Acetaminophen-related Acute Liver Failure Research Articles

Persistent But Not Transient Acute Kidney Injury Was Associated With Lower Transplant-Free Survival in Patients With Acute Liver Failure: A Multicenter Cohort Study.

Acute liver failure (ALF) is an orphan disease often complicated by acute kidney injury (AKI). We assessed the impact of transient versus persistent AKI on survival in patients with ALF. International multicenter retrospective cohort. U.S. ALF Study Group prospective registry. Patients with greater than or equal to 18 years and ALF in the registry from 1998 to 2016 were included. Patients with less than 3 days of follow-up, without kidney function evaluation on day 3, or with cirrhosis were excluded. AKI was defined by Kidney Disease Improving Global Outcomes guidelines on day 1. Kidney recovery was defined on day 3 as transient AKI, by a return to no-AKI within 48 hours or persistent AKI if no such recovery or renal replacement therapy (RRT) was observed. Primary outcome was transplant-free survival (TFS) at 21 days. Among 1,071 patients with ALF, 339 (31.7%) were males, and median (interquartile range) age was 39 years (29-51 yr). Acetaminophen-related ALF was found in 497 patients (46.4%). On day 1, 485 of 1,071 patients (45.3%) had grade 3-4 hepatic encephalopathy (HE), 500 of 1,070 (46.7%) required invasive mechanical ventilation (IMV), 197 of 1,070 (18.4%) were on vasopressors, and 221 of 1,071 (20.6%) received RRT. On day 1, 673 of 1,071 patients (62.8%) had AKI. On day 3, 72 of 1,071 patients (6.7%) had transient AKI, 601 of 1,071 (56.1%) had persistent AKI, 71 of 1,071 (6.6%) had late onset AKI, and 327 of 1,071 (30.5%) remained without AKI. Following adjustment for confounders (age, sex, race, etiology, HE grade, use of IMV and vasopressors, international normalized ratio, and year), although persistent acute kidney injury (adjusted odds ratio [aOR] [95% CI] 0.62 [0.44-0.88]) or late onset AKI (aOR [95% CI] 0.48 [0.26-0.89]) was associated with lower TFS, transient AKI was not (aOR [95% CI] 1.89 [0.99-3.64]). In a multicenter cohort of patients with ALF, persistent but not transient AKI was independently associated with lower short-term TFS.

Development of an organ failure score in acute liver failure for transplant selection and identification of patients at high risk of futility.

IntroductionKing’s College Hospital criteria are currently used to select liver transplant candidates in acetaminophen-related acute liver failure (ALF). Although widely accepted, they show a poor sensitivity in predicting pre-transplant mortality and cannot predict the outcome after surgery. In this study we aimed to develop a new prognostic score that can allow patient selection for liver transplantation more appropriately and identify patients at high risk of futile transplantation.MethodsWe analysed consecutive patients admitted to the Royal Free and Beaujon Hospitals between 1990 and 2015. Clinical and laboratory data at admission were collected. Predictors of 3-month mortality in the non-transplanted patients admitted to the Royal Free Hospital were used to develop the new score, which was then validated against the Beaujon cohort. The Beaujon-transplanted group was also used to assess the ability of the new score in identifying patients at high risk of transplant futility.Results152 patients were included of who 44 were transplanted. SOFA, CLIF-C OF and CLIF-ACLF scores were the best predictors of 3-month mortality among non-transplanted patients. CLIF-C OF score and high dosages of norepinephrine requirement were the only significant predictors of 3-month mortality in the non-transplanted patients, and therefore were included in the ALF-OFs score. In non-transplanted patients, ALF-OFs showed good performance in both exploratory (AUC = 0.89; sensitivity = 82.6%; specificity = 89.5%) and the validation cohort (AUC = 0.988; sensitivity = 100%; specificity = 92.3%). ALF-OFs score was also able to identify patients at high risk of transplant futility (AUC = 0.917; sensitivity = 100%; specificity = 79.2%).ConclusionALF-OFs is a new prognostic score in acetaminophen-related ALF that can predict both the need for liver transplant and high risk of transplant futility, improving candidate selection for liver transplantation.

Psychosocial and behavioral factors in acetaminophen-related acute liver failure and liver injury

ObjectivesAcetaminophen overdoses result in nearly 500 deaths annually and a much larger number of hospitalizations. Suicidal overdoses are exceeded in number in the United States by unintentional overdoses. We evaluated clinical, demographic and psychosocial factors among unintentional and intentional overdose patients whose acetaminophen (APAP) toxicity had resulted in acute liver failure. We hypothesized that APAP overdose patients would be more likely to suffer from behavioral health issues and display higher impulsivity scores than the general population. MethodsWithin 4days of admission and initial recovery of alertness, we administered a detailed questionnaire that included questions on APAP intake (e.g., dose taken, intent, other substances ingested), the Mini International Neuropsychiatric Interview modules on depression, alcohol use, substance use, and pain disorders and The Barratt Impulsiveness Scale-11. ResultsThe group included 44 intentional (single time point ingestions with the intent to self-harm) and 51 unintentional (multiple time point ingestions to manage pain or other condition) APAP patients enrolled in the Acute Liver Failure Study Group registry between 2007 and 2013. Both groups were characterized by similar frequencies of chronic pain, depressive symptoms at time of ingestion and alcohol and substance use disorders, all at higher rates than the general population. Overall, APAP patients scored higher than the general population for Non-planning aspects of impulsivity, with no apparent differences between other impulsivity scores or between intentional and unintentional APAP patients. ConclusionsDepression, mismanagement of problematic chronic pain, frequent substance abuse, and increased impulsivity appear to provide the substrate for many APAP overdoses.

A CASE REPORT ON ROLE OF N-ACETYLCYSTEINE IN NON–ACETAMINOPHEN RELATED ACUTE LIVER INJURY

Acute liver failure is a clinical entity associated with a high mortality rate and majority of these patients may require liver transplantation. N-Acetylcysteine (NAC), an antioxidant agent that replenishes mitochondrial and cytosolic glutathione stores, is an antidote for acetaminophen poisoning. But their role in non–acetaminophen-related acute liver failure is still not proven. Here, we discuss about a 67 year old male patient diagnosed with hepatitis with acute liver injury who was admitted in Emergency Medicine. He was treated with N- Acetylcysteine infusion for an average of 48 hours and later it was found that his liver function tests improved. In this study, we could find that N-Acetylcysteine plays a major role in improving the liver function test of patients with non–acetaminophen-related acute liver failure.

Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved.

Treatment of Acute Liver Failure in Resource-Constrained Settings without Transplantation Facilities Can Be Improved.

Hepatic Encephalopathy, Chronic Hepatic Encephalopathy (Portosystemic Encephalopathy), and Acute Liver Failure

Hepatic encephalopathy, also referred to as portosystemic encephalopathy (PSE), is a complex neuropsychiatric disorder resulting from chronic parenchymal liver disease or liver failure, often in conjunction with portosystemic shunts, either naturally occurring or surgically created. PSE is characterized by changes in personality, level of consciousness, motor function, and cognition. This chapter discusses the pathophysiology, pathogenesis, diagnosis, and treatment of hepatic encephalopathy as well as general considerations, clinical findings, complications, treatment, specific causes, and prognosis regarding acute liver failure (ALF). Tables describe the causes of cirrhosis of the liver, grades of hepatic encephalopathy, diagnostic criteria and precipitating factors for PSE, a comparison of PSE patients with spontaneous shunts and cirrhotic controls, factors that may result in overt PSE in patients with well-preserved liver function, considerations in the management of PSE, and causes of ALF. Figures illustrate the A-deletion and square, spiral, star, and signature tests; triphasic waves; and magnetic resonance images of a patient with PSE. Graphs show the relationship between rifaximin and risk of an episode of hepatic encephalopathy, causes of ALF, and incidence of acetaminophen-related ALF. This chapter contains 6 highly rendered figures, 8 tables, and 14 references.

Circulating levels of soluble receptor for advanced glycation end products and ligands of the receptor for advanced glycation end products in patients with acute liver failure.

Animal studies suggest that receptor for advanced glycation end products (RAGE)-dependent mechanisms contribute to acetaminophen-induced liver damage. We examined whether circulating levels of soluble receptor for advanced glycation end products (sRAGE) or RAGE ligands, including extracellular newly identified receptor for advanced glycation end products binding protein (EN-RAGE), high-mobility group box 1 (HMGB1), and Nε-(Carboxymethyl)lysine adducts (CML), could aid in prognostication after an acetaminophen overdose. Sixty well-characterized acetaminophen-related acute liver failure (ALF) patients (30 spontaneous survivors and 30 patients who underwent transplantation and/or died) who were enrolled in the National Institutes of Health-sponsored Acute Liver Failure Study Group, were matched by age, met standard criteria for encephalopathy, and had an international normalized ratio > 1.5 were retrospectively studied. HMGB1, EN-RAGE, CML, and sRAGE were detected by enzyme-linked immunosorbent assay methods in sera from ALF patients and 30 healthy controls. Levels of sRAGE, EN-RAGE, and HMGB1 (but not CML) were significantly greater (P < 0.001) in ALF patients versus normal controls. The levels of sRAGE, HMGB1, and EN-RAGE were significantly higher (P = 0.03, P < 0.01, and P = 0.03) in patients with a systemic inflammatory response syndrome (SIRS) score > 2 versus patients with a SIRS score ≤ 2. Nevertheless, only sRAGE levels were significantly higher in patients who underwent transplantation and/or died versus spontaneous survivors (P < 0.001), and they were positively associated with conventional markers of liver disease severity. Multivariate logistic regression identified an encephalopathy grade > 2 as an independent predictor of an adverse outcome on admission (odds ratio, 13; 95% confidence interval, 2.3-73; P < 0.001). The RAGE-ligand axis may interfere with liver regeneration and should be a promising objective for further research.

Update on acute liver failure.

Although advances in critical care management and liver transplantation have improved survival in acute liver failure (ALF), mortality remains significant. An evidence base to support management has been lacking, due to the condition's rarity, severity and heterogeneity. The purpose of this review is to critically appraise the latest evidence, updating clinicians on the current understanding of the best management. Transplant-free survival in acetaminophen-related ALF has improved considerably, such that reconsidering thresholds for transplant is required, perhaps utilizing biomarkers of liver regeneration. Autoimmune hepatitis-related ALF may be too advanced to permit rescue with corticosteroids, which could be deleterious in the sickest patients. Acute kidney injury is commoner in ALF than previously suspected. Intracranial pressure monitoring does not appear to alter mortality. Despite altered traditional indices of coagulation, new thrombin generation assays suggest a rebalanced coagulation in liver failure. Antimicrobial prophylaxis may not be required in all patients. Liver support systems remain controversial and require further evaluation. Traditional dogma in ALF management is questioned: transplant thresholds for acetaminophen overdose, steroid use in autoimmune ALF, routine antimicrobial prophylaxis, the coagulopathy of liver disease, the value of intracranial pressure monitoring and extracorporeal liver support.

Acetaminophen hepatotoxicity: an updated review.

As the most common cause of acute liver failure (ALF) in the USA and UK, acetaminophen-induced hepatotoxicity remains a significant public health concern and common indication for emergent liver transplantation. This problem is largely attributable to acetaminophen combination products frequently prescribed by physicians and other healthcare professionals, with unintentional and chronic overdose accounting for over 50 % of cases of acetaminophen-related ALF. Treatment with N-acetylcysteine can effectively reduce progression to ALF if given early after an acute overdose; however, liver transplantation is the only routinely used life-saving therapy once ALF has developed. With the rapid course of acetaminophen-related ALF and limited supply of donor livers, early and accurate diagnosis of patients that will require transplantation for survival is crucial. Efforts in developing novel treatments for acetaminophen-induced ALF are directed toward bridging patients to recovery. These include auxiliary, artificial, and bioartificial support systems. This review outlines the most recent developments in diagnosis and management of acetaminophen-induced ALF.

Acetylcysteine for Nonacetaminophen Acute Liver Failure

N-acetylcysteine (NAC) has shown benefit in patients with acetaminophen-related acute liver failure. Now, researchers have conducted a prospective,

Outcome of liver transplantation for drug-induced acute liver failure in the United States: Analysis of the united network for organ sharing database

Acute liver failure (ALF) is an uncommon but potentially lethal drug-related adverse effect that often leads to liver transplantation (LT) or death. A retrospective cohort study was performed with the United Network for Organ Sharing Standard Transplant Analysis and Research files. Recipients who underwent LT for drug-induced acute liver failure (DIALF) from 1987 through 2006 were analyzed. A total of 661 patients transplanted for DIALF were included in the analysis. The 4 leading implicated drug groups were acetaminophen (n = 265; 40%), antituberculosis drugs (n = 50; 8%), antiepileptics (n = 46; 7%), and antibiotics (n = 39; 6%). One-year estimated survival probabilities were 76%, 82%, 52%, 82%, and 79% for acetaminophen, antituberculosis drugs, antiepileptics, antibiotics, and others, respectively. The lower rate of survival among those exposed to antiepileptics was observed mainly in children. Of the 22 patients less than 18 years old who had ALF due to antiepileptics, 73% died within the first year. The difference in overall survival between acetaminophen-related and non-acetaminophen-related ALF was not statistically significant. Patients with acetaminophen-related ALF required dialysis prior to LT at a significantly higher rate than all other drug groups (27% versus 3%-10%, P < 0.0001). According to Cox proportional hazards regression analysis, the independent pretransplant predictors of death after LT were being on life support, DIALF due to antiepileptic drugs at age less than 18, and elevated serum creatinine. In conclusion, the leading drug groups causing LT due to DIALF in the United States were acetaminophen, antituberculosis drugs, antiepileptics, and antibiotics. Children who had ALF due to antiepileptics had a substantially higher risk of death after LT in comparison with other drugs. Patients transplanted for acetaminophen-related ALF required dialysis at a significantly higher rate. Being on life support, DIALF due to antiepileptics (at age less than 18), and elevated serum creatinine were independent pretransplant predictors of poor survival after LT for DIALF.

Intravenous N-Acetylcysteine Improves Transplant-Free Survival in Early Stage Non-Acetaminophen Acute Liver Failure

N-acetylcysteine (NAC), an antidote for acetaminophen poisoning, might benefit patients with non-acetaminophen-related acute liver failure. 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. 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). 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.

Reply:

(1) The American Association for the Study of Liver Diseases (AASLD) policy statement that 10% of cases of acetaminophen-related acute liver failure (ALF) occur in patients taking the manufacturer's recommended dose of the drug is based on a reported range from 7% (from the Acute Liver Failure Study Group's review of 275 carefully adjudicated cases)1 to 29% (as recently reported in a study from France).2 Accurate data are difficult to obtain because of poor recollection or altered mental status in patients who are hospitalized with ALF, but the evidence is clear that at least 7% of cases of acetaminophen-related ALF in the United States follows ingestion of therapeutic doses of the drug. Taking into account both studies, I conservatively estimated the overall incidence of low-dose acetaminophen-related ALF at 10%. (2) The AASLD policy statement proposed that products containing acetaminophen be required to have a warning label, stating that the drug can cause “severe or even fatal liver injury” and that the chances may be higher in patients ingesting certain other drugs. Among the list of high-risk agents was warfarin, based on data from a recent randomized, double-blind, placebo-controlled study in which patients on stable warfarin doses for >1 month who were given 4 g of acetaminophen daily for 14 days experienced a significant rise in International Normalized Ratio (INR = 3.45 for acetaminophen versus 2.66 for placebo at 14 days).3 Because this complication does not technically fall under the category of liver injury or liver failure, AASLD will revisit its decision to include warfarin among the list of agents that can potentiate acetaminophen-induced liver injury. Instead, a separate warning criterion will be proposed to indicate that acetaminophen can increase the likelihood of an adverse event (bleeding) in patients taking warfarin. (3) I stand by the statement that “most hepatologists might dispute” advertising touting acetaminophen as the safest over-the-counter analgesic. Each month the Acute Liver Failure Study Group identifies 4-6 patients with acetaminophen-related ALF, 30% of whom die. For each one of these cases, we typically discuss on our conference call two other “near misses,” patients admitted with severe acetaminophen-induced liver injury and coagulopathy who do not become encephalopathic. Fortunately, most of these latter patients recover, but they still undergo a near-fatal experience and represent a huge burden to the health care system. That amounts to 150 or more cases of severe acetaminophen hepatotoxicity each year from our own practices—hard to ignore! In summary, Drs. Kuffner and Baggish raise questions around the edges of the problem, while missing the larger issue: “What can we do, together, to stop the large number of needless acetaminophen deaths that occur annually?” William M. Lee M.D.*, * Division of Digestive and Liver Diseases, University of Texas Southwestern Medical Center, Dallas, TX.

Serum Apoptosis Markers in Acute Liver Failure: A Pilot Study

We sought to determine whether circulating apoptotic markers are altered in acute liver failure (ALF), differ with etiology, or predict clinical outcome in this condition. Serum levels of soluble Fas (sFas), tumor necrosis factor-alpha (TNF-alpha), hepatocyte growth factor (HGF), and interleukin-6 (IL-6) were measured in 67 acute liver failure patients, as well as controls. In a subset of the groups, we measured serum M-30 antigen, an exposed neoepitope from caspase cleavage. We also assessed M-30 immunoreactivity in liver tissue of ALF patients and controls. Median levels for TNF-alpha, HGF, IL-6, and M-30 antigen were at least 10-fold greater in ALF than in hepatitis C virus or normal controls (P < .0001). Median day 1 sFas, day 3 sFas, and day 1 HGF levels varied according to etiology of acute liver failure (P = .004, P = .011, and P = .019, respectively), with values for drug-induced liver injury and acetaminophen-related ALF higher than other etiologies. Median M-30 antigen levels were significantly higher in patients who were transplanted and/or died (2183 U/L) than spontaneous survivors (1004 U/L) (P = .026). M-30 immunoreactivity in liver tissue was significantly greater in ALF patients than HCV controls (P = .004). TNF-alpha, HGF, IL-6, and M-30 antigen were significantly elevated in ALF. High levels of sFas and HGF might help to confirm a diagnosis of drug-induced liver injury or acetaminophen-related ALF. Higher levels of M-30 antigen are associated with poor clinical outcomes in ALF.

Measurement of Serum Acetaminophen–Protein Adducts in Patients With Acute Liver Failure

Acetaminophen toxicity is the most common cause of acute liver failure (ALF) in the United States and Great Britain, but may be underrecognized in certain settings. Acetaminophen-protein adducts are specific biomarkers of drug-related toxicity in animal models and can be measured in tissue or blood samples. Measurement of serum adducts might improve diagnostic accuracy in acute liver failure (ALF) patients. We measured serum acetaminophen-protein adducts using high-pressure liquid chromatography with electrochemical detection in coded sera of 66 patients with ALF collected prospectively at 24 US tertiary referral centers. Samples were included from 20 patients with well-characterized acetaminophen-related acute liver failure, 10 patients with ALF owing to other well-defined causes, 36 patients with ALF of indeterminate etiology, and 15 additional patients without ALF but with known acetaminophen overdose and minimal or no biochemical liver injury. Acetaminophen-protein adducts were detected in serum in 100% of known acetaminophen ALF patients and in none of the ALF patients with other defined causes, yielding a sensitivity and specificity of 100%. In daily serial samples, serum adducts decreased in parallel with aminotransferase levels. Seven of 36 (19%) indeterminate cases demonstrated adducts in serum suggesting that acetaminophen toxicity caused or contributed to ALF in these patients. Low adduct levels were present in 2 of 15 patients with acetaminophen overdose without significant liver injury. Measurement of serum acetaminophen-protein adducts reliably identified acetaminophen toxicity, and may be a useful diagnostic test for cases lacking historical data or other clinical information.

Acetaminophen‐induced acute liver failure

Severe acetaminophen hepatotoxicity frequently leads to acute liver failure (ALF). We determined the incidence, risk factors, and outcomes of acetaminophen-induced ALF at 22 tertiary care centers in the United States. Detailed prospective data were gathered on 662 consecutive patients over a 6-year period fulfilling standard criteria for ALF (coagulopathy and encephalopathy), from which 275 (42%) were determined to result from acetaminophen liver injury. The annual percentage of acetaminophen-related ALF rose during the study from 28% in 1998 to 51% in 2003. Median dose ingested was 24 g (equivalent to 48 extra-strength tablets). Unintentional overdoses accounted for 131 (48%) cases, intentional (suicide attempts) 122 (44%), and 22 (8%) were of unknown intent. In the unintentional group, 38% took two or more acetaminophen preparations simultaneously, and 63% used narcotic-containing compounds. Eighty-one percent of unintentional patients reported taking acetaminophen and/or other analgesics for acute or chronic pain syndromes. Overall, 178 subjects (65%) survived, 74 (27%) died without transplantation, and 23 subjects (8%) underwent liver transplantation; 71% were alive at 3 weeks. Transplant-free survival rate and rate of liver transplantation were similar between intentional and unintentional groups. In conclusion, acetaminophen hepatotoxicity far exceeds other causes of acute liver failure in the United States. Susceptible patients have concomitant depression, chronic pain, alcohol or narcotic use, and/or take several preparations simultaneously. Education of patients, physicians, and pharmacies to limit high-risk use settings is recommended.

Changing patterns of causation and the use of transplantation in the United kingdom.

Acute liver failure (ALF) is a rare condition in the United Kingdom. Comprehensive supportive intensive care of extra-hepatic organ failure and the early recognition of and use of transplantation for those who will not survive form the cornerstone of its management. Over the last 30 years there has been a reduction in the proportion of cases resulting from viral and seronegative hepatitis, and a progressive rise in those resulting from severe acetaminophen-induced hepatotoxicity. The latter cases mostly result from deliberate self-poisoning and formed the major cause of ALF hospital admissions and indication for emergency liver transplantation. The increasing misuse of acetaminophen has paralleled a rise in sales and greater availability of the drug. Introduction of legislation to restrict sales of acetaminophen has been followed by a fall in hospital admissions resulting from self-poisoning, a 20% reduction in deaths, and a 50% fall in the number of patients undergoing emergency liver transplantation. The reduction in acetaminophen-related ALF has been paralleled by an increase in the number of transplants performed in ALF of nonacetaminophen etiologies.