Forms Of Acute Liver Failure Research Articles

The Use and Potential Benefits of N-Acetylcysteine in Non-Acetaminophen Acute Liver Failure: An Etiology-Based Review.

Acute liver failure represents a life-threatening organ dysfunction with high mortality rates and an urgent need for liver transplantation. The etiology of the disease varies widely depending on various socio-economic factors and is represented mainly by paracetamol overdose and other drug-induced forms of liver dysfunction in the developed world and by viral hepatitis and mushroom poisoning in less developed countries. Current medical care constitutes either specific antidotes or supportive measures to ensure spontaneous recovery. Although it has been proven to have beneficial effects in paracetamol-induced liver failure, N-acetylcysteine is widely used for all forms of acute liver failure. Despite this, few well-designed studies have been conducted on the assessment of the potential benefits, dose regimens, or route of administration of N-acetylcysteine in non-acetaminophen liver failure. This review aims to summarize the current evidence behind the use of this drug in different forms of liver failure.

A different form of acute liver failure

A different form of acute liver failure

Acute Liver Failure (ALF) in Pregnancy: How Much Is Pregnancy Related?

Acute liver failure (ALF), characterized by sudden onset of coagulopathy (international normalized ratio [INR]≥1.5) and encephalopathy, may occur during pregnancy either as a pregnancy-associated etiology or an unrelated and coincidental liver injury. The U.S. Acute Liver Failure Study Group, comprised of 33 tertiary care liver centers, has enrolled consecutive patients with ALF or acute liver injury (ALI; INR≥2.0 with no encephalopathy), over two decades. Etiologies, clinical features, and outcomes of 70 of 3,155 patients (2.2%) who developed ALF or ALI during pregnancy were reviewed to determine how many were pregnancy associated (pregnancy-associated liver disease; PAALD) and how many were attributed to other etiologies. Thirty-five of the 70 were considered PAALD, of whom nearly half were attributed to hemolysis, elevated liver enzymes, and low platelets (HELLP) syndrome and half to acute fatty liver of pregnancy (AFLP), although, in some instances, the distinction was unclear. Virtually all with PAALD had been delivered before hepatology referral, mostly by cesarean section. Acetaminophen toxicity accounted for 21 (60% of the remaining cases), with the remainder resulting from a variety of other causes, but not including viral hepatitis A through E. Although recovery with delivery or supportive measures was possible in most cases, 11 of 70 (16%) required liver transplantation and 8 (11%) died. Swansea criteria to diagnose AFLP were met by all patients with PAALD and also by virtually all women with other forms of ALF. Only half of those with ALF during pregnancy appeared to have HELLP or AFLP. Morbidity and mortality for mother and fetus are strongly associated with etiology of liver failure.

Selection for Liver Transplantation: Indications and Evaluation.

Purpose of ReviewLiver transplantation is an important therapeutic option for patients with life-limiting liver disease, which may present in the form of acute liver failure, end-stage chronic liver disease, primary hepatic cancers, or inborn metabolic disorders. While significant strides have been made with respect to liver transplantation outcomes, the practice is constrained by an organ supply/demand mismatch. The purpose of this review, therefore, is to review the general indications and contraindication to liver transplantation, and to provide an overview of the transplant evaluation process. These considerations ultimately shape the specific criteria for patient selection, which will continue to evolve as means are developed to expand the donor pool, improve surgical techniques, broaden indications for safe transplant, and extend the lifetime of a graft.Recent FindingsSelected patients with unresectable hilar cholangiocarcinoma may be candidates for liver transplantation. Patients over 65 years may be transplant candidates if they possess a favorable comorbidity profile. Patients at body mass index extremes (≥ 40 or < 18.5) have increased post-transplant mortality and require nutritional evaluation.SummaryLiver transplantation may be life saving for patients with acute liver failure or end-stage liver disease. It is therefore critical for healthcare providers caring for patients with liver disease to be familiar with the general indications for transplantation and to know when it is appropriate or inappropriate to refer for transplant evaluation.

31-Year-Old Woman With Jaundice and Abdominal Pain

31-Year-Old Woman With Jaundice and Abdominal Pain

Transplant-free Survival in Chronic Liver Disease Presenting as Acute Liver Failure in Childhood.

In adults, the absence of a preexisting chronic liver disease (CLD) is required to diagnose acute liver failure (ALF). The pediatric classification does not consider this aspect, thus previous studies pooled together children with ALF and children with unknown CLD presenting with acute hepatic decompensation (ALF-CLD). We aimed to compare prevalence, features, and outcome of children with ALF-CLD to those with a proper ALF. Patients admitted between 1996 and 2017 because of ALF defined by Pediatric Acute Liver Failure criteria (raised transaminases, International Normal Ratio ≥2.0, no history of liver disease) were classified as ALF-CLD if diagnosed with autoimmune hepatitis, Wilson disease, Budd-Chiari syndrome, hepatitis B virus reactivation, inborn errors of metabolism. The others were classified as ALF. Seventy-four children (median age, 4 years; 1.0-8.8; male/female, 36/38] with ALF were found; 18 of <1 year of age were excluded. Fifty-six (median age, 6.6 years; 2.7-11.7; male/female, 23/33], 22 with ALF-CLD (autoimmune hepatitis, n = 14; Wilson disease, n = 6; inborn errors of metabolism, n = 2) and 34 with ALF (paracetamol overdose, n = 6; viral infections, n = 3; mushroom poisoning, n = 5; indeterminate, n = 20) were compared. In ALF-CLD, the median age at onset was higher, alanine aminotransferase, albumin, and International Normal Ratio levels were lower, splenomegaly, ascites, and cirrhosis were more common (all P < 0.01). On multivariate analysis, the diagnosis of ALF-CLD was an independent predictor of transplant-free survival (P = 0.006). In children, ALF-CLD is common, has peculiar features, and is associated with a favorable outcome. This study suggests the need to distinguish this entity from other forms of ALF in children.

Acute Liver Failure, Acute-On-Chronic Liver Failure, Hepatorenal Syndrome, Hepatopulmonary Syndrome and Portopulmonary Hypertension, Artificial Liver Support on the ICU

Background Acute hepatic dysfunction in the form of acute liver failure (ALF) or acute-on-chronic liver failure (ACLF) is a disease with a high risk of mortality and requires interdisciplinary intensive care. Aim This article explains the nomenclature, pathophysiology, prognosis and possible treatment options of ALF and ACLF, including the possibilities of extracorporeal liver support therapy at the point of liver transplantation (LTx). Method Narrative review with a selective literature review and representative case studies. Results/Corner Points ALF and ACLF may have several causes and are associated with high mortality. The causes of ALF must be accurately diagnosed because targeted treatment options are available. Both ALF and ACLF may require a liver transplantation for the patient's survival. For ALF and ACLF there are different criteria for decision-making on liver transplantation and graft allocation. For extracorporeal liver support therapy, two methods have been established (MARS [molecuar adsorbent recirculating system] and FPSA [fractionated plasma separation and adsorption] Prometheus®). Both approaches may have the potential to increase the probability of survival of patients with ALF or ACLF. In some cases they can be used for bridging to liver transplantation, in individual cases also for primary poison elimination, e.g. after Amatoxin ingestion. Both methods are not suitable for long-term therapy. Conclusion Acute liver failure (ALF) and acute on chronic liver failure (ACLF) are serious diseases with a high risk of mortality. Affected patients should receive immediate interdisciplinary intensive care in a (tertiary) centre with the aim to clarify the cause of the disease as well as possible treatment options with respect to available extracorporeal liver support therapy and liver transplantation.

Risk Factors and Outcomes of Acute Kidney Injury in Patients With Acute Liver Failure

Patients with acute liver failure (ALF) frequently develop renal dysfunction, yet its overall incidence and outcomes have not been fully assessed. We investigated the incidence of acute kidney injury (AKI) among patients with ALF, using defined criteria to identify risk factors and to evaluate its effect on overall outcomes. We performed a retrospective review of data from 1604 patients enrolled in the Acute Liver Failure Study Group, from 1998 through 2010. Patients were classified by the Acute Kidney Injury Network criteria, as well as for etiology of liver failure (acetaminophen-based, ischemic, and all others). Seventy percent of patients with ALF developed AKI, and 30% received renal replacement therapy (RRT). Patients with severe AKI had higher international normalized ratio values than those without renal dysfunction (P < .001), and a higher proportion had advanced-grade coma (coma grades 3 or 4; P < .001) or presented with hypotension requiring vasopressor therapy (P< .001). A greater proportion of patients with acetaminophen-induced ALF had severe kidney injury than of patients with other etiologies of ALF; 34% required RRT, compared with 25% of patients with ALF not associated with acetaminophen or ischemia (P < .002). Of the patients with ALF who were alive at 3 weeks after study entry, significantly fewer with AKI survived for 1year. Although AKI reduced the overall survival time, more than 50% of patients with acetaminophen-associated or ischemic ALF survived without liver transplantation (even with RRT), compared with 19% of patients with ALF attribute to other causes (P < .001). Only 4% of patients requiring RRT became dependent on dialysis. Based on a retrospective analysis of data from more than 1600 patients, AKI is common in patients with ALF and affects short- and long-term outcomes, but rarely results in chronic kidney disease. Acetaminophen-induced kidney injury is frequent, but patients have better outcomes than those with other forms of ALF.

Pathogenesis of Liver Injury in Acute Liver Failure

Acute liver failure (ALF) represents the most severe damage an organ can sustain and can lead to shock, coagulopathy, altered mentation, cerebral edema, renal failure, infection, and, ultimately, multiorgan failure. The US Acute Liver Failure Study Group (ALFSG; available at: acuteliverfailure.org), convened a meeting on October 17 and 18, 2011, and included clinical, translational and fundamental investigators to discuss the pathogenesis of acute hepatocyte injury, how it occurs, and its downstream effects. The ALFSG has, for the past 14 years, carefully collected detailed clinical information and bio-samples from roughly 2000 patients with ALF at 24 tertiary medical centers across the United States. This meeting sought to summarize our current understanding of the pathogenetic factors that drive acute liver injury. These included consideration of (1) the contribution of innate immunity to liver injury, (2) the role of cytokine release in perpetuating liver injury and causing multiorgan failure, (3) mechanisms of apoptosis in ALF, (4) alterations in signal transduction with a focus on the role of c-Jun N-terminal kinase (JNK), (5) the contribution of infection to the pathogenesis of ALF, (6) the emerging centrality of inflammasome and sterile inflammation in the pathogenesis of ALF, (7) systems biology approaches to integrating and ordering the wide array of seemingly massively perturbed effectors in ALF, (8) host genetics and its contribution to ALF susceptibility, including a consideration of the power of next generation sequencing tools as they relate to ALF, and (9) contribution of liver regeneration to counteraction of ALF. Finally, we considered novel therapeutic strategies for ALF based on these pathogenetic concepts.

Drug-induced acute liver failure: Results of a U.S. multicenter, prospective study

Acute liver failure (ALF) due to drug-induced liver injury (DILI), though uncommon, is a concern for both clinicians and patients. The Acute Liver Failure Study Group has prospectively collected cases of all forms of acute liver failure since 1998. We describe here cases of idiosyncratic DILI ALF enrolled during a 10.5-year period. Data were collected prospectively, using detailed case report forms, from 1198 subjects enrolled at 23 sites in the United States, all of which had transplant services. A total of 133 (11.1%) ALF subjects were deemed by expert opinion to have DILI; 81.1% were considered highly likely, 15.0% probable, and 3.8% possible. Subjects were mostly women (70.7%) and there was overrepresentation of minorities for unclear reasons. Over 60 individual agents were implicated, the most common were antimicrobials (46%). Transplant-free (3-week) survival was poor (27.1%), but with highly successful transplantation in 42.1%, overall survival was 66.2%. Transplant-free survival in DILI ALF is determined by the degree of liver dysfunction, specifically baseline levels of bilirubin, prothrombin time/international normalized ratio, and Model for End-Stage Liver Disease scores. DILI is an uncommon cause of ALF that evolves slowly, affects a disproportionate number of women and minorities, and shows infrequent spontaneous recovery, but transplantation affords excellent survival.

Acetaminophen‐related acute liver failure in the United States

Acetaminophen overdoses are the number one cause of acute liver failure (ALF) in the United States; they account for 50% of all cases of ALF and carry a 30% mortality. Nevertheless, acetaminophen is a highly successful product with sales easily exceeding a billion dollars annually. A narcotic-containing acetaminophen preparation is the number one generic drug sold in the United States. Historically, a strong association was claimed with alcohol as a co-factor and the accidental nature of ingestions was emphasized but the association with alcohol remains a matter of debate. Recently, a very reliable assay has been developed which detects a byproduct of the toxic reaction, acetaminophen-CYS adducts, protein-acetaminophen compounds that are released from damaged hepatocytes in similar fashion to aminotransferases. The US Acute Liver Failure Study Group is a multi-center network established to gather data prospectively on all forms of acute liver failure, a rare but often fatal condition. The group has data on more than 500 acetaminophen cases and described 275 of them in detail in a recent paper. The clinical pattern of presentation is somewhat different in the US compared with the UK, since nearly half are considered to be unintentional, the result of overuse of acetaminophen-containing compounds for pain relief, without suicidal intent. Despite the relatively good prognosis for acetaminophen overdoses, 30% die once acute liver failure occurs and this is the largest cause of death in the entire ALF registry.

False positive acetaminophen concentrations in patients with liver injury

BackgroundAcetaminophen toxicity is the most common form of acute liver failure in the U.S. After acetaminophen overdoses, quantitation of plasma acetaminophen can aid in predicting severity of injury. However, recent case reports have suggested that acetaminophen concentrations may be falsely increased in the presence of hyperbilirubinemia. MethodsWe tested sera obtained from 43 patients with acute liver failure, mostly unrelated to acetaminophen, utilizing 6 different acetaminophen quantitation systems to determine the significance of this effect. In 36 of the 43 samples with bilirubin concentrations ranging from 1.0–61.5 mg/dl no acetaminophen was detectable by gas chromatography-mass spectroscopy. These 36 samples were then utilized to test the performance characteristics of 2 immunoassay and 4 enzymatic–colorimetric methods. ResultsThree of four colorimetric methods demonstrated ‘detectable’ values for acetaminophen in from 4 to 27 of the 36 negative samples, low concentration positive values being observed when serum bilirubin concentrations exceeded 10 mg/dl. By contrast, the 2 immunoassay methods (EMIT, FPIA) were virtually unaffected. The false positive values obtained were, in general, proportional to the quantity of bilirubin in the sample. However, prepared samples of normal human serum with added bilirubin showed a dose–response curve for only one of the 4 colorimetric assays. ConclusionsFalse positive acetaminophen tests may result when enzymatic–colorimetric assays are used, most commonly with bilirubin concentrations >10 mg/dl, leading to potential clinical errors in this setting. Bilirubin (or possibly other substances in acute liver failure sera) appears to affect the reliable measurement of acetaminophen, particularly with enzymatic–colorimetric assays.

Molecular Adsorbent Recirculating System (MARS)

Introduction: Molecular adsorbent recirculating system (MARS) for albumin liver dialysis has been used as a bridge to liver transplantation in patients with fulminant hepatic failure (FHF). This review examines the available data on its clinical use, its technical aspects and present gaps in knowledge. Methods: Peer-reviewed journals and monographs on the subject were covered. Results: FHF is associated with elevation in various substances including bilirubin, ammonia, lactate, free fatty acids and aromatic amino acids. Some of these toxic metabolites, such as ammonia and bilirubin, are believed to be central to the clinical manifestations of hepatic encephalopathy and acute renal failure. MARS ameliorates both biochemical and clinical manifestations of FHF by removing both water-soluble and protein-bound toxins. Among the benefits of MARS is the attenuation of severe cerebral oedema and raised intracranial pressure found in FHF, possibly through reduction in high concentrations of these toxins. Although MARS has been shown to be useful in FHF, its clinical efficacy in subfulminant hepatic failure and less severe forms of acute liver failure (ALF) remains uncertain. The current literature also suggests that it may be beneficial to treat cases of acute-on-chronic liver failure (AoCLF). Deranged systemic chemistries can be similarly ameliorated, but the impact of MARS on the natural history of AoCLF remains uncertain. The difficulty lies in being able to accurately quantify residual liver function and variability in the course of acute intercurrent events. The broader question is whether MARS can favourably change the natural history of ALF and FHF. For this, large multi-centre, randomised controlled trials are needed. Furthermore, it is also uncertain how hepatic excretory-assist devices, such as MARS, compare with bio-artificial liver-assist devices which have both synthetic and excretory hepatic functions in ALF treatment in intensive care unit patients. Nevertheless, MARS has proven to be a valuable homeostatic tool that may be useful in restoring the biochemical and clinical status quo in much the same way that continuous veno-venous haemofiltration and mechanical ventilation provide temporary artificial organ support while these organs are in distress. This is the evolving concept of multi-organ support therapy. Other major unresolved issues with MARS include the timing of initiation of albumin liver dialysis, the clinical and/or biochemical parameters to base this decision on, the intensity of MARS therapy (continuous versus intermittent) and the saturation capacity of the system for different metabolites in intermittent MARS. Conclusions: MARS is an effective and, thus far, safe homeostatic tool in treating FHF. More studies are needed to delineate its role as a homeostatic tool in less severe forms of ALF, including that which occurs in multi-organ failure and in AoCLF. Other studies need to focus on the optimal timing of initiation of and intensity of MARS albumin liver dialysis. The larger issue is to compare MARS with bio-assist liver devices in treating the whole spectrum of ALF.

Management of acute liver failure.

Acute liver failure (ALF) constitutes a medical emergency requiring the prompt response of experienced clinicians. As it is relatively infrequent, and tends to evolve rapidly, decisions concerning care and prognosis must be made promptly. Determining etiology is vital since prognosis is largely determined by the cause of the illness, and the use of antidotes may be lifesaving. Estimating the severity of the liver failure is also important, because if liver transplantation is necessary, it must be undertaken quickly. No treatment thus far is better than good general care of the comatose patient, with attention to the special problems associated with acute liver failure: cerebral edema, infection, circulatory collapse. A number of issues have been debated recently, including use of prostaglandins and N-acetylcysteine for treatment of all forms of acute liver failure, and the use of extracorporeal liver assist machines, however, the efficacy of non-specific treatments for this complex syndrome has not been proven.