Acetaminophen-induced Fulminant Hepatic Failure Research Articles

S3698 Acetaminophen-Induced Fulminant Hepatic Failure: A Rare Case With Unusually Low Dose Exposure

S3698 Acetaminophen-Induced Fulminant Hepatic Failure: A Rare Case With Unusually Low Dose Exposure

Recovery of acetaminophen-induced fulminant hepatic failure and encephalopathy after ten days of intravenous N-acetylcysteine administration in twin boys

We describe a case of liver failure in twin infants after frequent therapeutic doses of acetaminophen over 4 days at home to manage pyrexia due to a viral illness. The children were treated successfully with intravenous N-acetylcysteine (NAC) following the hospital’s protocol. This case highlights the importance of parental awareness of acetaminophen hepatotoxicity and physicians’ advice to parents in preventing hepatotoxicity induced by acetaminophen overdose during viral illness. Although Twin 1 met the King’s College Hospital criteria for liver transplantation, he was successfully treated with intravenous N-acetylcysteine for 10 days.

The pharmacokinetics and extracorporeal removal of N-acetylcysteine during renal replacement therapies

Objective: Acetaminophen-induced fulminant hepatic failure is associated with acute kidney injury, metabolic acidosis, and fluid and electrolyte imbalances, requiring treatment with renal replacement therapies. Although antidote, acetylcysteine, is potentially extracted by renal replacement therapies, pharmacokinetic data are lacking to guide potential dosing alterations. We aimed to determine the extracorporeal removal of acetylcysteine by various renal replacement therapies. Methods: Simultaneous urine, plasma and effluent specimens were serially collected to measure acetylcysteine concentrations in up to three stages: before, during and upon termination of renal replacement therapy. Alterations in pharmacokinetics were determined by applying standard pharmacokinetic equations. Results: Over 2 years, 10 critically ill patients in fulminant hepatic failure requiring renal replacement therapy coincident with acetylcysteine were consecutively enrolled. All 10 patients required continuous venovenous hemofiltration (n = 10) and 2 of the 10 also required hemodialysis (n = 2). There was a significant alteration in the pharmacokinetics of acetylcysteine during hemodialysis; the area under the curve (AUC) decreased 41%, the mean extraction ratio was 51%, the mean hemodialytic clearance was 114.01 ml/kg/h, and a mean 166.75 mg/h was recovered in the effluent or 41% of the hourly dose. Alteration in the pharmacokinetics of acetylcysteine during continuous venovenous hemofiltration did not appear to be significant: the AUC decreased 13%, the mean clearance was 31.77 ml/kg/h and a mean 62.12 mg/h was recovered in the effluent or 14% of the hourly dose. Conclusions: There was no significant extraction of acetylcysteine from continuous venovenous hemofiltration. In contrast, there was significant extracorporeal removal of acetylcysteine during hemodialysis. A reasonable dose adjustment may be to double the IV infusion rate or possibly supplement with oral acetylcysteine during hemodialysis.

Intravenous acetylcysteine for the treatment of acetaminophen overdose

Importance of the field: Acetaminophen is a leading cause of overdose-related hepatotoxicity. Although acetylcysteine prevents or minimizes acetaminophen-induced hepatotoxicity and reduces mortality, some patients presenting with complicated overdose scenarios (massive ingestions or combination or modified-release formulations) may develop toxicity despite administration of recommended dosage regimen.Areas covered in this review: The article evaluates evidence regarding intravenous acetylcysteine's effectiveness in patients with acute overdoses who receive treatment within 10 h or > 10 h, patients with chronic supratherapeutic ingestions, and those with acetaminophen-induced fulminant hepatic failure. Intravenous and oral acetylcysteine are compared.What the reader will gain: A one-size-fits-all approach towards acetylcysteine therapy provides suboptimal care in some patients. High-risk patients are identified. Specific discontinuation criteria are presented.Take home message: The standard intravenous regimen will effectively treat most early-presenting uncomplicated overdoses. Acetylcysteine dosing should be individualized in patients with complicated presentations and in particular situations in which plasma acetaminophen concentrations may be persistently elevated at the end of the infusion or in late presenters. More studies are needed to evaluate the optimal intravenous dosage regimen and the role of oral acetylcysteine in these high-risk patients. Treatment decisions may be aided by consultation with a poison center and/or clinical toxicologist.

NAC: still the way to go

We would like to thank Yang and colleagues for their attempt to determine the possibility of delayed hepatic recovery with N-acetylcysteine (NAC) administration in acetaminophen-induced hepatotoxicity [1]. We are concerned, however, about the possible consequences that may arise from their conclusions. Owing to the wide availability of acetaminophen, intentional and unintentional overdoses are one of the leading causes of liver failure in the world [2]. NAC is currently a highly effective and safe antidote to treat acute acetaminophen overdose, and is most efficacious when administered within 8 hours of ingestion [3]. Furthermore, one landmark study showed that even in patients who presented with delayed acetaminophen-induced fulminant hepatic failure, intravenous NAC administration improved survival versus control individuals (48% vs. 20%) [4]. Another study found that the infusion of acetylcysteine in patients with acetaminophen-induced liver failure resulted in an increase in mean oxygen delivery and in an increased mean arterial pressure [5]. It is difficult to believe that the mouse model of Yang and colleagues has any correlation to humans, since the already established human data are so overwhelmingly positive. The amount of acetaminophen administered in their study caused hepatotoxicity but did not induce death, and therefore is not applicable to real-life situations where people may ingest potentially fatal doses of acetaminophen. It is not clear to us why the authors came to explore this study topic. The conclusions drawn from their article are potentially dangerous and should be viewed with caution and scepticism.

Reuse of liver graft from a brain dead recipient

Brain death in fulminant hepatic failure (FHF) is a rare occurrence after successful orthotopic liver transplantation (OLT). Reuse of the liver graft may be considered. We report a successful OLT using such an organ in a 62-yr-old man with hematochromatosis-related cirrhosis and hepatocellular carcinoma. Liver donor was 56-yr-old man with normal liver function tests. First recipient was a 26-yr-old woman with an acetaminophen-induced FHF. Before OLT, she developed progressive coma without obvious cerebral edema on the cerebral CT-scan. The transplantation proceeded as planned and was uneventful. However, patient exhibited bilateral non-reactive mydriasis during postoperative hours and was declared brain dead. Transplanted liver was functioning adequately. Its reuse was discussed with her family and the second recipient. After informed consent, the transplanted liver and heart were harvested. First and second liver cold ischemia times were 10 h and 75 min, respectively. Second recipient recovered uneventful and discharged 23 d after OLT. Liver function is still normal 30 months after OLT without rejection or hepatocellular carcinoma recurrence. Even after OLT, brain death remains possible in FHF. In absence of contraindications, reuse of transplanted liver allows for a rational use of already rare liver grafts.

Prognostic impact of lactate in acute liver failure

Prognostic impact of lactate in acute liver failure

Prognostic implications of hyperlactatemia, multiple organ failure, and systemic inflammatory response syndrome in patients with acetaminophen-induced acute liver failure*

Hyperlactatemia has been suggested as a prognostic marker in acetaminophen-induced fulminant hepatic failure, and a modification of the King's College Hospital criteria to incorporate arterial lactate measurements has recently been proposed. The aims of the present study were to further evaluate arterial lactate as a prognostic marker in acetaminophen-induced fulminant hepatic failure and to analyze its relationship to known causes of hyperlactatemia such as multiple organ failure and inflammation. Data were collected early after admission and again at the time of onset of grade 3-4 hepatic encephalopathy from acetaminophen-induced fulminant hepatic failure. Multiple organ failure and inflammatory response were assessed by the sequential organ failure assessment (SOFA) score and manifestation of the severe inflammatory response syndrome (SIRS), respectively. A specialized liver intensive care unit at a tertiary liver center. One hundred and one consecutive patients with acetaminophen-induced fulminant hepatic failure and grade 3-4 hepatic encephalopathy. None. Arterial lactate was higher in nonsurvivors than in survivors both early after admission (9.8 +/- 6.5 mmol/L vs. 5.2 +/- 4.2 mmol/L, p = .00004) and at the time of onset of hepatic encephalopathy (6.9 +/- 5.6 mmol/L vs. 3.2 +/- 2.0 mmol/L, p < .00001). At both time points, arterial lactate significantly correlated with SOFA score and the number of SIRS components fulfilled. Applying the lactate modification of the King's College Hospital criteria increased their sensitivity but reduced their specificity to <50%. The study confirmed arterial lactate as a prognostic marker in acetaminophen-induced fulminant hepatic failure. Arterial lactate correlated with SOFA score and with the number of SIRS components fulfilled. The lactate modification of the King's College Hospital criteria showed no obvious advantages over the existing selection criteria.

Potentiation of Acetaminophen Hepatotoxicity by Phenytoin, Leading to Liver Transplantation

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.

Fulminant hepatic failure

Abstract Analysis of the first 150 cases collected from 73 centers reporting to the Fulminant Hepatic Failure Surveillance Study showed that 80 patients had presumable viral hepatitis, of whom 62 died. Of 41 patients who had recent surgery, 36 died. In 35 patients massive liver necrosis developed less than three weeks after halothane anesthesia, and 27 (77 per cent) of these had multiple exposures to halothane. The risk from halothane is small, but this complication was present in nearly one quarter of the cases reported in our study. When the use of halothane is desired, multiple exposure should be avoided, if possible. Moreover, postoperative fever after exposure to halothane, otherwise "unexplained," is an important warning sign, and should be thoroughly investigated and taken into consideration when further exposure to this anesthetic is contemplated. The physician prescribing halothane must balance need against risk.

Galactose elimination capacity as a prognostic marker in patients with severe acetaminophen-induced hepatotoxicity: 10 years’ experience

Background & Aims: Patients with acetaminophen-induced fulminant hepatic failure may have the capacity for recovery if sufficient liver cell mass remains to allow regeneration. We investigated the prognostic potential of the galactose elimination capacity (GEC) as a noninvasive measurement of functioning liver cell mass in severe acetaminophen-induced hepatotoxicity. Methods: All patients admitted with acetaminophen poisoning during a 10-year period were studied retrospectively. A total of 220 patients who had at least one GEC performed were included in the study. Results: The GEC was lower in patients with than without hepatic encephalopathy (14.5 ± 5.6 μmol/min/kg vs. 23.2 ± 6.7 μmol/min/kg; P < 0.0001). Among patients with hepatic encephalopathy, the GEC was significantly higher in spontaneous survivors than in nonsurvivors (16.8 ± 5.6 μmol/min/kg vs. 12.2 ± 4.7 μmol/min/kg; P < 0.0001). In a logistic regression analysis, GEC was associated independently with mortality (odds ratio: 1.28 per 1 μmol/min/kg decrease in GEC; 95% confidence interval: 1.14–1.45). A threshold GEC of 16.5 μmol/min/kg to identify nonsurvivors had a sensitivity of 90%, a specificity of 72%, a positive predictive value of 49%, and a negative predictive value of 96%. None of 14 patients with hepatic encephalopathy and a GEC less than 10 μmol/min/kg survived. Conclusions: The GEC was strongly associated with development of hepatic encephalopathy and death from acetaminophen-induced fulminant hepatic failure. The GEC was too unspecific to be used alone for identification of transplantation candidates, but it may be useful as a supplement to other selection criteria.

812 Applicability of MELD scoring system to predict prognosis in patients with acute liver failure

Plasma levels of growth factors may be important in determining the extent of liver regeneration in patients with fulminant hepatic failure and in this study human hepatocyte growth factor and biliprotein (bilirubin covalently bound to albumin) were determined in patients with fulminant hepatic failure, mainly as a result of acetaminophen overdose. Admission values for plasma human hepatocyte growth factor were significantly raised, although with a wide range in acetaminophen-induced fulminant hepatic failure (median 7.4 ng/ml, range 0.45–48.4 ng/ml, n=34) and in fulminant hepatic failure from other causes (3.8 ng/ml, 1.72–25.1 ng/ml, n=9) as compared to normal subjects (0.24 ng/ml, 0–0.5 ng/ml, n=30). Higher plasma human hepatocyte growth factor was observed in patients who died (10.1 ng/ml, 3.8–48.4 ng/ml, n=19) than in those who survived (4.3 ng/ml, 0.45–25.1 ng/ml, n=22, p<0.02), which may reflect lack of hepatic clearance in the former group. The median plasma biliprotein on admission (13.2 mg/l, range 6.3–100.7 mg/l, n=43) was significantly increased compared to normal subjects (1.3 mg/l, 0–4.1 mg/l, n=7, p<0.001) with no difference between patients who survived or died, although when plasma biliprotein results were expressed as a percentage of the total bilirubin, the values were slightly higher in survivors (median 14.4%, range 10.8–40.5%, n=23) compared to those who died (12.1%, 7.7–20.9%, n=20, p=0.004). In cases where serial analyses during the course of illness were available, plasma human hepatocyte growth factor tended to decrease during the course of the illness in survivors and increase in those who died, whereas the biliprotein expressed as a percentage of total bilirubin increased in survivors with little change in non-survivors.

Energy expenditure in acetaminophen-induced fulminant hepatic failure.

To determine energy expenditure in critically ill patients suffering from acetaminophen-induced fulminant hepatic failure and compare it with values obtained in matched, healthy control subjects and in patients studied during the anhepatic period of elective liver transplantation. Prospective, controlled, observational study. A ten-bed intensive therapy unit and a liver transplant unit at a University teaching hospital. Sixteen patients suffering from acetaminophen-induced fulminant hepatic failure who were sedated, paralyzed, and mechanically ventilated; 16 age-, gender-, and weight-matched, awake, healthy control subjects; and 16 patients with chronic liver disease, undergoing elective liver transplantation, who were studied during the anhepatic period of surgery. None. The mean energy expenditure was calculated in each case for a 30-min period, using indirect calorimetry. In the patients undergoing liver transplantation, measurements were performed after clamping the hepatic veins and recipient hepatectomy. Energy expenditure was markedly increased in the fulminant hepatic failure group (mean energy expenditure, 4.05 [SD 0.52] kJ x kg(-1) x hr(-1)), in comparison with healthy control subjects (mean, 3.44 [0.27] kJ x kg(-1) x hr(-1); mean difference, 18%; p < .001) and in comparison with patients during the anhepatic period of liver transplantation (mean, 3.15 [0.61] kJ x kg(-1) x hr(-1); mean difference, 29%; p < .001). These differences were even more pronounced when a correction factor for differences in core temperature was included in the calculation. Harris-Benedict predictions of energy expenditure were unreliable in the patients with acute liver failure. No correlations were found among energy expenditure and hemodynamic variables, the requirement for vasoconstrictors, or the presence of renal failure. Despite the loss of functioning liver cell mass, the metabolic rate is substantially increased in patients with acetaminophen-induced fulminant hepatic failure. This finding is consistent with the marked systemic inflammatory response, which accompanies acute hepatic failure. The Harris-Benedict equation is unreliable when an estimation of energy expenditure is required in patients with this condition.

Clinical Use of a Bioartificial Liver in the Treatment of Acetaminophen-Induced Fulminant Hepatic Failure

Patients with acetaminophen-induced fulminant hepatic failure (FHF) who meet the King's College Hospital criteria have a high mortality risk (>90%) if they do not undergo liver transplantation. We have developed a treatment strategy for these patients based on the use of an extracorporeal bioartificial liver (BAL) support system. In this study, we report the results of the clinical application of BAL support in patients with acetaminophen-induced FHF. All patients were admitted to a dedicated surgical intensive care unit. They were evaluated for urgent liver transplantation and received the standard medical measures, including N-acetylcysteine administration and intracranial pressure monitoring. Moreover, they underwent daily 6-hour BAL treatments. Eight patients were treated. Three patients were bridged to liver transplantation, and five patients recovered without a transplant. All patients experienced neurological and metabolic improvement after treatments with the BAL support system. The BAL support system seems to improve the outcome of high-risk patients with acetaminophen-induced FHF, even in the absence of liver transplantation. Avoiding liver transplantation is particularly important in an era of organ shortage and high cost of transplants.

Treatment of acetaminophen-induced fulminant hepatic failure with a bioartificial liver

Treatment of acetaminophen-induced fulminant hepatic failure with a bioartificial liver

Expression of liver-specific functions in rat hepatocytes following sublethal and lethal acetaminophen poisoning

Aim: In order to study the short-term effect of moderate and severe reduction of liver function by acetaminophen poisoning of different severity on gene expression for liver-specific functions, rats were given 3.75 and 7.5 g per kg body weight acetaminophen intragastrically. The lower dose is associated with low mortality; after the higher dose, most rats die at between 12 and 24 h. Methods: In the morning 1 1 2 ,3,6,9, and 12 h after the injection, the rats were killed and RNA was extracted from liver tissue. By slot-blot hybridization mRNA steady-state levels were determined for enzymes involved in metabolic liver functions, i.e. unreagenesis, gluconeogensis, and drug metabolism, for acute phase proteins, “house-keeping” proteins, and for proteins related to liver regeneration. Results were expressed as per cent of the level in similarly fasted, untreated rats of the same stock Results: After the smaller dose of acetaminophen, most of the examined mRNA levels were increasing during the experimental period, being two- to four-fold elevated in relation to control after 6 to 12 h. Rats receiving the lethal dose either showed no or a later and smaller increase, and in several cases a fall towards the end of the experiment. The greatest differences were seen for mRNA of arginase, β-fibrinogne, α1-acid glycoprotein, α-tubulin, histone 3, TGFβ, and cyclin d, i.e. proteins associated with acute phase response and liver cell replication and maintenance. Conclusions: It is concluded that reversible intoxication with acetaminophen induces an adaptive modulation of mRNA expression of liver functions and regeneration which is lacking after severe intoxication. This adaptation, with emphasis on acute phase response and regeneration, may be crucial for recovery after acetaminophen intoxication. If this also applies to the intoxication in man, estimates of the corresponding variables may be clues to the prognosis of acetaminophen-induced fulminant hepatic failure.

Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure

Data reported by Bernuau et al. have strongly supported the measurement of coagulation factor V as the best prognostic indicator in fulminant hepatic failure (FHF) and as the test on which selection for urgent liver transplantation should be made. In this study, we have measured plasma factor V in 110 patients with FHF, in grades I-IV coma, in 88 of whom the etiology was acetaminophen overdose. On admission, patients who did not survive had significantly lower factor V levels (median, 5%; range, 1-27; n = 49), compared with those who did (median, 10%; range, 2-70; P < .001). In the 81 patients with acetaminophen-induced FHF who did not receive a transplant, there was no cutoff level of factor V that clearly separated the patients. On statistical analysis, a positive predictive value (the mortality in patients predicted to have a poor prognosis) of 0.49 was calculated for factor V <20% and 0.57 for factor V < 10%. If the prognostic criteria included deep coma (grades III and IV) as well as factor V <20%, a positive predictive value of 0.73 was calculated. This compared with a value of 0.92 for the well-established King's prognostic criteria based on pH, and a combination of international normalized ratio (INR), renal failure, and coma. In the 17 mixed, nonacetaminophen group of patients who did not receive a liver graft, the positive predictive value was 0.85 for a factor V level <20% and 1.00 for factor V <10%, compared with 0.93 for the King's criteria for that etiologic group. This study demonstrates that the predictive accuracy of plasma factor V level is much less effective than the well-validated King's criteria in the selection of patients with acetaminophen-induced FHF needing liver grafting, although it may be useful in patients with FHF due to other causes.

Coagulation factor V levels as a prognostic indicator in fulminant hepatic failure

Data reported by Bernuau et al. have strongly supported the measurement of coagulation factor V as the best prognostic indicator in fulminant hepatic failure (FHF) and as the test on which selection for urgent liver transplantation should be made. In this study, we have measured plasma factor V in 110 patients with FHF, in grades I-IV coma, in 88 of whom the etiology was acetaminophen overdose. On admission, patients who did not survive had significantly lower factor V levels (median, 5%; range, 1-27; n = 49), compared with those who did (median, 10%; range, 2-70; P < .001). In the 81 patients with acetaminophen-induced FHF who did not receive a transplant, there was no cutoff level of factor V that clearly separated the patients. On statistical analysis, a positive predictive value (the mortality in patients predicted to have a poor prognosis) of 0.49 was calculated for factor V <20% and 0.57 for factor V < 10%. If the prognostic criteria included deep coma (grades III and IV) as well as factor V <20%, a positive predictive value of 0.73 was calculated. This compared with a value of 0.92 for the well-established King's prognostic criteria based on pH, and a combination of international normalized ratio (INR), renal failure, and coma. In the 17 mixed, nonacetaminophen group of patients who did not receive a liver graft, the positive predictive value was 0.85 for a factor V level <20% and 1.00 for factor V <10%, compared with 0.93 for the King's criteria for that etiologic group. This study demonstrates that the predictive accuracy of plasma factor V level is much less effective than the well-validated King's criteria in the selection of patients with acetaminophen-induced FHF needing liver grafting, although it may be useful in patients with FHF due to other causes. (Hepatology 1996 Jun;23(6):1507-11)

Admission levels of serum Gc-globulin: predictive value in fulminant hepatic failure.

Gc-globulin scavenges actin released from necrotic hepatocytes to the extracellular space. In 77 patients with fulminant hepatic failure (FHF) (excluding patients treated with liver transplantation), admission levels of serum Gc-globulin and degree of complexing with monomeric actin (complex ratio) were determined to evaluate their predictive values in relation to survival/nonsurvival. Gc-globulin levels were significantly reduced in 47 nonsurvivors, compared with 30 survivors (96 +/- 71 mg/L vs. 169 +/- 101 mg/L, P < .001), whereas the complex ratio in nonsurvivors did not differ significantly from that of survivors. Gc-globulin levels were significantly lower in 59 patients with non-acetaminophen-induced FHF, compared with 18 patients with acetaminophen-induced FHF (P < .01). Using a cutoff level of serum Gc-globulin of 100 mg/L, a lesser value correctly predicted nonsurvival in 79 percent of patients with non-acetaminophen-induced FHF, whereas a higher value predicted survival in 60 percent. In patients with acetaminophen-induced FHF, nonsurvival was correctly predicted in 100 percent of patients and survival in 53 percent. In comparison, the King's College Hospital (KCH) criteria correctly predicted nonsurvival and survival in 69 percent and 57 percent, respectively, of the same non-acetaminophen-induced FHF patients and in 60 percent and 38 percent, respectively, of the acetaminophen-induced FHF patients. Thus, in our study population, the predictive properties of Gc-globulin were in the same range as the KCH criteria. An advantage of Gc-globulin is that it gives an estimate of the outcome already on admission. Acute liver transplantation should be considered in FHF patients with Gc-globulin less than 100 mg/L.

Admission levels of serum Gc-globulin: Predictive value in fulminant hepatic failure

Gc-globulin scavenges actin released from necrotic hepatocytes to the extracellular space. In 77 patients with fulminant hepatic failure (FHF) (excluding patients treated with liver transplantation), admission levels of serum Gc-globulin and degree of complexing with monomeric actin (complex ratio) were determined to evaluate their predictive values in relation to survival/nonsurvival. Gc-globulin levels were significantly reduced in 47 nonsurvivors, compared with 30 survivors (96 +/- 71 mg/L vs. 169 +/- 101 mg/L, P < .001), whereas the complex ratio in nonsurvivors did not differ significantly from that of survivors. Gc-globulin levels were significantly lower in 59 patients with non-acetaminophen-induced FHF, compared with 18 patients with acetaminophen-induced FHF (P < .01). Using a cutoff level of serum Gc- globulin of 100 mg/L, a lesser value correctly predicted nonsurvival in 79 percent of patients with non-acetaminophen-induced FHF, whereas a higher value predicted survival in 60 percent. In patients with acetaminophen-induced FHF, nonsurvival was correctly predicted in 100 percent of patients and survival in 53 percent. In comparison, the King's College Hospital (KCH) criteria correctly predicted nonsurvival and survival in 69 percent and 57 percent, respectively, of the same non-acetaminophen-induced FHF patients and in 60 percent and 38 percent, respectively, of the acetaminophen-induced FHF patients. Thus, in our study population, the predictive properties of Gc-globulin were in the same range as the KCH criteria. An advantage of Gc-globulin is that it gives an estimate of the outcome already on admission. Acute liver transplantation should be considered in FHF patients with Gc-globulin less than 100 mg/L. (Hepatology 1996 Apr;23(4):713-8)