ABSTRACT
Acute hepatitis E virus (HEV) infection is a leading cause of acute liver failure (ALF) in many developing countries, yet rarely identified in Western countries. Given that antibody testing for HEV infection is not routinely obtained, we hypothesized that HEV-related ALF might be present and unrecognized in North American ALF patients. Serum samples of 681 adults enrolled in the U.S. Acute Liver Failure Study Group were tested for anti-HEV immunoglobulin (Ig) M and anti-HEV IgG levels. Subjects with a detectable anti-HEV IgM also underwent testing for HEV RNA. Mean patient age was 41.8 years, 32.9% were male, and ALF etiologies included acetaminophen (APAP) hepatotoxicity (29%), indeterminate ALF (23%), idiosyncratic drug-induced liver injury DILI (22%), acute hepatitis B virus infection (12%), autoimmune hepatitis (12%), and pregnancy-related ALF (2%). Three men ages 36, 39, and 70 demonstrated repeatedly detectable anti-HEV IgM, but all were HEV-RNA negative and had other putative diagnoses. The latter 2 subjects died within 3 and 11 days of enrollment whereas the 36-year-old underwent emergency liver transplantation on study day 2. At admission, 294 (43.4%) of the ALF patients were anti-HEV IgG positive with the seroprevalence being highest in those from the Midwest (50%) and lowest in those from the Southeast (28%). Anti-HEV IgG+ subjects were significantly older, less likely to have APAP overdose, and had a lower overall 3-week survival compared to anti-HEV IgG- subjects (63% vs. 70%; P = 0.018). CONCLUSION: Acute HEV infection is very rare in adult Americans with ALF (i.e., 0.4%) and could not be implicated in any indeterminate, autoimmune, or pregnancy-related ALF cases. Past exposure to HEV with detectable anti-HEV IgG was significantly more common in the ALF patients compared to the general U.S. POPULATION: (Hepatology 2016;64:1870-1880).
Subject(s)
Hepatitis Antibodies/blood , Hepatitis E virus/immunology , Hepatitis E/blood , Hepatitis E/complications , Immunoglobulin G/blood , Immunoglobulin M/blood , Liver Failure, Acute/blood , Liver Failure, Acute/complications , Adult , Aged , Female , Hepatitis E/epidemiology , Humans , Male , Prospective Studies , Seroepidemiologic Studies , United StatesABSTRACT
BACKGROUND & AIMS: In the United States, nearly 1000 annual cases of heat stroke are reported but the frequency and outcome of severe liver injury in such patients is not well described. The aim of this study was to describe cases of acute liver injury (ALI) or failure (ALF) caused by heat stroke in a large ALF registry. METHODS: Amongst 2675 consecutive subjects enrolled in a prospective observational cohort of patients with ALI or ALF between January 1998 and April 2015, there were eight subjects with heat stroke. RESULTS: Five patients had ALF and three had ALI. Seven patients developed acute kidney injury, all eight had lactic acidosis and rhabdomyolysis. Six patients underwent cooling treatments, three received N-acetyl cysteine (NAC), three required mechanical ventilation, three required renal replacement therapy, two received vasopressors, one underwent liver transplantation, and two patients died-both within 48 hours of presentation. All cases occurred between May and August, mainly in healthy young men because of excessive exertion. CONCLUSIONS: Management of ALI and ALF secondary to heat stroke should focus on cooling protocols and supportive care, with consideration of liver transplantation in refractory patients.
Subject(s)
Heat Stroke/complications , Heat Stroke/mortality , Liver Failure, Acute/therapy , Liver/physiopathology , Acetylcysteine/therapeutic use , Acute Kidney Injury/etiology , Adult , Female , Humans , Liver Failure, Acute/etiology , Liver Transplantation , Male , Middle Aged , Prospective Studies , Registries , Renal Replacement Therapy , Rhabdomyolysis/etiology , United StatesABSTRACT
BACKGROUND: Acute liver failure (ALF) is a rare syndrome of severe, rapid-onset hepatic dysfunction-without prior advanced liver disease-that is associated with high morbidity and mortality. Intensive care and liver transplantation provide support and rescue, respectively. OBJECTIVE: To determine whether changes in causes, disease severity, treatment, or 21-day outcomes have occurred in recent years among adult patients with ALF referred to U.S. tertiary care centers. DESIGN: Prospective observational cohort study. (ClinicalTrials .gov: NCT00518440). SETTING: 31 liver disease and transplant centers in the United States. PATIENTS: Consecutively enrolled patients-without prior advanced liver disease-with ALF (n = 2070). MEASUREMENTS: Clinical features, treatment, and 21-day outcomes were compared over time annually for trends and were also stratified into two 8-year periods (1998 to 2005 and 2006 to 2013). RESULTS: Overall clinical characteristics, disease severity, and distribution of causes remained similar throughout the study period. The 21-day survival rates increased between the two 8-year periods (overall, 67.1% vs. 75.3%; transplant-free survival [TFS], 45.1% vs. 56.2%; posttransplantation survival, 88.3% vs. 96.3% [P < 0.010 for each]). Reductions in red blood cell infusions (44.3% vs. 27.6%), plasma infusions (65.2% vs. 47.1%), mechanical ventilation (65.7% vs. 56.1%), and vasopressors (34.9% vs. 27.8%) were observed, as well as increased use of N-acetylcysteine (48.9% vs. 69.3% overall; 15.8% vs. 49.4% [P < 0.001] in patients with ALF not due to acetaminophen toxicity). When examined longitudinally, overall survival and TFS increased throughout the 16-year period. LIMITATIONS: The duration of enrollment, the number of patients enrolled, and possibly the approaches to care varied among participating sites. The results may not be generalizable beyond such specialized centers. CONCLUSION: Although characteristics and severity of ALF changed little over 16 years, overall survival and TFS improved significantly. The effects of specific changes in intensive care practice on survival warrant further study. PRIMARY FUNDING SOURCE: National Institutes of Health.
Subject(s)
Liver Failure, Acute/therapy , Adult , Cause of Death , Critical Care , Female , Humans , Liver Failure, Acute/etiology , Liver Failure, Acute/mortality , Liver Failure, Acute/surgery , Liver Transplantation , Male , Middle Aged , Prospective Studies , Risk Factors , Severity of Illness Index , Survival Rate , United StatesABSTRACT
BACKGROUND & AIMS: Patients with acute liver failure (ALF) have a high risk of death that can be substantially reduced with liver transplantation. It is a challenge to predict which patients with ALF will survive without liver transplant because available prognostic scoring systems are inadequate. We devised a mathematical model, using a large dataset collected by the Acute Liver Failure Study Group, which can predict transplant-free survival in patients with ALF. METHODS: We performed a retrospective analysis of data from 1974 subjects who met criteria for ALF (coagulopathy and hepatic encephalopathy within 26 weeks of the first symptoms, without pre-existing liver disease) enrolled in the Acute Liver Failure Study Group database from January 1, 1998 through June 11, 2013. We randomly assigned the subjects to development and validation cohorts. Data from the development cohort were analyzed to identify factors associated with transplant-free survival (alive without transplantation by 21 days after admission to the study). Statistically significant variables were used to create a multivariable logistic regression model. RESULTS: Most subjects were women (70%) and white (78%); acetaminophen overdose was the most common cause (48% of subjects). The rate of transplant-free survival was 50%. Admission values of hepatic encephalopathy grade, ALF etiology, vasopressor use, and log transformations of bilirubin and international normalized ratio were significantly associated with transplant-free survival, based on logistic regression analysis. In the validation cohort, the resulting model predicted transplant-free survival with a C statistic value of 0.84, 66.3% accuracy (95% confidence interval, 63.1%-69.4%), 37.1% sensitivity (95% confidence interval, 32.5%-41.8%), and 95.3% specificity (95% confidence interval, 92.9%-97.1%). CONCLUSIONS: Using data from the Acute Liver Failure Study Group, we developed a model that predicts transplant-free survival of patients with ALF based on easily identifiable hospital admission data. External validation studies are required.
Subject(s)
Decision Support Techniques , Liver Failure, Acute/diagnosis , Liver Failure, Acute/pathology , Models, Theoretical , Adult , Female , Humans , Male , Middle Aged , Prognosis , Retrospective Studies , Survival AnalysisABSTRACT
BACKGROUND & AIMS: Published estimates of survival associated with mushroom (amatoxin)-induced acute liver failure (ALF) and injury (ALI) with and without liver transplant (LT) are highly variable. We aimed to determine the 21-day survival associated with amatoxin-induced ALI (A-ALI) and ALF (A-ALF) and review use of targeted therapies. METHODS: Cohort study of all A-ALI/A-ALF patients enrolled in the US ALFSG registry between 01/1998 and 12/2014. RESULTS: Of the 2224 subjects in the registry, 18 (0.8%) had A-ALF (n = 13) or A-ALI (n = 5). At admission, ALF patients had higher lactate levels (5.2 vs. 2.2 mm, P = 0.06) compared to ALI patients, but INR (2.8 vs. 2.2), bilirubin (87 vs. 26 µm) and MELD scores (28 vs. 24) were similar (P > 0.2 for all). Of the 13 patients with ALF, six survived without LT (46%), five survived with LT (39%) and two died without LT (15%). Of the five patients with ALI, four (80%) recovered and one (20%) survived post-LT. Comparing those who died/received LT (non-spontaneous survivors [NSS]) with spontaneous survivors (SS), N-acetylcysteine was used in nearly all patients (NSS 88% vs. SS 80%); whereas, silibinin (25% vs. 50%), penicillin (50% vs. 25%) and nasobiliary drainage (0 vs. 10%) were used less frequently (P > 0.15 for all therapies). CONCLUSION: Patients with mushroom poisoning with ALI have favourable survival, while around half of those presenting with ALF may eventually require LT. Further study is needed to define optimal management (including the use of targeted therapies) to improve survival, particularly in the absence of LT.
Subject(s)
Amanitins/toxicity , Chemical and Drug Induced Liver Injury/etiology , Liver Failure, Acute/etiology , Mushroom Poisoning/epidemiology , Acetylcysteine/therapeutic use , Adult , Chemical and Drug Induced Liver Injury/therapy , Cohort Studies , Female , Humans , Liver Failure, Acute/mortality , Liver Failure, Acute/therapy , Liver Transplantation , Male , Middle Aged , Mushroom Poisoning/therapy , North America/epidemiology , Penicillins/therapeutic use , Registries , Silybin , Silymarin/therapeutic useABSTRACT
BACKGROUND AND AIMS: Acetaminophen (APAP) is the most common cause of acute liver failure (ALF) in the west. It is unknown if APAP overdose in combination with diphenhydramine or opioids confers a different clinical presentation or prognosis. Study objectives were to compare (1) baseline patient characteristics; (2) initial clinical presentation; and (3) clinical outcomes among patients with ALF due to APAP alone or in combination with diphenhydramine or opioids. METHODS: We analyzed 666 cases of APAP-related liver failure using the Acute Liver Failure Study Group database from 1998 to 2012. The database contains detailed demographic, laboratory, and clinical outcome data, including hemodialysis, transplantation, and death and in-hospital complications such as arrhythmia and infection. RESULTS: The final sample included 666 patients with APAP liver injury. A total 30.3% of patients were overdosed with APAP alone, 14.1% with APAP/diphenhydramine, and 56.6% with APAP/opioids. Patients taking APAP with opioids were older, had more comorbidities, and were more likely to have unintentional overdose (all P<0.0001). On presentation, 58% in the APAP/opioid group had advanced encephalopathy as compared with 43% with APAP alone (P=0.001) The APAP/diphenhydramine group presented with the highest serum aminotransferase levels, no differences in laboratory values were noted at 3 days postenrollment. No significant differences were observed in clinical outcomes among the groups. CONCLUSIONS: Most patients with APAP-induced ALF were taking APAP combination products. There were significant differences in patient characteristics and clinical presentation based on the type of product ingested, however, there were no differences noted in delayed hepatotoxicity or clinical outcomes.
Subject(s)
Acetaminophen/adverse effects , Chemical and Drug Induced Liver Injury/etiology , Liver Failure, Acute/chemically induced , Acetaminophen/administration & dosage , Adult , Analgesics, Opioid/administration & dosage , Analgesics, Opioid/adverse effects , Chemical and Drug Induced Liver Injury/epidemiology , Databases, Factual , Diphenhydramine/administration & dosage , Diphenhydramine/adverse effects , Drug Combinations , Drug Overdose , Female , Humans , Liver Failure, Acute/epidemiology , Male , Middle Aged , Prognosis , Risk Factors , Time Factors , Young AdultABSTRACT
Importance: Results show the short-term risk of hemorrhage in treating patients with acute transient ischemic attack (TIA) or minor acute ischemic stroke (AIS) with clopidogrel plus aspirin or aspirin alone. Objective: To characterize the frequency and kinds of major hemorrhages in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial. Design, Setting, and Participants: This secondary analysis of the POINT randomized, double-blind clinical trial conducted in 10 countries in North America, Europe, and Australasia included patients with high-risk TIA or minor AIS who were randomized within 12 hours of symptom onset and followed up for 90 days. The total enrollment, which occurred from May 28, 2010, through December 17, 2017, was 4881 and constituted the intention-to-treat group; 4819 (98.7%) were included in the as-treated analysis group. The primary safety analyses were as-treated, classifying patients based on study drug actually received. Intention-to-treat analyses were performed as secondary analyses. Data were analyzed in April 2018. Interventions: Patients were assigned to receive clopidogrel (600 mg loading dose on day 1 followed by 75 mg daily for days 2-90) or placebo; all patients also received open-label aspirin, 50 to 325 mg/d. Main Outcomes and Measures: The primary safety outcome was all major hemorrhages. Other safety outcomes included minor hemorrhages. Results: A total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years [interquartile range, 55-74 years]; 2195 women [45.0%]); the primary results have been published previously. In the as-treated analyses, major hemorrhage occurred in 21 patients (0.9%) receiving clopidogrel plus aspirin and 6 (0.2%) in the aspirin alone group (hazard ratio, 3.57; 95% CI, 1.44-8.85; P = .003; number needed to harm, 159). There were 4 fatal hemorrhages (0.1%; 3 in the clopidogrel plus aspirin group and 1 in the aspirin alone group); 3 of the 4 were intracranial. There were 7 intracranial hemorrhages (0.1%); 5 were in the clopidogrel plus aspirin group and 2 in the aspirin plus placebo group. The most common location of major hemorrhages was in the gastrointestinal tract. Conclusions and Relevance: The risk for major hemorrhages in patients receiving either clopidogrel plus aspirin or aspirin alone after TIA or minor AIS was low. Nevertheless, treatment with clopidogrel plus aspirin increased the risk of major hemorrhages over aspirin alone from 0.2% to 0.9%. Trial Registration: ClinicalTrials.gov identifier: NCT00991029.
Subject(s)
Aspirin/therapeutic use , Clopidogrel/therapeutic use , Gastrointestinal Hemorrhage/epidemiology , Intracranial Hemorrhages/epidemiology , Ischemic Attack, Transient/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Stroke/drug therapy , Aged , Brain Ischemia/drug therapy , Double-Blind Method , Drug Therapy, Combination , Female , Gastrointestinal Hemorrhage/chemically induced , Gastrointestinal Hemorrhage/mortality , Hematuria/chemically induced , Hematuria/epidemiology , Hemorrhage/chemically induced , Hemorrhage/epidemiology , Hemorrhage/mortality , Humans , Intracranial Hemorrhages/chemically induced , Intracranial Hemorrhages/mortality , Kaplan-Meier Estimate , Male , Middle Aged , Proportional Hazards Models , Secondary Prevention , Severity of Illness IndexABSTRACT
Importance: Debate continues about the value of event adjudication in clinical trials and whether independent centralized assessments improve reliability and validity of study results in masked randomized trials compared with local, investigator-assessed end points. Objective: To assess the results of the adjudicated end point process in the Platelet-Oriented Inhibition in New TIA and Minor Ischemic Stroke (POINT) trial by comparing end points assessed by local site investigators with centrally adjudicated end points. Design, Setting, and Participants: This is an ad hoc secondary analysis of a randomized, double-blind clinical trial comparing safety and effectiveness of clopidogrel bisulphate plus aspirin vs placebo plus aspirin. Patients received either 600 mg of clopidogrel bisulphate on day 1, then 75 mg per day through day 90 plus 50 to 325 mg of aspirin per day, or the same range of dosages of placebo plus aspirin. Investigators reported all potential end points; independent masked adjudicators were randomly assigned to review using definitions specified in the study protocol. This was a multicenter study; 269 international sites in 10 countries enrolled from May 28, 2010, to December 19, 2017. The study enrolled 4881 patients 18 years or older with transient ischemic attack or minor acute ischemic stroke within 12 hours of symptom onset and followed for 90 days from randomization; last follow-up was completed in March 2018. Main Outcomes and Measures: Independent adjudicators external to the study and masked to study treatment assignment adjudicated 467 primary and secondary effectiveness outcomes and major and minor bleeding events, including the primary composite end point, which was the risk of a composite of major ischemic events at 90 days, defined as ischemic stroke, myocardial infarction, or death from an ischemic vascular event. The primary safety end point was major hemorrhage. All components of the primary and safety outcomes were adjudicated. Results: In this secondary analysis of an international randomized clinical trial, a total of 269 sites worldwide randomized 4881 patients (median age, 65.0 years; interquartile range, 55-74 years); 55.0% were male. The primary results have been published previously. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary composite end point were 0.75 (95% CI, 0.59-0.95) for adjudicator-assessed events and 0.76 (95% CI, 0.60-0.95) for investigator-assessed events. Agreement between adjudicator and investigator assessments was 90.7%. The hazard ratios for clopidogrel plus aspirin vs placebo plus aspirin for the primary safety end point were 2.32 (95% CI, 1.10-4.87) for adjudicator-assessed events and 2.58 (95% CI, 1.19-5.58) for investigator-assessed events, with an agreement rate of 77.5%. Conclusions and Relevance: Independent end point adjudication did not substantially alter estimates of the primary treatment effectiveness in the POINT trial. Trial Registration: ClinicalTrials.gov identifier: NCT00991029.
Subject(s)
Aspirin/therapeutic use , Clopidogrel/therapeutic use , Ischemic Attack, Transient/drug therapy , Platelet Aggregation Inhibitors/therapeutic use , Stroke/drug therapy , Aged , Aspirin/pharmacology , Clopidogrel/pharmacology , Double-Blind Method , Drug Therapy, Combination , Endpoint Determination , Female , Humans , Male , Middle Aged , Platelet Aggregation Inhibitors/pharmacology , Research Design , Secondary Prevention , Treatment OutcomeABSTRACT
BACKGROUND: The prothrombotic milieu seen in subarachnoid hemorrhage (SAH) poses a unique challenge to neurovascular surgeons with regard to device use and microcatheter practice. OBJECTIVE: To determine how demographic factors and balloon practices impact diffusion-weighted imaging (DWI) abnormalities and outcomes in patients with SAH compared to those without (non-SAH). METHODS: We retrospectively analyzed 77 patients with SAH treated by balloon-assisted coiling in a single institution compared with 81 consecutive patients with unruptured aneurysms treated by balloon-assisted coiling at the same institution. Data were collected with regard to demographic factors, procedural and anatomic considerations, and DWI abnormalities on postprocedural magnetic resonance imaging. RESULTS: SAH patients were significantly more likely to have DWI abnormality (75% vs 21%, P < .0001) and had a higher number and volume of DWI (4.0 vs 3.0, P = .0421 and 1.3 vs 0.3 cc, P = .0041) despite similar balloon practices. SAH patients were not more likely to have DWI abnormality in vascular territory distal to the treated aneurysm but had a higher likelihood of DWI in a vascular territory unrelated to the aneurysm (81.5% vs 47.1%, P = .0235). Patients without DWI abnormality were significantly more likely to have a good outcome as defined by modified Rankin Score 0 to 2 (95.6% vs 81.6%, P = .0328). Patients with DWI abnormality more often underwent 4-vessel angiography (70.5% vs 48.0%, P = .0174), but this was not found to be significant on multivariate analysis. CONCLUSION: Balloon-assisted coiling does not result in increased incidence of downstream ischemic events in SAH patients compared to non-SAH patients and is safe in this cohort of patients. Other factors, such as 4-vessel angiography of the SAH milieu itself, may predispose patients to a higher rate of ischemic events.
Subject(s)
Aneurysm, Ruptured/diagnostic imaging , Embolization, Therapeutic/methods , Intracranial Aneurysm/diagnostic imaging , Adult , Aged , Aneurysm, Ruptured/pathology , Aneurysm, Ruptured/surgery , Cohort Studies , Diffusion Magnetic Resonance Imaging/methods , Embolization, Therapeutic/instrumentation , Female , Humans , Intracranial Aneurysm/pathology , Intracranial Aneurysm/surgery , Male , Middle Aged , Retrospective Studies , Subarachnoid Hemorrhage/etiology , Treatment OutcomeABSTRACT
BACKGROUND/AIM: Acetaminophen (APAP) hepatotoxicity is related to the formation of N-acetyl-p-benzoquinone imine (NAPQI), which is detoxified through conjugation with reduced glutathione (GSH). Ophthalmic acid (OA) is an analogue of GSH in which cysteine is replaced with 2-aminobutyrate. Metabolomics studies of mice with APAP-induced acute liver failure (APAP-ALF) identified OA as a marker of oxidative stress and hepatic GSH consumption. The aim of the current study was to determine whether OA is detectable in APAP-ALF human patients either early (day 2) or late (day 4) and whether OA levels were associated with in-hospital survival in the absence of liver transplant. METHODS: Serum samples from 130 APAP-ALF patients (82 survivors, 48 non-survivors) were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS) and correlated with clinical data from the United States Acute Liver Failure Study Group (US ALFSG) Registry (2004-2011). RESULTS: Survivors had significantly lower admission bilirubin (4.2 vs. 5.7 mg/dl) and lactate levels (3.3 vs. 6.5 µmol/l, p<0.05 for all). During the first 7 days of the study, survivors were less likely to require mechanical ventilation (55% vs. 88%), vasopressor support (9.8% vs. 67%) or renal replacement therapy (26% vs. 63%, p< 0.001 for all). Non-survivors were more likely to have detectable OA levels early (31% vs. 15%, p = 0.034) and late (27% vs. 11%, p = 0.02). However there were no significant differences in mean OA levels between non-survivors and survivors (early 0.48 vs. 0.36, late 0.43 vs. 0.37, P > 0.5 for all). CONCLUSION: OA was detectable more frequently in APAP-ALF non-survivors but mean OA levels were not associated with survival. The routine clinical administration of N-acetyl cysteine could replenish GSH levels and prevent OA production.