Management Of Acute Liver Failure Research Articles

Acute Liver Failure Due to Suspected Herpes Simplex Virus Hepatitis: A Call to Consider Empirical Acyclovir in High-risk Cases

Background: Although rare, Herpes simplex virus (HSV-2) is a fatal cause of acute liver failure (ALF) if unrecognized or with delayed treatment. The accepted protocol for empirical management of ALF has a well-defined role for N-acetylcysteine (NAC), but none for antivirals. We have encountered three HSV ALF cases recently, with varying clinical courses, compelling us to highlight this unresolved issue. Case: A 25-year-old man with sickle trait presented with 1-week of fever, headache and myalgia. He claimed sexual monogamy and no medication/drug use. On admission, he was tachycardic, hypotensive, oriented mentally, with tender hepatomegaly and abdomen and lymphadenopathy in axilla/groin. Labwork suggested mild renal insufficiency, low platelets, leukopenia, coagulopathy (INR 2.4) with marked transaminasemia (AST/ALT 4009/3504), mild hyperbilirubinemia (1.8mg/dL) and LDH 4400, but negative Tylenol, salicylate and viral hepatitis panel and imaging unrevealing of cause. Patient was initiated on NAC protocol, but worsened hemodynamically, clinically and biochemically, required intubation, DIC management but eventually died due to multi-organ failure. While all serologies were negative, HSV-2 came positive (titer >1x108). Histopathology on autopsy showed HSV-2 (Fig 1).Figure 1Another woman, aged 30 years was admitted with right upper quadrant pain, headache, fever, increased transaminases in hepatocellular pattern (AST/ALT 1721/975), Hyperbilirubinemia (2.3) and LDH 3930, leukopenia, low platelets, high INR (2). The patient was initiated on NAC protocol, additionally started on empirical Acyclovir given her high-risk sexual behavior, while awaiting serologies. On day 4 of admission transaminases started to improve (AST/ALT 303/567) and so did the coagulopathy. Her HSV-2 titers resulted positive on day 3 (titer >1x10 8). Liver biopsy confirmed HSV-2 hepatitis with Cowdry type A bodies. The patient had uneventful recovery after completion of antivirals. Discussion: Mortality with HSV hepatitis progressing to ALF is high (˜90%). Diagnosis is often delayed (HSV PCR), or false negative (serology) or based on Tzank smear (only if rash is present) or liver biopsy (risky because of coagulopathy). Patients can have maculopapular rash, leukopenia, thrombocytopenia, but fever and anicteric hepatitis are the hallmark features of HSV hepatitis, which if seen should serve as red flags. Based on our experiences, we urge clinicians to remain cognizant in young ALF patients to consider Acyclovir, which may be life-saving. This further raises a debate if Acylovir dose should be included as a part of ALF management protocol, while awaiting serologies, especially in high-risk patients with above mentioned suggestive clinical features.

Current management of acute liver failure.

Acute liver failure (ALF) is a rare but life-threatening systemic disorder. Survival rates with or without emergency liver transplantation (ELT) are increasing. The benefit of ELT in some cases has been questioned and the potential for survival with medical management alone is changing our approach to the management of this disease. Survival rates for all causes of ALF are increasing because of improvements in the care of the critically ill patient. A multifactorial approach involving support of respiratory, circulatory and renal function together with measures to avoid intracranial hypertension, metabolic disequilibrium and sepsis are required. For those who do not respond to these measures or specific antidotes, the selection methods for those likely to benefit from transplantation remain imperfect and novel methods based on the prediction of hepatic regeneration are required. For patients with ALF secondary to acetaminophen overdose, some experts believe a randomized controlled trial is required to find those most likely to benefit from ELT. ALF remains a life-threatening condition with a high mortality rate requiring prompt support of multiorgan failure. Historical listing criteria for ELT are being questioned and improvement in medical management offers the option of continued improvements in transplant-free survival.

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.

Liver transplantation in acute-on-chronic liver failure: lessons learnt from acute liver failure setting.

Acute-on-chronic liver failure is a clinical entity with high risk of mortality. These patients can have severe liver dysfunction complicated with multiple organ failure. Liver transplantation is the definitive treatment for these patients. Literature regarding management of acute liver failure with special emphasis on liver transplantation was reviewed. Lessons learnt from the management of patients with acute liver failure which could be extrapolated to the management of patients with acute-on-chronic liver failure are discussed. Significant improvement in outcomes of acute liver failure has been reported across the world. Several aspects in transplantation for acute liver failure were found to be relevant to the management of acute-on-chronic liver failure. These include defining criteria to identify patients needing early liver transplantation, prioritizing patients with acute liver failure on the waiting list, defining when to abandon transplantation in acute liver failure, emphasis on graft quality and the need for a multi-disciplinary approach to manage multiple organ dysfunction. Useful lessons can be learnt from the progress made in the management of acute liver failure and these can be extrapolated to the management of patients with acute-on-chronic liver failure.

Recent advances in management of acute liver failure.

Acute liver failure (ALF) is a life-threatening illness, where a previously normal liver fails within days to weeks. Sudden loss of synthetic and detoxification function of liver results in jaundice, encephalopathy, coagulopathy, and multiorgan failure. The etiology of ALF varies demographically. The mortality of ALF is as high as 40–50%. The initial care of patients with ALF depends on prompt recognition of the condition and early detection of etiology. Management includes intensive care support, treatment of specific etiology if present and early detection of candidates for liver transplantation. Liver transplantation remains the only therapeutic intervention with proven survival benefit in patients with irreversible ALF. Living related liver transplantation, auxiliary liver transplantation, and ABO-incompatible liver transplantation are coming up in a big way. Liver assist devices and hepatocyte transplant remain experimental and further advances are required. Public health measures to control hepatitis A, B, E, and drug-induced liver injury will reduce the incidence and mortality of ALF.

N-acetyl cysteine in the management of rodenticide consumption - life saving?

Rodenticide is a commonly ingested poison in India. Many rodenticides contain hepatotoxic agents and can cause acute liver failure (ALF). There is no antidote for rodenticide poison, and consumption is often fatal. The Role of N acetyl cysteine (NAC) in acetaminophen induced ALF is well established. Additionally some studies have shown that it may be useful in non-acetaminophen induced ALF also. Cases with ALF secondary to suicidal rodenticide consumption have been reported, and some reports show that NAC is beneficial in these cases. Our study was a retrospective analysis of patients admitted with rodenticide consumption, comparing outcomes in those receiving standard of care management and those who were treated with NAC also. Case sheets of all inpatients of a tertiary medical college hospital between January 2010 and December 2012 admitted with an alleged history of rodenticide consumption were surveyed and data was extracted and analysed. Patients were analysed with respect to age, sex, mode of presentation, interval between consumption of rodenticide and starting NAC; the outcome in patients treated with acetylcysteine was compared to outcomes in those not treated with acetylcysteine A total of 100 patients were studied out of which 18 died. Sixteen of the deaths were in patients who had not been treated with NAC. We found that patients who had received NAC had lower mortality, lower peak values of AST/ALT, and shorter hospital stay. NAC may have a role in the management of ALF associated with rodenticide consumption.

Alginate microencapsulated hepatocytes optimised for transplantation in acute liver failure.

Background and AimIntraperitoneal transplantation of alginate-microencapsulated human hepatocytes is an attractive option for the management of acute liver failure (ALF) providing short-term support to allow native liver regeneration. The main aim of this study was to establish an optimised protocol for production of alginate-encapsulated human hepatocytes and evaluate their suitability for clinical use.MethodsHuman hepatocyte microbeads (HMBs) were prepared using sterile GMP grade materials. We determined physical stability, cell viability, and hepatocyte metabolic function of HMBs using different polymerisation times and cell densities. The immune activation of peripheral blood mononuclear cells (PBMCs) after co-culture with HMBs was studied. Rats with ALF induced by galactosamine were transplanted intraperitoneally with rat hepatocyte microbeads (RMBs) produced using a similar optimised protocol. Survival rate and biochemical profiles were determined. Retrieved microbeads were evaluated for morphology and functionality.ResultsThe optimised HMBs were of uniform size (583.5±3.3 µm) and mechanically stable using 15 min polymerisation time compared to 10 min and 20 min (p<0.001). 3D confocal microscopy images demonstrated that hepatocytes with similar cell viability were evenly distributed within HMBs. Cell density of 3.5×106 cells/ml provided the highest viability. HMBs incubated in human ascitic fluid showed better cell viability and function than controls. There was no significant activation of PBMCs co-cultured with empty or hepatocyte microbeads, compared to PBMCs alone. Intraperitoneal transplantation of RMBs was safe and significantly improved the severity of liver damage compared to control groups (empty microbeads and medium alone; p<0.01). Retrieved RMBs were intact and free of immune cell adherence and contained viable hepatocytes with preserved function.ConclusionAn optimised protocol to produce GMP grade alginate-encapsulated human hepatocytes has been established. Transplantation of microbeads provided effective metabolic function in ALF. These high quality HMBs should be suitable for use in clinical transplantation.

Update in intensive care medicine

Acute liver failure (ALF) is associated with significant mortality. Although specific therapies may be available, the evidence base for these and for many aspects of supportive therapy has been slow to emerge. Liver transplantation continues to be a cornerstone of treatment, and the management of ALF, therefore, remains the domain of the specialist ICU. The purpose of this review is to identify and critically appraise the recent evidence and to inspire those who strive to provide excellent care for a difficult patient cohort. Effective vaccination programmes have reduced the incidence of viral hepatitis in Europe and the USA. Spontaneous survival has improved in causes such as acetaminophen toxicity. Early recognition and proactive intensive management have reduced the incidence of early neurological death. The use of artificial liver assist devices and therapeutic plasma exchange is controversial, yet intriguing, with some early evidence of efficacy. Increasingly sophisticated prognostication tools are evolving, which have the potential to transform clinical decision-making. A review of the indications for transplantation in acetaminophen toxicity is overdue. The use of therapeutic plasma exchange and extracorporeal liver support in ALF requires further investigation.

Management of acute liver failure in infants and children: Consensus statement of the pediatric gastroenterology chapter, Indian academy of pediatrics

Selected members were requested to prepare guidelines on specific issues, which were reviewed by two other members. These guidelines were then incorporated into a draft statement, which was circulated to all members. On 17th December 2011, Kunwar Viren Oswal round table conference was organized by the Apollo Center for Advanced Pediatrics, Indraprastha Apollo Hospital, New Delhi and the Sub-specialty Chapter of Pediatric Gastroenterology, Indian Academy of Pediatrics. Presentations, ensuing discussions, and opinions expressed by the participants were incorporated into the final draft. To formulate comprehensive evidence based guidelines for management of acute liver failure in India. Viral hepatitis is the leading cause of acute liver failure (ALF) in India. Search for metabolic etiology, particularly in infants and neonates, and in apparently idiopathic cases needs to be done. Planning for early transfer is important as the risks involved with patient transport may increase or even preclude transfer at later stages. Management should be in an intensive care setting in select situations. There is currently insufficient evidence to routinely prescribe branched-chain amino acids, non-absorbable antibiotics or lactulose. Group recommends use of N-acetyl cysteine routinely in patients with ALF. Administration of antibiotics is recommended where infection is present or the likelihood of impending sepsis is high. Enteral nutrition is preferred to parenteral nutrition. Protein restriction is not recommended. An international normalized ratio >4 or Factor V concentration of <25% are the best available criteria for listing for liver transplantation. Overall 40-50% of ALF patients survive without transplantation. Survival in patients fulfilling criteria for liver transplantation and not transplanted is 10-20%. Liver transplantation is a definite treatment for ALF with high one-and five-year survival rates.

625 Development and Pilot of a Checklist for Management of Acute Liver Failure in the Intensive Care Unit

625 Development and Pilot of a Checklist for Management of Acute Liver Failure in the Intensive Care Unit

Organ Sharing in the Management of Acute Liver Failure

BackgroundLiver transplantation (OLT) for acute liver failure (ALF) is associated with high morbidity and mortality rates in the early posttransplant course. An efficient organ-sharing organization may grant favorable results. MethodsThis is a retrospective analysis of prospectively collected data on patients wait listed for ALF at a single center. Patients were listed for OLT when matching King's College Criteria. Based on patients' clinical status, ABO-incompatible grafts were used. ResultsFrom January 2001 to December 2010, 37 patients were wait listed for ALF. Two patients were de-listed (5.4%) for improvement of their clinical conditions; two patients (5.4%) died on the list and 33 (89.2%) underwent OLT. Among these latter, 21 (63.6%) were Italian and 12 (36.4%) were foreign citizens, with four referred from their home country on the basis of international agreements on ALF management. Donors were procured in our region in 10 cases (30.3%), nationally in 22 (66.6%), and outside Italy in 1 (3.1%). Mean time from wait listing to OLT was 1 day (range 0–6), and seven patients received an ABO-incompatible graft. Graft and patient survivals at 1 month, 1 year, and 3 years were 78.8%, 72.7%, 66.5%, and 81.8%, 75.8%, and 72.7%, respectively. Five patients underwent retransplantation: two on postoperative day (POD) 2 for primary nonfunction of the liver graft, two on POD 8 and 95 for hepatic artery thrombosis, and one at 18 months for nonanastomotic biliary stenosis. ConclusionsPrompt referral to a OLT center and efficient organ-sharing system play a fundamental role in optimizing the outcome of the patient with ALF. Development of international organ exchange programs might further improve the results for this category of patients. In very selected cases, ABO-incompatible grafts may be a valuable resource.

Advances in the management of acute liver failure

Acute liver failure (ALF) is an uncommon but dramatic clinical syndrome characterized by hepatic encephalopathy and a bleeding tendency due to abrupt loss of liver function caused by massive or submassive liver necrosis in a patient with a previously healthy liver. The causes of ALF encompass a wide variety of toxic, viral, metabolic, vascular and autoimmune insults to the liver, and identifying the correct cause can be difficult or even impossible. Many patients with ALF develop a cascade of serious complications involving almost every organ system, and death is mostly due to multi-organ failure, hemorrhage, infection, and intracranial hypertension. Fortunately, the outcome of ALF has been improved in the last 3 decades through the specific treatment for the disease of certain etiology, and the advanced intensive care management. For most severely affected patients who fail to recover after treatment, rapid evaluation for transfer to a transplantation center and consideration for liver transplantation is mandatory so that transplantation can be applied before contraindications develop. This review focuses on the recent advances in the understanding of various contributing etiologies, the administration of etiology-specific treatment to alleviate the liver injury, and the management of complications (e.g., encephalopathy, coagulopathy, cardiovascular instability, respiratory failure, renal failure, sepsis and metabolic disturbance) in patients with ALF. Assessment of the need for liver transplantation is also presented.

Preterm Delivery in a Parturient Candidate for Emergency Liver Transplantation After Hepatitis B Virus Infection Related Fulminant Liver Failure

This case shows the development of fulminant hepatic failure due to acute hepatitis B virus infection in a multipara (32(nd) week of gestation) candidate for an emergency liver transplantation. Preterm labor began and she delivered a preterm healthy male baby. Postpartum, there were complications including a massive hemorrhage that was managed adequately. We also reviewed the literature regarding causes, complications, and management of acute liver failure during pregnancy and labor.

Organ Sharing in the Management of Acute Liver Failure

Organ Sharing in the Management of Acute Liver Failure

Bone marrow mononuclear cell transplant therapy in mice with CCl4-induced acute liver failure

Stem cell transplantation has theoretical potential for the treatment of certain liver diseases. However, the use of bone marrow mononuclear cells as a therapy for liver disease has received little attention. The present study was to examine whether bone marrow mononuclear cells might be useful in the management of acute liver failure in an animal model. MATERIALS AND METHOTS: Bone marrow mononuclear cells were harvested from BALB/c mice and then labeled with the fluorescent dye PKH26. The labeled cells were subsequently infused into the tail veins of mice in which hepatic injury had been induced by CCl4 toxicity. After transplantation, the labeled cells in the liver were studied by fluorescent microscopy, and the levels of proliferating cell nuclear antigen and albumin were quantified in bone marrow mononuclear cell-treated and untreated groups. Serum aminotransferase activity was also monitored at various time points post-liver injury. Transplanted bone marrow mononuclear cells labeled with PKH26 were found to populate the damaged liver around the portal and centrolobular regions, and they appeared to differentiate into albumin-producing hepatocyte-like cells. Animals that received bone marrow mononuclear cells also showed a trend toward improved liver enzymes as well enhanced survival rates, relative to controls. These findings suggest that systemically delivered bone marrow mononuclear cells may relocate to and be retained by the injured liver; transplantation of bone marrow mononuclear cells showed an overall beneficial effect in a murine model of acute liver failure.

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.

Liver transplantation for acute liver failure

Liver transplantation is now an integral part of the management of acute liver failure. The challenge for clinicians is to select the appropriate candidates with a combination of need and high likelihood of benefiting from the transplant. This is achieved through a combination of prognostic modelling and ongoing clinical evaluation. Although the outcomes after liver transplantation are good the survival rates do not quite match those achieved after elective transplantation.

Maintenance of rat hepatocytes under inflammation by coculture with human orbital fat-derived stem cells

Preservation of hepatocyte functions in vitro will undoubtedly help the management of acute liver failure. The coculture system may be able to prevent functional decline of hepatocytes. It has already been shown that hepatocytes, when cocultured with bone marrow mesenchymal stem cells, could undergo long-term culture in vitro without loss of functions. In this study, human orbital fat-derived stem cells were isolated and cocultured with rat hepatocytes. When treated with serum from an acute liver failure patient, rat hepatocyte monoculture showed reduction of cell viability and loss of liverspecific functions. However, rat hepatocytes in the coculture system were still able to secret albumin and synthesize urea. IL-6 was significantly elevated in the coculture of rat hepatocyte with orbital fat-derived stem cells, and it might be the key immunoregulator which protects rat hepatocytes against inflammation. Our data confirmed that orbital fat-derived stem cells, or other adipose tissue-derived stem cells, are an ideal candidate to support rat hepatocyte functions in vitro.

P76 Meta-analysis of published evidence supports use of King's College criteria over model for end stage liver disease in outcome prediction in acute liver failure

IntroductionOutcome prediction is a cornerstone of the management of Acute Liver Failure (ALF) where Emergency Liver Transplantation (ELT) is indicated for predicted death. The King's College Criteria (KCC) for paracetamol...

Epidemiology of liver failure

The etiology of fulminant hepatitis varies in different countries and at different times. The main causes of fulminant hepatitis are viruses, paracetamol, drugs (other than paracetamol), poisons and 15-30% remained of undetermined origin. The prevalence of these etiologies varies according to the geographic region and has changed over the past 10 years. Paracetamol has now overtaken viruses (particularly hepatitis B virus) as the leading cause of fulminant hepatitis. Establishing the cause of fulminant hepatitis is an important step in the management of acute liver failure, so that specific therapy can be initiated and any contraindications to liver transplantation be eliminated.