BACKGROUND:Whereas paracetamol poisoning is predominantly seen in adolescents and young adults, the majority of paracetamol associated deaths occur in an older population.AIMS:The aim of the present study was to evaluate age as a risk factor for fulminant hepatic failure (FHF) and death in a large population of patients with paracetamol poisoning.PATIENTS:A total of 746 patients transferred to a specialised unit with severe paracetamol poisoning and 273 unselected patients admitted from the local region over a 10 year period.METHODS:A partly retrospective study based on hospital charts. The risk associated with age was evaluated by multivariate analysis.RESULTS:Paracetamol poisoning most frequently occurred in the age group 15-24 years. Transferred patients were significantly older than local patients (median age 37 years v 29 years; p = 0.0006). In contrast, FHF and death from paracetamol poisoning most frequently occurred in patients aged 40 years or above. In a logistic regression analysis, "age >/=40 years" was associated with an excess risk of FHF (odds ratio (OR) 2.33 (95% confidence interval (CI) 1.50-3.64)) and death or liver transplantation (OR 4.18 (95% CI 2.17-8.05)). In addition, older age was associated with other risk factors for paracetamol hepatotoxicity such as regular alcohol abuse and late presentation.CONCLUSIONS:Age 40 years or above was identified as a significant independent risk factor for FHF and mortality following paracetamol overdose. Patients aged 40 years or above should be considered as high risk patients, in particular when older age appears in combination with regular alcohol abuse or late presentation.

An increase in alpha-fetoprotein (AFP) following hepatic necrosis is considered indicative of hepatic regeneration. This study evaluated the prognostic value of serial AFP measurements in patients with severe acetaminophen-induced liver injury. Prospectively, serial measurements of AFP were performed in 239 patients with acetaminophen intoxication and a peak alanine aminotransferase (ALT) level above 1,000 U/L. AFP was measured using an enzyme-linked immunoassay (EIA) with a detection limit below 0.4 μg/L. The optimum threshold of AFP to discriminate nonsurvivors was identified. An increase in AFP above 4 μg/L occurred in 158 (79%) of 201 survivors compared with 11 of 33 nonsurvivors (33%; P < .00001). The increase in AFP occurred a mean of 1.0 days (range, −2 to +6 days) after peak ALT in survivors compared with 4.1 days (range, +2 to +7 days) in nonsurvivors (P < .00001). Starting on the day of peak ALT, AFP values were significantly higher in survivors than in nonsurvivors. A threshold AFP of 3.9 μg/L on day +1 after peak ALT to identify nonsurvivors had a sensitivity of 100%, a specificity of 74%, a positive predictive value of 45%, and a negative predictive value of 100%. In conclusion, an increase in AFP was strongly associated with a favorable outcome in patients with acetaminophen-induced liver injury. AFP may be useful as a supplement to existing prognostic criteria. We suggest that the introduction of highly sensitive EIAs for the detection of AFP will require a reevaluation of AFP as a prognostic marker in acute nonneoplastic liver disease. (HEPATOLOGY 2005;41:26–31.)

Background and aim: N-acetylcysteine is used to treat paracetamol overdose but depresses the activity of plasma coagulation factors II, VII, and X, which are often used to assess liver injury. The aim of this study was to investigate the effect of N-acetylcysteine on haemostasis in normal volunteers. Methods: Haemostatic parameters in 10 healthy subjects were analysed before and following intravenous infusion of therapeutic doses of N-acetylcysteine, as well as in vitro. Results: N-acetylcysteine induced significant decreases in plasma levels of vitamin K dependent haemostatic proteins in vivo, being maximal at one hour following the start of infusion, with maximal decreases from 1.00 to 0.73 (0.67–0.79) (mean (95% confidence interval)), 0.66 (0.58–0.73), 0.81 (0.73–0.90), 0.64 (0.57–0.70), 0.74 (0.65–0.82), and 0.61 (0.54–0.67) for factor II, VII, IX, and X activities, protein C activity, and free protein S reactivity, respectively. These data suggest that N-acetylcysteine induces protein modifications affecting activity. Five subjects developed an adverse reaction to infusion of N-acetylcysteine and these were associated with a rapid increase in levels of factor VIII and its carrier protein von Willebrand factor (vWf) from 1.0 to 1.85 (1.08–2.62) and 1.77 (0.83–2.71), respectively, which suggests that the allergic reaction induced release of vWf from endothelial cells. N-acetylcysteine did not affect factor VIII or vWf in subjects without adverse reactions, and nor did it affect factor V or antithrombin in any of the subjects. Conclusion: Therapeutic doses of N-acetylcysteine cause abnormal haemostatic activity, and this should be taken into account when using haemostatic function tests as an indicator of hepatic injury.

BACKGROUND:Hyperamylasaemia and even acute pancreatitis have been reported in patients with paracetamol poisoning.AIMS:To describe the incidence, clinical characteristics, and prognostic implications of hyperamylasaemia in paracetamol poisoning.PATIENTS:Six hundred and two patients transferred to a specialized unit with severe paracetamol poisoning and 212 unselected patients admitted from the local region.METHODS:Retrospective study based on hospital charts. The optimum threshold of serum amylase to discriminate non-survivors was identified.RESULTS:An elevated serum amylase (>100 U/L) occurred in 28 of the unselected patients (13%), in 218 of the transferred patients (36%), and in 118 of 148 patients (80%) with fulminant hepatic failure. Only 33 cases of paracetamol-associated acute pancreatitis were diagnosed. A threshold serum amylase of 150 U/L to discriminate non-survivors had sensitivity 76%, specificity 85%, positive predictive value 33%, and negative predictive value 97%. In a logistic regression analysis, a serum amylase > 150 U/L was associated with an excess mortality (odds ratio 5.0, 2.6-9.7).CONCLUSIONS:Hyperamylasaemia is frequent in patients with paracetamol poisoning, whereas clinical acute pancreatitis occurs rarely. The incidence of hyperamylasaemia increases with the degree of hepatic dysfunction. A serum amylase exceeding 1.5 times the upper normal limit indicates a poor prognosis.

Background: Liver failure is associated with low concentrations of branched‐chain amino acids and high concentrations of most other amino acids. In this study the effect of treatment with the Molecular Adsorbents Recirculating System (MARS) on arterial amino acid levels and cerebral amino acid metabolism was examined in patients with severe hepatic encephalopathy. Methods: The study included seven patients with hepatic encephalopathy from fulminant hepatic failure (FHF) and five patients with hepatic encephalopathy from acute‐on‐chronic liver failure (AoCLF). Cerebral blood flow and cerebral arteriovenous differences in amino acids were measured before and after 6 h of treatment with MARS. Results: During MARS treatment, the total arterial amino acid concentration decreased by 20% from 8.92 ± 7.79 mmol/L to 7.16 ± 5.64 mmol/L (P < 0.05). The concentration decreased in all amino acids with the exception of the branched‐chain amino acids. Fischer's ratio of branched‐chain to aromatic amino acids increased from 0.73 ± 0.47 to 0.91 ± 0.54 (P < 0.05). A net cerebral efflux of amino acids in patients with FHF (8.94 ± 8.34 μmol/100 g/min) as well as AoCLF (7.35 ± 24.97 μmol/100 g/min) was not affected by the MARS treatment. MARS had no effect on the cerebral metabolic rate of any single amino acid in either group. Conclusions: MARS treatment tends to normalize the arterial amino acid concentrations in patients with hepatic encephalopathy. Even though the overall reduction in plasma amino acids and improvement in amino acid dysbalance may well be beneficial, it was not accompanied by any immediate improvement in cerebral amino acid metabolism in patients with FHF or AoCLF.

BACKGROUND:Survival after liver transplantation for fulminant hepatic failure has been reported to be less favorable than survival for patients with chronic liver diseases. METHODS:We have studied all patients (n=229) undergoing highly urgent liver transplantation from 1990 to 2001 in the Nordic countries. The impact of patient and donor characteristics, with emphasis on donor-recipient ABO matching (identical, compatible, incompatible), has been studied. RESULTS:One-year and 3-year patient survival rates were 73% and 70% for the total period and 86% and 78% for the last 4-year period. Patients receiving an ABO-compatible liver allograft had significantly lower patient survival rates than those receiving an ABO-identical donor organ (1-year patient survival rates 66% of vs. 79%, P=0.03). Graft survival rates varied less (1-year graft survival rates of 64% vs. 74%, P=0.09). Patients receiving an ABO-incompatible liver allograft had patient survival rates of 70% at 1 year and 60% at 3 years but low graft survival rates (40% and 30% at 1 and 3 years). In a multiple regression analysis, significant independent predictors of poor patient survival were early year of transplantation, ABO-compatible donor, high donor age, and waiting time more than 3 days and less than 9 days. CONCLUSION:Survival after highly urgent liver transplantation has improved and is comparable to that observed in patients receiving a liver allograft because of chronic liver disease. Patients receiving an ABO-identical donor organ had significantly higher patient survival rates compared with those receiving an ABO-compatible donor liver.

BACKGROUND:Tobacco smoke contains a number of substances that are capable of inducing cytochrome P450. Consequently, current tobacco use may enhance the hepatotoxicity from a paracetamol overdose by increasing the oxidative metabolism of paracetamol.AIM:To evaluate, by multivariate analysis, the effect of current tobacco use on the morbidity and mortality from paracetamol-induced hepatotoxicity.METHODS:A retrospective study was carried out on the basis of the hospital charts of 602 patients admitted with single-dose paracetamol poisoning for whom information on current tobacco use was available.RESULTS:In patients admitted with paracetamol poisoning, the rate of current daily tobacco use of 70% (424 of 602 patients) was considerably higher than the rate of 31% in the background population (chi-squared test: P < 0.0001). Current tobacco use was an independent risk factor for the development of hepatic encephalopathy (odds ratio, 2.68; 95% confidence interval, 1.28-5.62) and mortality (odds ratio, 3.64; 95% confidence interval, 1.23-10.75). Current tobacco use was independently associated with high peak values of alanine transaminase and the international normalized ratio.CONCLUSIONS:Current tobacco use was very frequent in patients admitted with paracetamol poisoning. It was an independent risk factor of severe hepatotoxicity, acute liver failure and death following paracetamol overdose.

Background. Interindividual variability in dosage requirements of the calcineurin inhibitor immunosuppressive agents cyclosporine and tacrolimus after liver transplantation may result from differences in the CYP3A activity of the liver graft. Early postoperative erythromycin breath test (ERMBT) is an in vivo measure of graft CYP3A activity. This study evaluates the usefulness of an early postoperative ERMBT in predicting early morbidity in liver transplant recipients. Methods. In 26 liver transplant recipients, ERMBT was performed within 2 hr after transplantation. Main end points were the occurrence of cyclosporine and tacrolimus nephrotoxicity, episodes of early graft rejection, early graft function, and graft survival. Results. Cyclosporine and tacrolimus nephrotoxicity were associated with low postoperative ERMBT values (mean 0.63%±0.25% 14C/hr vs. 1.35%±0.84% 14C/hr, P =0.02). No significant association between early graft rejection and ERMBT values was demonstrated. There was a significant inverse correlation between postoperative ERMBT values and the time to normalization of international normalized ratio as a measure of early graft function (r =−0.78, P <0.001). Graft loss was associated with low postoperative ERMBT values (0.21%±0.15% 14C/hr vs. 1.09%±0.72% 14C/hr, P =0.002). Conclusion. An early postoperative ERMBT may be useful in predicting the development of cyclosporine and tacrolimus nephrotoxicity, severe graft dysfunction, or even graft loss in liver transplant recipients when calcineurin inhibitors are administered according to protocols. Whether ERMBT results may be used to individualize dosage of calcineurin inhibitors needs to be explored.

The aim of the study is to evaluate the effect of a single treatment with the molecular adsorbents recirculating system (MARS) on systemic hemodynamics and oxygen consumption (VO(2)) in patients with hyperacute liver failure (HALF). In a controlled design, eight patients with HALF were assigned to a 6-hour MARS treatment, and five patients, to a control group that was mechanically cooled to match the MARS group. Systemic hemodynamic variables were determined hourly during the study period. In the MARS group, systemic vascular resistance index increased by 46% from 1,215 +/- 437 to 1,778 +/- 710 dynes x s x cm(-5) x m(-2) (P <.0001), which significantly exceeded a 6% increase in the control group. Mean arterial pressure increased from 69 +/- 5 to 83 +/- 11 mm Hg in the MARS group (P <.0001) and was unchanged in the control group. Cardiac index decreased by 20% from 4.6 +/- 1.8 to 3.7 +/- 1.1 L/min x m(-2) (P =.0007) in the MARS group and by 7% in the control group. Heart rate decreased from 105 +/- 21 to 85 +/- 15 beats/min in the MARS group (P <.0001) and was unchanged in the control group. In the MARS group, oxygen delivery decreased from 621 +/- 198 to 486 +/- 141 mL/min x m(-2) (P <.05), and VO2, from 142 +/- 31 to 112 +/-21 mL/min x m(-2) (P <.05). Arterial lactate and pH levels were unchanged. In conclusion, systemic hemodynamic values tend to normalize, whereas systemic VO(2) decreases during MARS treatment in patients with HALF. These effects cannot be explained by the degree of cooling associated with MARS.

The aim of this study was to determine by multivariate analysis how alcohol and other factors affect the clinical course and outcome in patients with acetaminophen (paracetamol) poisoning. A total of 645 consecutive patients admitted from 1994 to 2000 with single-dose acetaminophen poisoning were studied, giving special attention to alcohol history, time between overdose and intravenous N-acetylcysteine (NAC) treatment ("time to NAC"), and other data available at the time of admittance. Up until 72 hours after ingestion, time to NAC was the single most important independent risk factor. With a time to NAC less than 12 hours, the mortality rate was 0.42% (95% CI, 0.05-2.7). When time to NAC exceeded 12, 24, and 48 hours, the mortality rate increased to 6.1%, 13%, and 19%, respectively. Chronic alcohol abuse was an independent risk factor of mortality (odds ratio [OR], 3.52; 95% CI, 1.78-6.97). Acute alcohol ingestion was an independent protective factor regarding mortality in alcoholic patients (OR, 0.08; 95% CI, 0.01-0.66) but not in nonalcoholic patients (OR, 0.21; 95% CI, 0.03-1.67). Patient age and quantity of acetaminophen were independent risk factors. In conclusion, time to NAC was confirmed as the major risk factor in acetaminophen-induced hepatotoxicity and mortality. Chronic alcohol abuse was an independent risk factor that could be counteracted by concomitant acute alcohol ingestion. We suggest that patients with chronic alcoholism and suspected acetaminophen poisoning due to an increased risk of developing hepatotoxicity should be treated with NAC regardless of risk estimation.

Acetylcysteine treatment reduces liver damage after paracetamol overdose, but can affect the prothrombin index, which is used to assess the progress of overdose patients. We aimed to assess retrospectively the effect of intravenous acetylcysteine on the prothrombin index in patients with paracetamol poisoning without signs of hepatocellular injury. Prothrombin index had been recorded before, and serially during, acetylcysteine treatment in 87 patients. After initiation of treatment, prothrombin index decreased (mean 0.33, 95% CI 0.29-0.38) in all patients, and was strongly associated with the start of acetylcysteine infusion. In patients with uncomplicated paracetamol poisoning, a fall in this index might be misinterpreted as a sign of liver failure, leading to prolonged treatment time.

BACKGROUND:Patients admitted with paracetamol overdose frequently receive one or more types of regular medication that may affect the outcome of the paracetamol intoxication.AIM:To describe the use of regular medication in patients with paracetamol poisoning and to evaluate its effects on morbidity and mortality.METHODS:Seven hundred and thirty-seven consecutive patients admitted with paracetamol poisoning were studied and the use of regular medication was recorded. The relative risk of hepatic encephalopathy, death or liver transplantation, severe hepatic dysfunction and severe hepatocellular injury was evaluated by multivariate analysis.RESULTS:Regular medication was received by 332 patients (45%). Medication with benzodiazepines (105 cases), antidepressants (100 cases), neuroleptics (75 cases), paracetamol (58 cases), oral contraceptives (51 cases), beta-agonists (40 cases), opioid analgesics (32 cases) and anticonvulsants (27 cases) predominated. Regular medication with opioid analgesics was associated with a high incidence of hepatic dysfunction (odds ratio, 5.39; 95% confidence interval, 1.13-25.8). No significant findings were demonstrated for benzodiazepines, antidepressants, neuroleptics, paracetamol, oral contraceptives, beta-agonists or anticonvulsants in the multivariate analysis.CONCLUSIONS:Regular medication with psychotropic medication, analgesics, oral contraceptives, beta-agonists or anticonvulsants was frequent in patients admitted with paracetamol poisoning. Medication with opioid analgesics was associated with a significantly increased incidence of hepatic dysfunction, whereas the other medications did not appear to affect the outcome of the paracetamol intoxication.

Hypophosphatemia is frequently observed in acetaminophen-induced hepatotoxicity and may be involved in the pathogenesis of hepatic failure. The aim of the study was to evaluate the prognostic value of serial measurements of serum phosphate in patients with severe acetaminophen poisoning. Prospectively, serial measurements of serum phosphate were performed in 125 patients with severe acetaminophen poisoning. The optimum threshold value of serum phosphate to discriminate nonsurvivors was identified. Prognostic value and speed of identification were compared with those of the King's College Hospital (KCH) criteria. Phosphate concentrations were significantly higher in nonsurvivors than in survivors at 48 to 72 hours after overdose (mean 2.65 +/- 1.18 mmol/L vs. 0.68 +/- 0.22 mmol/L, P <.001) as well as 72 to 96 hours after overdose (2.12 +/- 0.22 mmol/L vs. 0.59 +/- 0.23 mmol/L, P <.001). A threshold phosphate concentration of 1.2 mmol/L at 48 to 96 hours after overdose had sensitivity 89%, specificity 100%, accuracy 98%, positive predictive value 100%, and negative predictive value 98%. The phosphate criteria had higher sensitivity, accuracy, and positive and negative predictive values than the KCH criteria, and it identified patients significantly earlier after transferal [median 1 hour (range 1-38 hours) vs. 12 hours (2-192 hours), P <.05, respectively]. In nonsurvivors, the degree of hyperphosphatemia correlated with renal dysfunction (R =.55; P =.02). In conclusion, hyperphosphatemia after acetaminophen overdose is seen exclusively in nonsurvivors, which makes it a highly specific as well as sensitive predictor of nonsurvival. We propose that hyperphosphatemia is caused by renal dysfunction in the absence of hepatic regeneration, as the latter appears to be associated with lowering of serum phosphate.

AIMS:Paracetamol is frequently involved in intended self-poisoning, and concomitant overdosing of other drugs is commonly reported. The purpose of the study was to investigate further concomitant drug overdose in patients with paracetamol poisoning and to evaluate its effects on the outcome of the paracetamol intoxication.METHODS:Six hundred and seventy-one consecutive patients admitted with paracetamol poisoning were studied and concomitant drug intake was recorded. The relative risk of hepatic encephalopathy, death or liver transplantation, hepatic dysfunction, liver cell damage, and renal dysfunction associated with concomitant overdosing of other drugs was evaluated by multivariate analysis.RESULTS:Concomitant drug overdose was found in 207 patients (31%, 95% confidence interval [CI] 27, 34%). Concomitant overdosing of benzodiazepines (99 cases), opioid analgesics (38 cases), acetylsalicylic acid (33 cases), and NSAID (32 cases) predominated. Concomitant benzodiazepine overdose was an independent risk factor in the development of hepatic encephalopathy (odds ratio [OR] 1.91; CI 1.00, 3.65) and renal dysfunction (OR 1.81; CI 1.00, 3.22). Concomitant overdosing of opioid analgesics was a protective factor in the development of hepatic encephalopathy (OR 0.26; CI 0.07, 0.96). Concomitant acetylsalicylic acid overdose was a risk factor in the development of hepatic encephalopathy (OR 4.87; CI 1.52, 15.7) and death or liver transplantation (OR 6.04; CI 1.69, 21.6). A tendency towards a more favourable outcome was observed in patients with concomitant NSAID overdose.CONCLUSIONS:Concomitant overdosing of benzodiazepines or analgesics is frequent in patients admitted with paracetamol poisoning. Concomitant benzodiazepine or acetylsalicylic acid overdose was associated with more severe toxicity, whereas concomitant overdosing of opioid analgesics was associated with less toxicity.

INTRODUCTIONAn increased incidence of suicides and suicidal behaviour among immigrants has been described in other countries. In Denmark, misuse of paracetamol is suspected in some foreign-born minority groups, although no data have been produced to substantiate this suspicion.METHODOLOGYA retrospective study of the incidence of paracetamol poisoning in patients admitted to a specialised department of hepatology from 1994 to 1999 was carried out.RESULTSOf a total of 580 patients, 56 (9.7%; 95%-confidence interval 7.2-12.1%) were immigrants, among whom a significant overrepresentation was found of immigrants from Turkey, Iran, Pakistan, and Lebanon (Observed/Expected-ratios of 1.95, 4.14, 2.67, and 2.45 respectively; p < 0.05). The immigrants differed from the Danish-born patients being younger (21 vs 35 years of age; p < 0.05), having a lower level of alcohol consumption (3% vs 30% with regular alcohol abuse; p < 0.05), and in general being less severely intoxicated (3% vs 22% developing hepatic encephalopathy; p < 0.05). Compared to the Danish-born patients, the immigrants more frequently stated socio-economic problems as the reason for their self-poisoning (29% vs 10%; p < 0.05).CONCLUSIONSThe study demonstrates an overrepresentation of immigrants among patients admitted with paracetamol poisoning in Denmark.