Non-acetaminophen-induced Acute Liver Failure Research Articles

Use of Oral N-Acetylcysteine (NAC) in Non-Acetaminophen-Induced Acute Hepatic Failure.

Acute liver failure (ALF) is a syndrome rather than a specific disease with several possible causes, and viral hepatitis is a major cause. The objective of the study was to assess the benefit of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). A total of six patients with a diagnosis of acute liver failure (ALF) were included in the study. All six patients received oral NAC for 72 hrs. The parameters evaluated were demographic, clinical, biochemical, outcome, and length of ICU and hospital stay. The primary outcome was a reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate the safety of NAC and assess factors predicting mortality. All patients improved and returned to normal or near-normal liver function with the use of NAC. No side effects were noted, and the use of NAC was associated with a shorter hospital stay. In patients with non-acetaminophen-related acute liver failure, N-acetyl-L-cysteine (NAC)significantly improves overall survival and also decreases the length of hospital stay.

Performance of the Liver Maximum Function Capacity Test, Fibrinogen, and Transient Elastography in Patients with Acute Liver Injury

Background: Acute liver failure (ALF) occurs as a rare, sudden, extensive loss of liver function in a previously healthy liver. In advanced cases, ALF may require liver transplantation (LT). Available prognostic parameters have limited accuracy to decide, which patient to consider for LT. The liver maximum function capacity test (LiMAx) can accurately determine liver function and was assessed as predictor of survival, along with coagulation parameters and liver stiffness in nonacetaminophen-induced ALF. Methods: Various liver function tests, including LiMAx measurements, coagulation factors, and transient elastography (TE), were analyzed retrospectively for associations with clinical outcome in 34 patients with ALF or acute hepatitis (AH). Data were compared between patients with spontaneous recovery (SR) and non-SR (3-month mortality/LT; NSR). Results: The analysis included 34 patients (22 ALF, 12 AH; 19 males, 15 females; age 36.7 ± 14.6 years) with drug-induced liver injury (DILI) (n = 12), autoimmune hepatitis (AIH; n = 13), AIH-DILI overlap (n = 1), viral (n = 9), or cryptogenic liver failure (n = 1). Thirty-one patients recovered spontaneously, 2 patients died, and 1 patient underwent LT. The LiMAx was 197.6 (±68.4) for SR versus 92.33 (±65.0) for NSR (p = 0.0157). Fibrinogen was significantly lower in patients with NSR than in SR patients (209.0 vs. 106.3; p = 0.02). Mean liver stiffness measured by TE was 39.3 for NSR and 17.3 for SR (p = 0.26). KCC was fulfilled in only 4 patients (3 SR, 1 NSR). LiMAx results correlated positively with serum fibrinogen and antithrombin III concentrations and correlated negatively with liver stiffness. No other analyzed factor could differentiate between SR and NSR. Conclusion: Decision-making in ALF remains challenging. LiMAx and fibrinogen might predict the prognosis in patients with nonacetaminophen-induced ALF and in combination could be feasible tools to decide if LT is necessary.

N-acetylcysteine for non-acetaminophen induced acute liver failure: A review.

The use of N-acetylcysteine (NAC) for non-acetaminophen-induced acute liver failure (NAI-ALF) has been increasing despite controversy in its efficacy. National guidelines are in disagreement for NAC use as standard of care; however, many healthcare centers continue to adopt the use of NAC outside of acetaminophen poisoning. While NAC may have multiple mechanisms of action in treatment of ALF, this has not translated to clinical benefit. Murine models have reported antioxidant and anti-inflammatory properties, as well as improvement in liver-specific microcirculation. Multiple case studies and series have reported positive outcomes of NAC treatment for ALF of various etiologies. While prospective studies suggested the benefit of NAC treatment, these studies have methodological and statistical shortcomings that affect the validity of the results. In this review, we aimed to summarize the existing literature on the efficacy of NAC for NAI-ALF including mechanism of action, case studies and series demonstrating outcomes, and prospective studies that have led to its current widespread use, along with the reported rate of adverse events.

Efficacy and safety of N-acetylcysteine for the treatment of non-acetaminophen-induced acute liver failure: an updated systematic review and meta-analysis.

Aim of the studyN-acetylcysteine (NAC) is the treatment of choice for acetaminophen-induced liver injury. However, recent years have witnessed growing interest in its role in the treatment of acute liver failure (ALF) due to other aetiologies. This study aims to determine both its safety and efficacy by pooling data from multiple studies.Material and methodsA search was conducted for all controlled randomized/non-randomized studies that measured the efficacy and safety of NAC in adult patients with non-acetaminophen-induced acute liver failure (NAI-ALF). Transplant-free survival (TFS) was considered the primary endpoint, while secondary endpoints such as length of hospital stay, and incidence of adverse events during treatment, were included in our analysis. Data were pooled via a random-effects model, I2 was used as a measure of heterogeneity, and publication bias was assessed via a funnel plot.ResultsA total of 3 studies [2 randomized controlled trials (RCTs) and 1 non-randomized cohort] were pooled in this meta-analysis. TFS was significantly higher in patients given NAC, when compared to the placebo/control (PBO) group (RR = 1.54, CI = 1.19-1.98, p = 0.01, I2 = 0.0%). No secondary endpoint was observed to have improved significantly in patients prescribed NAC: length of hospital stay (SMD = –0.405, CI = –1.44-0.63, p = 0.445, I2 = 91.1%), renal failure (RR = 1.01, CI = 0.65-1.57, p = 0.967, I2 = 21.3%), infections (RR = 1.18, CI = 0.91-1.52, p = 0.208, I2 = 2.3%), pulmonary failure (RR = 1.19, CI = 0.57-2.49, p = 0.649, I2 = 84.6%). Minimal side effects were reported in around 10-14% of the patients prescribed NAC.ConclusionsNAC was shown to significantly improve TFS in adult patients with NAI-ALF, while no significant benefit was observed concerning the secondary endpoints of length of hospital stay and incidence of adverse effects.

2298 Novel Use of N-Acetylcysteine in the Management of Immunotherapy-Induced Acute Liver Injury

INTRODUCTION: There is limited research regarding the use of N-Acetylcysteine (NAC) to manage non-acetaminophen induced acute liver failure (NAI-ALF). NAC has an anti-inflammatory, antioxidant effect, and improves oxygenation by vasodilating microcirculation. A mortality benefit and association with lower hospitalization length has been seen when using NAC in NAI-ALF. Use of immunotherapy to treat cancer has recently increased, and acute liver injury has been reported with many agents. This case examines using NAC to manage immunotherapy induced acute liver injury (ITI-ALI). CASE DESCRIPTION/METHODS: Patient is a 67-year-old Caucasian female with a medical history of hyperlipidemia and well-differentiated angiosarcoma of the right breast, diagnosed in 2011. She had mastectomy and adjuvant chemo-radiotherapy resulting in remission. Surveillance abdominal CT, in 2017 showed new enhancing hepatic lesions. Abdominal MRI confirmed these concerning lesions. A cervical mass was noted, which was biopsied, and diagnostic of metastatic angiosarcoma. She was started on Pazopanib. Two weeks into therapy, she experienced darkened urine, myalgia, and abdominal pain. Labs just prior to admission showed transamninits, ALT of 522 units/L and AST of 456 units/L. Admission labs showed worsening transaminitis, ALT 1377 units/L and AST 1212 units/L. Exam showed jaundice and diffuse abdominal pain. Acetaminophen levels were undetectable. Abdominal ultrasound showed patent hepatic vasculature, normal liver size, appearance, echogenicity, and no intrahepatic ductal dilation or masses. Additionally, serologies for herpes simplex virus, Ebstein Barr virus, cytomegalovirus, viral hepatitis, anti-nuclear antibody, and anti-smooth muscle antibody were negative. Ultimately, her acute liver injury was suspected to be ITI-ALI. NAC was started and Pazopanib was held. Hepatic function was serially monitored, and her acute liver injury rapidly improved. She was discharged and repeat labs on follow-up continued showing improvement in transaminases (Figure 1). DISCUSSION: The use of NAC in NAI-ALF was described in a prospective study by Mumtaz, Azam, et al, and in a randomized, case-control trial by Nabi, et al. Neither studies had patients who had developed ITI-ALI. Both studies were able to conclude that using NAC in NAI-ALF reduced mortality and hospitalization length. Further prospective studies should be conducted to identify if there is a statistically significant effect on mortality and length of hospitalization by using of NAC in ITI-ALI.

Effect of N-Acetylcysteine on Mortality and Liver Transplantation Rate in Non-Acetaminophen-Induced Acute Liver Failure: A Multicenter Study.

Previous studies and systematic reviews have not provided conclusive evidence on the effect of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). We aimed to study the value of intravenous NAC in reducing liver transplantation and mortality in NAI-ALF. In a prospective, multicenter, observational study, acute liver failure patients without clinical or historical evidence of acetaminophen overdose were enrolled. NAC infusion (in empirical dose) was given as 150mg/kg in 100ml dextrose 5% over half an hour, then 70mg/kg in 500ml dextrose 5% over 4h, then 70mg/kg in 500ml dextrose 5% over 16h. Thereafter continuous infusion was administered over 24h of 150mg/kg in 500ml dextrose 5% until up to two consecutive normal international normalized ratios (INRs) were obtained. Our endpoints were recovery, transplantation, or death. The primary outcome of the study was to assess reduction in mortality or liver transplantation. The secondary outcome was the evaluation of other clinical outcomes (length of ICU and hospital stays, organ system failure, and hepatic encephalopathy). The study included a total of 155 adults; the NAC group (n=85) were given NAC between January 2011 to December 2013 and the control group (n=70) were not given NAC and were included from files dating between 2010 and 2011. Both groups (before NAC) were comparable with regard to etiology, age, sex, smoking, presence of co-morbidities, encephalopathy, liver profile, and INR. The success rate (transplant-free survival) in the NAC group was 96.4%. While in the control group, 17 patients (23.3%) recovered and 53 (76.6%) did not recover, of these 37 (53.3%) had liver transplantation and 16 (23.3%) died (p<0.01). The NAC group had significantly shorter hospital stays (p<0.001), less encephalopathy (p=0.02), and less bleeding (p<0.01) than the control group. The control group reported a higher ICU admission (p=0.01) rate and abnormal creatinine and electrolytes (p=0.002, p<0.01, respectively). Liver profile and INR (after NAC infusion) differed significantly between the two groups with regard to bilirubin (increased in controls, p=0.02), AST and INR (decreased in NAC group, p<0.001 for both), but the ALT decrease showed no statistical significance between the two groups. When administered on admission, intravenous NAC caused a reduction in NAI-ALF mortality and need for transplantation. NAC decreased encephalopathy, hospital stay, ICU admission, and failure of other organs.

Role of N-acetylcysteine treatment in non-acetaminophen-induced acute liver failure: A prospective study.

Background/Aims:Acute liver failure (ALF) is a rare but severe medical emergency. To date, there is no established treatment for non-acetaminophen-induced acute liver failure (NAI-ALF) other than liver transplantation, and little is known about the use of N-acetylcysteine (NAC) in NAI-ALF. A randomized case control study was conducted with the aim to determine the effect of NAC on the mortality of NAI-ALF patients, as well as to evaluate the safety and efficacy of NAC use.Patients and Methods:A total of 80 patients diagnosed with NAI-ALF were included in the study. Forty patients received NAC infusion for 72 h whereas the control group received placebo. The variables evaluated were demographic characteristics, signs and symptoms, biochemical parameters, and clinical course during hospitalization.Results:The two groups (NAC and control) were comparable for various baseline characteristics (such as etiology of ALF, INR, alanine aminotransferase, creatinine, albumin, and grade of encephalopathy), except for age. Although majority of patients had undetermined etiology (32.5% in NAC group and 42.5% in control group), the second main cause was acute hepatitis E and drug or toxin-induced ALF. The mortality decreased to 28% with the use of NAC versus 53% in the control group (P = 0.023). The use of NAC was associated with shorter length of hospital stay in survived patients (P = 0.002). Moreover, the survival of patients was improved by NAC (P = 0.025). Also, drug-induced ALF showed improved outcome compared to other etiologies.Conclusion:The findings of the study recommend the use of NAC along with conventional treatments in patients with NAI-ALF in non-transplant centers while awaiting referrals and conclude the use of NAC as safe.

Efficacy and safety of acetylcysteine in “non-acetaminophen” acute liver failure: A meta-analysis of prospective clinical trials

Acute liver failure (ALF) is a rare but highly mortal condition without liver transplantation (LT). N-acetylcysteine (NAC), a glutathione precursor that detoxifies the reactive metabolite of acetaminophen and replenishes hepatic glutathione stores, is a highly effective drug for the prevention of ALF caused by acetaminophen. However, therapeutic use of NAC in non-acetaminophen-induced ALF (NAI-ALF) including alcohol intoxication, hepatitis virus infection, or drug and toxin-related hepatotoxicity is still inconclusive. The aim of this article is using meta-analysis method to analyze recent prospective clinical trials for the safety and efficacy of NAC in patients with ALF not caused by acetaminophen poisoning. Prospective clinical trials comparing efficacy and safety between NAC and control in the treatment of NAI-ALF were identified by searching Pubmed (2000-2014) and EMBASE (2000-2014) using the search terms acetylcysteine or NAC and NAI-ALF. The primary outcome was overall survival. Secondary outcomes included liver transplantation-free survival, post transplantation survival, length of ICU and hospital stays, and the relationship with coma grade. The safety profiles were also analyzed. Four clinical trials were selected for meta-analysis. A total of 331 patients receiving treatment with NAC (oral or intravenously) and 285 patients in control group were included for meta-analysis. No statistical difference was identified between NAC group and control group for overall survival [236/331 (71%) vs 191/285 (67%); 95% CI 1.16 (0.81-1.67); P=0.42]. However, there were significant differences between NAC group and control group regarding the survival with native liver [112/273 (41%) vs 68/226 (30%); 95% CI 1.61 (1.11-2.34); P=0.01] and post-transplantation survival [78/91 (85.7%) vs 50/70 (71.4%); 95% CI 2.44 (1.11-5.37); P=0.03]. The identified side effects of NAC included nausea, vomiting, and diarrhea or constipation. Rarely, it could cause rashes, fever, headache, drowsiness, low blood pressure, and elevated serum transaminase levels in a patient with cystic fibrosis. At the dose used for acetaminophen toxicity, acetylcysteine does not have hepatotoxic effects. NAC is safe for NAI-ALF. It can prolong patients' survival with native liver without transplantation and survival after transplantation, but it cannot improve the overall survival.

Character and temporal evolution of apoptosis in acetaminophen-induced acute liver failure*.

To evaluate the role of hepatocellular and extrahepatic apoptosis during the evolution of acetaminophen-induced acute liver failure. A prospective observational study in two tertiary liver transplant units. Eighty-eight patients with acetaminophen-induced acute liver failure were recruited. Control groups included patients with nonacetaminophen-induced acute liver failure (n = 13), nonhepatic multiple organ failure (n = 28), chronic liver disease (n = 19), and healthy controls (n = 11). Total and caspase-cleaved cytokeratin-18 (M65 and M30) measured at admission and sequentially on days 3, 7, and 10 following admission. Levels were also determined from hepatic vein, portal vein, and systemic arterial blood in seven patients undergoing transplantation. Protein arrays of liver homogenates from patients with acetaminophen-induced acute liver failure were assessed for apoptosis-associated proteins, and histological assessment of liver tissue was performed. Admission M30 levels were significantly elevated in acetaminophen-induced acute liver failure and non-acetaminophen induced acute liver failure patients compared with multiple organ failure, chronic liver disease, and healthy controls. Admission M30 levels correlated with outcome with area under receiver operating characteristic of 0.755 (0.639-0.885, p < 0.001). Peak levels in patients with acute liver failure were seen at admission then fell significantly but did not normalize over 10 days. A negative gradient of M30 from the portal to hepatic vein was demonstrated in patients with acetaminophen-induced acute liver failure (p = 0.042) at the time of liver transplant. Analysis of protein array data demonstrated lower apoptosis-associated protein and higher catalase concentrations in acetaminophen-induced acute liver failure compared with controls (p < 0.05). Explant histological analysis revealed evidence of cellular proliferation with an absence of histological evidence of apoptosis. Hepatocellular apoptosis occurs in the early phases of human acetaminophen-induced acute liver failure, peaking on day 1 of hospital admission, and correlates strongly with poor outcome. Hepatic regenerative/tissue repair responses prevail during the later stages of acute liver failure where elevated levels of M30 are likely to reflect epithelial cell death in extrahepatic organs.

Intravenous acetylcysteine for indications other than acetaminophen overdose

The use of intravenous acetylcysteine for off-label indications, specifically non-acetaminophen-induced acute liver failure (NAI-ALF), severe alcoholic hepatitis, and contrast-induced nephropathy (CIN), is reviewed. I.V. acetylcysteine is most often used as an antidote for acetaminophen overdose due to its ability to increase levels of glutathione; however, it is also used to treat NAI-ALF and severe alcoholic hepatitis and to prevent CIN. Although the i.v. and oral formulations of acetylcysteine have been evaluated for these indications, most studies have examined the i.v. form. I.V. acetylcysteine is used in the treatment of NAI-ALF to improve oxygenation to the liver. One large randomized trial of 173 adults with NAI-ALF from any etiology and of any grade encephalopathy demonstrated overall improvement in transplant-free survival, particularly for patients with low-grade encephalopathy, though overall survival was not improved. When used to treat severe alcoholic hepatitis, i.v. acetylcysteine serves as an antioxidant and glutathione source. A trial of 174 patients with severe alcoholic hepatitis revealed that patients had 28-day survival benefit when treated with acetylcysteine; improvement in patients with hepatorenal syndrome was also noted. When used for the prevention of CIN, i.v. acetylcysteine provides antioxidants and vasodilation. The benefit for this indication is limited to surrogate markers such as serum creatinine and in patients with multiple risk factors for the development of CIN. Data regarding the use of i.v. acetylcysteine for the treatment of NAI-ALF and severe alcoholic hepatitis and in the prevention of CIN are inconclusive, though some evidence supports its use in certain populations.

King's College Hospital Criteria for Non-Acetaminophen Induced Acute Liver Failure in an International Cohort of Children

To validate King's College Hospital criteria (KCHC) in children with non-acetaminophen induced pediatric acute liver failure (PALF) and to determine whether re-optimizing the KCHC would improve predictive accuracy. We used the PALF study group database. Primary outcomes were survival without liver transplantation vs death at 21 days following enrollment. Classification and regression tree analysis was used to determine if modification of KCHC parameters would improve classification of death vs survival. Among 163 patients who met KCHC, 54 patients (33.1%) died within 21 days. Sensitivity of KCHC in this cohort was significantly lower than in the original study (61% vs 91%, P = .002), and specificity did not differ significantly. The positive predictive value (PPV) and negative predictive value (NPV) of KCHC for this cohort was 33% and 88% respectively. Classification and regression tree analysis yielded the following optimized parameters to predict death: grade 2-4 encephalopathy, international normalized ratio >4.02, and total bilirubin >2.02 mg/dL. These parameters did not improve PPV, but NPV was significantly better (88% vs 92%, P < .0001). KCHC does not reliably predict death in PALF. With a PPV of 33%, twice as many participants who met KCHC recovered spontaneously than died, indicating that using KCHC may cause over utilization of liver transplantation. Re-optimized cutpoints for KCHC parameters improved NPV, but not PPV. Parameters beyond the KCHC should be evaluated to create a predictive model for PALF.

Role of N-acetylcysteine in adults with non-acetaminophen-induced acute liver failure in a center without the facility of liver transplantation

We aimed to study the role of N-acetylcysteine (NAC) in non-acetaminophen-induced acute liver failure (NAI-ALF). A total of 47 adult patients were prospectively enrolled with NAI-ALF (group 1 or NAC group) and oral NAC was given. The primary outcome was reduction in mortality with the use of NAC in NAI-ALF. The secondary outcomes were to evaluate safety of NAC and to assess factors predicting mortality. We compared these results with records of NAI-ALF patients admitted in our hospital from 2000 to 2003 (n=44) who were not given NAC (group 2 or historical controls). The two groups were comparable for the etiology of ALF, prothrombin time (PT), alanine aminotransferase, creatinine, albumin, etc. The mean age in group 1 was 27.7±11.8years and in group 2 37.5±18.8years (P=0.004). Bilirubin was 20.63±11.03 and 14.36±8.90mg/dl in groups 1 and 2, respectively (P=0.004). There were 8 (17%) and 1 (2.3%) pregnant ALF women with acute hepatitis E virus (HEV) infection in groups 1 and 2, respectively (P=0.031). All patients were given supportive care, including mechanical ventilation. A total of 34 (37.36%) patients survived; 22 (47%) in group 1 (NAC group) and 12 (27%) in group 2 (controls) (P=0.05). On multivariable regression analysis, patients not given NAC (odds ratio [OR]=10.3, 95% confidence interval [CI]=1.6-65.7), along with age older than 40years (OR=10.3, 95% CI=2.0-52.5), PT more than 50s (OR=15.4, 95% CI=3.8-62.2), patients requiring mechanical ventilation (OR=20.1, 95% CI=3.1-130.2), and interval between jaundice and hepatic encephalopathy (OR=5.0, 95% CI=1.3-19.1) were independent predictors of mortality. The use of NAC causes reduction in NAI-ALF mortality and its use was safe.

MELD score to predict outcome in adult patients with non‐acetaminophen‐induced acute liver failure

A model for end stage liver disease (MELD) score >30 was proposed as an excellent predictor of mortality in patients with non-acetaminophen-induced acute liver failure (ALF). We analyzed the prognostic value of MELD score in our patients with ALF who were prospectively registered in our database since 1990. Overall, 106 patients met the criteria of ALF. Excluding seven patients with acetaminophen etiology, 99 patients (42+/-15 years, 40M/59F) were studied. Causes were cryptogenic (n=38), viral (n=29), drugs (n=20) and miscellaneous (n=12). Of these, 37% (n=37) survived with medical management alone (group I), 16% (n=16) died (group II) and 46% (n=46) underwent liver transplantation (group III). The strongest predictors of poor outcome were advanced encephalopathy, cryptogenic/drug-induced/hepatitis B etiology and a high MELD score. At the time of diagnosis, King's College Hospital criteria and MELD score >30 had similar high negative predictive value (92% and 91%, respectively) and low positive predictive value (52% and 56%, respectively). The predictive values improved only slightly during follow-up. The best cut-off point for MELD score to discriminate between survivors and nonsurvivors was >35, with a sensitivity and specificity of 86% and 75%, respectively. MELD score, which mostly takes into consideration the degree of liver impairment, has a similar prognostic value as King's College Hospital criteria to predict outcome in adult patients with nonacetaminophen-induced ALF. Overall, all current scores miss accuracy and therefore there is a clear need for factors that can better predict the regeneration of the liver in this setting.

Safety and efficacy of N-acetylcysteine in children with non-acetaminophen-induced acute liver failure

Acute liver failure (ALF) carries a high mortality in children. N-acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, has been used in the treatment of late acetaminophen-induced ALF and non-acetaminophen-induced ALF. In our unit, NAC was introduced as additional treatment for non-acetaminophen-induced ALF in 1995. The aim of this study was to evaluate the safety and efficacy of NAC in children with ALF not caused by acetaminophen poisoning. A retrospective review of medical records of 170 children presenting with nonacetaminophen-induced ALF between 1989 and 2004 was undertaken. ALF was defined as either international normalized ratio of prothrombin time (INR) > 2 and abnormal liver function or INR >1.5 with encephalopathy and abnormal liver function. Children were divided into the following groups: Group 1 (1989-1994), standard care (n = 59; 34 [58%] male; median age 2.03 yr, range 0.003-15.8 yr); and Group 2 (1995-2004), standard care and NAC administration (n = 111; 57 [51%] male; median age 3.51 yr, range 0.005-17.4 yr). NAC was administered as a continuous infusion (100 mg/kg/24 hours) until INR < 1.4, death, or liver transplantation (LT). The median duration of NAC administration in Group 2 was 5 (range, 1-77) days. Complications were noted in 8 (10.8%) children: rash in 3, arrhythmia in 3, and dizziness and peripheral edema in 1. One child had an allergic reaction (bronchospasm) and NAC was stopped. A total of 41 (71%) children in Group 1 vs. 85 (77%) in Group 2 required admission to intensive care, P = not significant (ns). The length of intensive care stay was 6 (range, 1-58) days in Group 1 vs. 5 (range, 1-68) days in Group 2, P = ns and length of hospital stay was 25 (range, 1-264) days vs. 19 (range, 1-201) days, P = 0.05. The 10-yr actuarial survival was 50% in Group 1 compared to 75% in Group 2, P = 0.009. Survival with native liver occurred in 13 (22%) in Group 1 vs. 48 (43%) in Group 2, P = 0.005; 15 (25%) in Group 1 died without transplant vs. 21 (19%) in Group 2, P = ns; and LT was performed in 32 (54%) vs. 42 (38%), P = ns. Death after transplantation occurred in 15 (39%) in Group 1 vs. 8 (16%) in Group 2, P = 0.02. In conclusion, NAC is safe in non-acetaminophen-induced ALF. In this retrospective study NAC was associated with a shorter length of hospital stay, higher incidence of native liver recovery without transplantation, and better survival after transplantation.

Reduced monocyte HLA-DR expression: A novel biomarker of disease severity and outcome in acetaminophen-induced acute liver failure

Acute liver failure (ALF) shares striking similarities with septic shock where a decrease in HLA-DR expression on monocytes is associated with disease severity and predicts outcome. We investigated monocyte HLA-DR expression in ALF in relation to inflammatory mediator levels and clinical outcome. Monocyte HLA-DR expression was determined in 50 patients with acetaminophen-induced ALF (AALF) and 20 non-acetaminophen-induced ALF (NAALF). AALF patients were divided into dead/transplanted (AALF-NS, n = 26) and spontaneous survivors (AALF-S, n = 24). Fifty patients with chronic liver disease (CLD) and 50 healthy volunteers served as controls. Monocyte HLA-DR expression was determined by double-color flow-cytometry with monoclonal antibodies detecting HLA-DR and monocyte specific CD14. Serum levels of interleukin (IL) -4, -6, -10, tumor necrosis factor (TNF)-alpha and interferon (IFN)-gamma were concomitantly measured by ELISA. Compared to healthy volunteers (75%) and CLD (67%) monocyte HLA-DR percentage expression was lower in AALF (15%, P < .001) and NAALF (22 %, P < .001). Compared to AALF-S, AALF-NS had lower monocyte HLA-DR % (11% vs. 36%, P < .001) and higher levels of IL-4, IL-6, IL-10 and TNF-alpha (P < .001). HLA-DR percentage negatively correlated with INR, blood lactate, pH and levels of encephalopathy (r = -0.8 to -0.5, P < .01), IL-10 (r = -0.8, P < .0001), TNF-alpha (r = -0.4, P = .02). HLA-DR percentage level <or=15% has a 96% sensitivity and 100% specificity and 98% accuracy in predicting poor prognosis. In conclusion, the strong relationship of monocyte HLA-DR expression with indices of disease severity, mediators of inflammation and outcome indicates a key role for this molecule as a biomarker of disease severity and prognosis.