in a membranous distribution on injured hepatocytes in POD patients., Conclusion: Increased PTX3 levels are associated with adverse outcomes following POD, suggesting that the humoral innate immune system plays an underrecognized role in this condition.

Acetaminophen poisoning remains one of the more common drugs taken in overdose with potentially fatal consequences. Early recognition and prompt treatment with N-acetylcysteine can prevent hepatic injury. With acute overdose, the Rumack-Matthew nomogram is a useful tool to assess risk and guide management. Equally common to acute overdose is the repeated use of excessive amounts of acetaminophen. Simultaneous ingestion of several different acetaminophen-containing products may result in excessive dosage. These patients also benefit from N-acetylcysteine. Standard courses of N-acetylcysteine may need to be extended in patients with persistently elevated plasma concentrations of acetaminophen or with signs of hepatic injury., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Liver failure resulting from deliberate or accidental paracetamol overdose continues to be an important reason for referral to liver transplant centres. Severe hepatic dysfunction often appears 72-96 h after overdose. Liver injury can be prevented by timely administration of the specific antidote, N-acetylcysteine. Unfortunately, administration of N-acetylcysteine is frequently delayed due to late presentation or late administration. While N-acetylcysteine works best if given within 8 h of overdose, it is beneficial at any time period and should always be given if there is concern about significant overdose, irrespective of interval from time of ingestion. Early discussion with liver transplant unit is suggested if there is any doubt or evidence of liver failure.

Introduction: Acetaminophen (APAP) is a widely used medication in pregnancy and is considered safe. Unfortunately, APAP is also among the most commonly reported agents implicated in overdoses during pregnancy. We present a unique case of a pregnant patient with fulminant hepatic failure resulting in a liver transplant from repeated supratherapeutic ingestions of APAP., Case Report: A 22 year pregnant female presented with abdominal pain and hepatotoxicity after taking supratherapeutic amounts of APAP to treat dental pain. The patient denied intentional or acute ingestion of APAP but did admit to taking approximately 8-9 grams of APAP per day for 10-14 days for dental pain. Other cause of hepatotoxicity, including acute fatty liver of pregnancy, were evaluated for and ruled out. She developed fulminant hepatic failure and required liver transplantation which was successful. The pregnancy remained viable through the operation but intrauterine fetal demise occurred 2 weeks later. An MRI of the fetus showed extensive peri-cerebral and intraventricular hemorrhage with extensive periventricular leukomalacia., Discussion: The degree of morbidity from repeated supratherapeutic ingestions of APAP seen in this case is rare and poorly described in a pregnant patient. There are no prior reports describing the need for liver transplant after repeated supratherapeutic ingestions of APAP during pregnancy. Along with the typical cause of hepatotoxicy several unique pregnancy-related causes also had to be evaluated for. This case highlights the significant morbidity that can occur with even unintentional APAP toxicity and the need to educate patients, especially pregnant patients, of the risk of excessive APAP use.

Acetaminophen-induced acute liver failure (ALF) is a complex multiorgan illness. An assessment of the prognosis is essential for the accurate identification of patients for whom survival without liver transplantation (LT) is unlikely. The aims of this study were the comparison of prognostic models [King's College Hospital (KCH), Model for End-Stage Liver Disease, Sequential Organ Failure Assessment (SOFA), and Acute Physiology and Chronic Health Evaluation II (APACHE II)] and the identification of independent prognostic indicators of outcome. We evaluated consecutive patients with severe acetaminophen-induced ALF who were admitted to the intensive care unit. At admission, demographic, clinical, and laboratory parameters were recorded. The discriminative ability of each prognostic score at the baseline was evaluated with the area under the receiver operating characteristic curve (AUC). In addition, using a multiple logistic regression, we assessed independent factors associated with outcome. In all, 125 consecutive patients with acetaminophen-induced ALF were evaluated: 67 patients (54%) survived with conservative medical management (group 1), and 58 patients (46%) either died without LT (28%) or underwent LT (18%; group 2). Group 1 patients had significantly lower median APACHE II (10 versus 14) and SOFA scores (9 versus 12) than group 2 patients (P < 0.001). The independent indicators associated with death or LT were a longer prothrombin time (P = 0.007), the inspiratory oxygen concentration (P = 0.005), and the lactate level at 12 hours (P < 0.001). The KCH criteria had the highest specificity (83%) but the lowest sensitivity (47%), and the SOFA score had the best discriminative ability (AUC = 0.79). In conclusion, for patients with acetaminophen-induced ALF, the SOFA score performed better than the other prognostic scores, and this reflected the presence of multiorgan dysfunction. A further evaluation of SOFA with the KCH criteria is warranted., (Copyright © 2012 American Association for the Study of Liver Diseases.)

A comatose 23-year-old woman with acute liver failure due to an overdose of acetaminophen had indications of intracranial hypertension and underwent liver transplantation. Her level of arousal did not improve, and on postoperative day 1, clinical signs of cerebral herniation became apparent. An intracranial pressure monitor was placed, and intracranial hypertension was documented. Elevations in intracranial pressure persisted despite maximal osmotherapy, and therapeutic hypothermia was started. Normalization of intracranial pressure was rapid. Findings on neurological examination improved and the patient was discharged from the hospital with no neurological impairment.

Liver transplantation (LT) programs encounter patients with fulminant hepatic failure resulting from suicide attempts involving acetaminophen or multidrug ingestion. Members of transplant teams often have different opinions about whether these patients should be offered transplantation. Disagreements can delay the transfer of these patients to a transplant facility and negatively affect their management. Currently, transplant programs have no guidelines to help them with their decisions about the appropriateness of LT for these patients. Here we present a clinical case encountered at our facility, and we discuss ethical principles that should help programs to make informed decisions about transplantation for these patients., (Copyright © 2011 American Association for the Study of Liver Diseases.)

Aims: Paracetamol (acetaminophen) hepatotoxicity is the commonest cause of acute liver failure (ALF) in the UK. Conflicting data regarding the outcomes of paracetamol-induced ALF resulting from different overdose patterns are reported., Methods: Using prospectively defined criteria, we have analysed the impact of overdose pattern upon outcome in a cohort of 938 acute severe liver injury patients admitted to the Scottish Liver Transplantation Unit., Results: Between 1992 and 2008, 663 patients were admitted with paracetamol-induced acute severe liver injury. Of these patients, 500 (75.4%) had taken an intentional paracetamol overdose, whilst 110 (16.6%) had taken an unintentional overdose. No clear overdose pattern could be determined in 53 (8.0%). Unintentional overdose patients were significantly older, more likely to abuse alcohol, and more commonly overdosed on compound narcotic/paracetamol analgesics compared with intentional overdose patients. Unintentional overdoses had significantly lower admission paracetamol and alanine aminotransferase concentrations compared with intentional overdoses. However, unintentional overdoses had greater organ dysfunction at admission, and subsequently higher mortality (unintentional 42/110 (38.2%), intentional 128/500 (25.6%), P < 0.001). The King's College poor prognostic criteria had reduced sensitivity in unintentional overdoses (77.8%, 95% confidence intervals (CI) 62.9, 88.8) compared with intentional overdoses (89.9%, 95% CI 83.4, 94.5). Unintentional overdose was independently predictive of death or liver transplantation on multivariate analysis (odds ratio 1.91 (95% CI 1.07, 3.43), P = 0.032)., Conclusions: Unintentional paracetamol overdose is associated with increased mortality compared with intentional paracetamol overdose, despite lower admission paracetamol concentrations. Alternative prognostic criteria may be required for unintentional paracetamol overdoses., (© 2011 The Authors. British Journal of Clinical Pharmacology © 2011 The British Pharmacological Society.)

Acute liver failure is a rare disorder with high mortality and resource cost. In the developing world, viral causes predominate, with hepatitis E infection recognised as a common cause in many countries. In the USA and much of western Europe, the incidence of virally induced disease has declined substantially in the past few years, with most cases now arising from drug-induced liver injury, often from paracetamol. However, a large proportion of cases are of unknown origin. Acute liver failure can be associated with rapidly progressive multiorgan failure and devastating complications; however, outcomes have been improved by use of emergency liver transplantation. An evidence base for practice is emerging for supportive care, and a better understanding of the pathophysiology of the disorder, especially in relation to hepatic encephalopathy, will probably soon lead to further improvements in survival rates., (Copyright 2010 Elsevier Ltd. All rights reserved.)

Background: Acetaminophen-induced hepatotoxicity is the most common cause of acute liver failure (ALF) in the UK. Patients often consume the drug with suicidal intent or with a background of substance dependence., Aims and Methods: We compared the severity of pretransplant illness, psychiatric co-morbidity, medical and psychosocial outcomes of all patients who had undergone liver transplantation (LT) emergently between 1999-2004 for acetaminophen-induced ALF (n=36) with age- and sex-matched patients undergoing emergent LT for non-acetaminophen-induced ALF (n=35) and elective LT for chronic liver disease (CLD, n=34)., Results: Acetaminophen-induced ALF patients undergoing LT had a greater severity of pre-LT illness reflected by higher Acute Physiology and Chronic Health Evaluation II scores and requirement for organ support compared with the other two groups. Twenty (56%) acetaminophen-induced ALF patients had a formal psychiatric diagnosis before LT (non-acetaminophen-induced ALF=0/35, CLD=2/34; P<0.01 for all) and nine (25%) had a previous suicide attempt. During follow-up (median 5 years), there were no significant differences in rejection (acute and chronic), graft failure or survival between the groups (acetaminophen-induced ALF 1 year 87%, 5 years 75%; non-acetaminophen-induced ALF 88%, 78%; CLD 93%, 82%: P>0.6 log rank). Two acetaminophen-induced ALF patients reattempted suicide post-LT (one died 8 years post-LT)., Conclusions: Despite a high prevalence of psychiatric disturbance, outcomes for patients transplanted emergently for acetaminophen-induced ALF were comparable to those transplanted for non-acetaminophen-induced ALF and electively for CLD. Multidisciplinary approaches with long-term psychiatric follow-up may contribute to low post-transplant suicide rates seen and low rates of graft loss because of non-compliance.

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.

Liver transplantation (LT) may be life-saving in severe acute liver failure (ALF). The aim of this study was to compare the utilization of LT in acetaminophen and non-acetaminophen ALF. Between 1992 and 2006, 469 patients with ALF were admitted, and 104 underwent LT. Acetaminophen was the most common etiology, but LT proceeded more frequently in the non-acetaminophen cohort (acetaminophen: 45/326 patients received LT, 13.8%; non-acetaminophen: 59/143 patients received LT, 41.3%; P < 0.01). A retrospective analysis of the individual steps in the management of patients revealed more ALF patients in the non-acetaminophen cohort fulfilled the King's College Hospital poor prognostic criteria (non-acetaminophen: 91/143, 63.6%; acetaminophen: 165/326, 50.6%; P < 0.01), more patients had contraindications to LT in the acetaminophen cohort (acetaminophen: 99/165, 60%; non-acetaminophen: 21/91, 23.1%; P < 0.01), and survival on the LT waiting list was reduced in the acetaminophen cohort (acetaminophen: 45/66, 68.2%; non-acetaminophen: 59/70, 84.3%; P < 0.05). Post-LT survival was similar in the 2 groups. An analysis of cohorts admitted in 1993-1996 and 2002-2005 revealed that LT proceeded less commonly in acetaminophen ALF in the later cohort (1993-1996: 16/99 LT, 16.2%; 2002-2005: 4/81 LT, 5%; P < 0.01) in comparison with the non-acetaminophen cohort, in which transplantation proceeded more commonly in the later cohort (1993-1996: 11/34 LT, 32.4%; 2002-2005: 24/49 patients, 49.0%; P < 0.01). This was due to an increase in the number of patients with psychiatric contraindications to transplantation (predominantly resistant and severe alcohol dependence). In conclusion, at all decision steps between admission and emergency LT, LT is favored in non-acetaminophen patients, and nonoperative management is favored in acetaminophen ALF patients., ((c) 2009 AASLD.)

Objectives: Acute pancreatitis, which can develop after any whole-organ transplant, is often associated with immunosuppression. Pancreatitis that complicates a liver transplant can be a significant problem that results in a high mortality rate., Materials and Methods: We describe the successful use of minimally invasive techniques to treat severe acute pancreatitis. To our knowledge, this is the first reported case in which major laparotomy was precluded by the use of percutaneous necrosectomy to manage necrotizing pancreatitis in a liver transplant recipient. We also briefly review the published literature on severe acute pancreatitis in liver transplant recipients., Results: Our patient, who had a Model for End- Stage Liver Disease score of 39 when transplanted and an Acute Physiology and Chronic Health Evaluation II score of 19 when infected necrosis in his pancreas was diagnosed, recovered completely after 92 days of hospitalization. He underwent 2 percutaneous drainage procedures and 3 percutaneous necrosectomies to treat his pancreatic complication. A review of the literature revealed that severe acute pancreatitis significantly increases morbidity and mortality in liver transplant recipients. Unlike necrotizing pancreatitis, which develops outside the context of liver transplant where there is a distinct shift towards minimally invasive procedures, infected necrosis associated with fulminant liver failure or a liver transplant is usually treated with open necrosectomy., Conclusions: Severe acute pancreatitis in liver transplant recipients should be managed exactly as it is in patients who have not received a liver transplant. Anatomically guided minimally invasive necrosectomy appears to be beneficial, especially when patients are critically unwell, as they are following a liver transplant.

Background: To review evidence-based treatment options in patients with cerebral edema complicating fulminant hepatic failure (FHF) and discuss the potential applications of hypothermia., Method: Case-based observations from a medical intensive care unit (MICU) in a tertiary care facility in a 27-year-old female with FHF from acetaminophen and resultant cerebral edema., Results: Our patient was admitted to the MICU after being found unresponsive with presumed toxicity from acetaminophen which was ingested over a 2-day period. The patient had depressed of mental status lasting at least 24 h prior to admission. Initial evaluation confirmed FHF from acetaminophen and cerebral edema. The patient was treated with hyperosmolar therapy, hyperventilation, sedation, and chemical paralysis. Her intracranial pressure remained elevated despite maximal medical therapy. We then initiated therapeutic hypothermia which was continued for 5 days. At re-warming, patient had resolution of her cerebral edema and intracranial hypertension. At discharge, she had complete recovery of neurological and hepatic functions., Conclusion: In patients with FHF and cerebral edema from acetaminophen overdose, prolonged therapeutic hypothermia could potentially be used as a life saving therapy and a bridge to hepatic and neurological recovery. A clinical trial of hypothermia in patients with this condition is warranted.

Objective: To determine the clinical characteristics of patients with acute liver failure of indeterminate cause and their long-term outcome in comparison with patients with acute liver failure of obvious aetiology (acetaminophen and mushroom poisoning, Budd-Chiari syndrome, acute viral hepatitis) and other controls (idiosyncratic drug reactions, autoimmune hepatitis and Wilson's disease)., Material and Methods: All patients with acute liver failure and listed for liver transplantation in Sweden between 1984 and 2006 were included in a retrospective analysis., Results: A total of 71 patients with acute liver failure were identified, 33 with indeterminate cause (IDC group), 23 with obvious aetiology (OE group) and 15 other controls (OC group). Before admission to the transplant centre, IDC patients were hospitalized in the referring hospital for 9 days (4-15) versus 1.5 days (1-3) in the OE group (p<0.001) and 7 days (2-14) in the OC group (NS). Serum bilirubin was higher (p<0.001), whereas peak creatinine was lower (p=0.001) in the IDC group compared with the OE group but was not significantly different from the OC group. There were no significant differences in 1-, 3-, 5- and 10-year patient and graft survival rates between the IDC group and the OE or the OC group., Conclusions: Patients with acute liver failure of indeterminate cause seem to differ from those with obvious aetiology in clinical and biochemical presentation but are similar to other controls. The overall long-term outcome seems to be similar in patients with an unknown aetiology as in those with a specific aetiology.

Introduction: Acetaminophen (paracetamol) overdose (AOD) has recently emerged as the leading cause of acute liver failure (ALF) in the United States, with an incidence approaching that seen in the United Kingdom. We describe a new way to treat AOD ALF patients fulfilling King's College criteria for "super-urgent" liver transplantation., Methods: Beginning in June 1998, we have been piloting a clinical program of subtotal hepatectomy and auxiliary orthotopic liver transplantation (ALT) for AOD ALF. Our technique is based on the following principles: (1) subtotal hepatectomy; (2) auxiliary transplantation of a whole liver graft; (3) gradual withdrawal of immunosuppression after recovery. Results were compared with patients who had undergone an orthotopic liver transplantation (OLT) for AOD ALF in the same period. Quality of life comparisons were made using the SF36 questionnaire., Results: Thirteen patients underwent this procedure between June 1998 and March 2005. Median survival is 68 months (range, 0-102 m). Actual survival data show that 9 of 13 patients are alive (69%) compared with 7 of 13 OLT patients (54%). One ALT patient required a retransplantation with an OLT due to hepatic vein thrombosis, and immunosuppression is therefore maintained. The other 8 surviving ALT patients are off immunosuppression. These 8 ALT patients have normal liver function and have a better quality of life compared with the 7 surviving OLT patients., Conclusion: Our results with this new technique are encouraging: 69% actual survival, no long-term immunosuppression requirement, and improved quality of life in the 62% successful cases.

Background: Poisoning with paracetamol (acetaminophen) is a common cause of hepatotoxicity in the Western World. Inhibition of absorption, removal from the vascular system, antidotes, and liver transplantation are interventions for paracetamol poisoning., Objectives: To assess the benefits and harms of interventions for paracetamol overdose., Search Strategy: We identified trials through electronic databases, manual searches of bibliographies and journals, authors of trials, and pharmaceutical companies until December 2005., Selection Criteria: Randomised clinical trials and observational studies were included., Data Collection and Analysis: The primary outcome measure was all-cause mortality plus liver transplantation. Secondary outcome measures were clinical symptoms, (eg, hepatic encephalopathy, fulminant hepatic failure), hepatotoxicity, adverse events, and plasma paracetamol concentration. We used Peto odds ratios and odds ratios with 95% confidence intervals (CI) for analysis of outcomes. Random- and fixed-effects meta-analyses were performed., Main Results: Ten small and low-methodological quality randomised trials, one quasi-randomised study, and 48 observational studies were identified. It was not possible to perform relevant meta-analyses of randomised trials that have addressed our outcome measures. Activated charcoal, gastric lavage, and ipecacuanha are able to reduce the absorption of paracetamol, but the clinical benefit is unclear. Of these, activated charcoal seems to have the best risk-benefit ratio. N-acetylcysteine seems preferable to placebo/supportive treatment, dimercaprol, and cysteamine, but N-acetylcysteine's superiority to methionine is unproven. It is not clear which N-acetylcysteine treatment protocol offers the best efficacy. No strong evidence supports other interventions for paracetamol overdose. N-acetylcysteine may reduce mortality in patients with fulminant hepatic failure (Peto OR 0.26, 95% CI 0.09 to 0.94, one trial). Liver transplantation has the potential to be life saving in fulminant hepatic failure, but refinement of selection criteria for transplantation and long-term outcome reporting are required., Authors' Conclusions: Our results highlight a paucity of randomised trials on interventions for paracetamol overdose. Activated charcoal seems the best choice to reduce absorption. N-acetylcysteine should be given to patients with overdose but the selection criteria are not clear. No N-acetylcysteine regime has been shown to be more effective than any other. It is a delicate balance when to proceed to liver transplantation, which may be life-saving for patients with poor prognosis.

We report the case of a 22-year-old man who developed fulminant hepatic failure 3 days after an intentional acetaminophen overdose. The patient had a history of a seizure disorder for which he was taking phenytoin. The acetaminophen level at presentation was in the "nontoxic" range. Emergent liver transplantation was performed 4 days after the ingestion. This is the first reported case of successful liver transplantation for acetaminophen-induced fulminant hepatic failure in the setting of phenytoin therapy.

Studies of acute liver failure from drugs have included cases mostly attributed to acetaminophen (APAP) but have reported limited data on other drugs. We used the United Network for Organ Sharing (UNOS) liver transplant database from 1990 to 2002 to identify recipients and estimate a U.S. population-based rate of liver transplantation due to acute liver failure from drugs. Patients were identified if their diagnosis was acute hepatic necrosis from an implicated drug at the time of transplant. Liver transplantation for drug hepatotoxicity accounted for 15% of liver transplants for acute liver failure over the study period. In our cohort (n = 270), 206 (76%) recipients were female. APAP alone, or in combination with another drug, accounted for 133 (49%) cases. In the non-acetaminophen (non-APAP) group (n = 137), the most frequently implicated drugs were: isoniazid, n = 24 (17.5%); propylthiouracil, n = 13 (9.5%); and phenytoin and valproate in 10 (7.3%) cases each. One-year patient and graft survival for the entire cohort was 77 and 71%, respectively. Among Caucasians (n = 206) and African-Americans (n = 48), APAP only was implicated in 110 (53%) patients and 12 (25%) patients, respectively, and non-APAP drugs were implicated in 96 (47%) patients and 36 (75%) patients, respectively (P =.0004). Among African-Americans in the non-APAP group, 28 (78%) were women. In conclusion four drugs were implicated in 42% of patients undergoing liver transplantation for acute liver failure due to drugs other than APAP. The increased frequency of African-American women undergoing liver transplantation for non-APAP drug induced liver injury warrants further study.

In long-term alcohol users, the syndrome of hepatotoxicity from acetaminophen taken in therapeutic or modestly excessive doses is distinctive. It is characterized by striking elevation of transaminase levels and the potential for acute liver failure with high morbidity and mortality rates. A high index of suspicion should be maintained; in any patient with evidence of acute hepatic injury, a complete history of over-the-counter drug use should be obtained and acetaminophen levels checked. If there is doubt about the dose or time of ingestion, one should err on the side of treatment with acetylcysteine, because it is both effective and safe. Therapy should be initiated as early as possible, but even late administration may be of benefit. Timely contact with a medical center that has liver transplantation capabilities should be made before encephalopathy becomes advanced. Heightened awareness of this preventable and treatable condition is needed by healthcare providers and acetaminophen users alike. Because the minimum safe dose of acetaminophen is not known in the setting of chronic alcohol use, it seems prudent in such situations to avoid acetaminophen altogether, especially during brief periods of abstinence.

Background: Paracetamol is a readily available, widely used analgesic that can cause serious hepatic injury when taken in overdose. The aims of this study were to assess the frequency of attendance at the Austin and Repatriation Medical Centre for paracetamol overdose, the frequency of referral to the Victorian liver transplant unit after serious overdoses, the morbidity and mortality rates in all patients treated and the appropriateness of treatment., Methods: A review of the Austin and Repatriation Medical Centre medical records and of the Victorian liver transplant unit database of all patients attending because of paracetamol overdose from 1988-1995 was undertaken. One hundred and fifty-two patients (103 females, 49 males) files were reviewed., Results: One hundred and thirty-one patients presented directly from the community and 21 were referred specifically for consideration for possible transplantation. The most important predictor of liver injury was time between overdose and arrival at hospital (P< 0.01). Thirteen patients developed fulminant hepatic failure, one of whom received a liver transplant; this patient died post-transplantation and was the only death in the series., Conclusions: We found that serious liver injury following overdose was uncommon, liver transplantation was rarely needed and death was rare. Although inappropriate delay in instituting N-acetylcysteine treatment after admission to hospital or failure to treat still occurred in a number of cases, delay in presentation to hospital was the main predictor of liver damage.

Once defined clinical criteria are fulfilled in acetaminophen-induced hepatotoxicity, prognosis without orthotopic liver transplantation (OLT) may be very poor. In the present study, we examined the application and outcome of OLT in 548 patients admitted to a single center between 1990 and 1996. Four hundred twenty-four (77%) of the patients studied did not fulfill transplantation criteria, and 396 of these (93%) survived. The majority of the 28 nonsurvivors (7%) in this group fulfilled two of three combined criteria, and the finding of a high APACHE III score could be used as an indicator for the need for OLT. Of the 56 patients (45%) not listed, in only a small proportion was this caused by psychiatric reasons, and in the majority, it was a consequence of the rapid development of multiple organ failure and cerebral edema. This also applied to 24 (35%) of the 68 listed patients in whom the rapidity of clinical deterioration, reflected in increasing APACHE III scores, was such that even with the prompt availability of donor organs, OLT was not possible. In the final event, only 44 (35%) of those who fulfilled criteria underwent OLT, of whom 33 (75%) survived to leave the hospital. Survival was greatest in those receiving unreduced grafts, and markers of early graft function differed significantly between survivors and nonsurvivors. Liver transplantation is an effective treatment in a relatively small number of patients with acetaminophen-induced hepatotoxicity, and for a substantial proportion, transplantation was never an option because of the rapidity of clinical deterioration. APACHE III scoring may be of value in decision making and in better defining patients in clinical trials.