Acute Fulminant Liver Failure Research Articles

Bioavailable Trace Metals in Neurological Diseases.

Medical treatment in Wilson's disease includes chelators (D-penicillamine and trientine) or zinc salts that have to be maintain all the lifelong. This pharmacological treatment is categorised into two phases; the first being a de-coppering phase and the second a maintenance one. The best therapeutic approach remains controversial, as only a few non-controlled trials have compared these treatments. During the initial phase, progressive increase of chelators' doses adjusted to exchangeable copper and urinary copper might help to avoid neurological deterioration. Liver transplantation is indicated in acute fulminant liver failure and decompensated cirrhosis; in cases of neurologic deterioration, it must be individually discussed. During the maintenance phase, the most important challenge is to obtain a good adherence to lifelong medical therapy. Neurodegenerative diseases that lead to a mislocalisation of iron can be caused by a culmination of localised overload (pro-oxidant siderosis) and localised deficiency (metabolic distress). A new therapeutic concept with conservative iron chelation rescues iron-overloaded neurons by scavenging labile iron and, by delivering this chelated metal to endogenous apo-transferrin, allows iron redistribution to avoid systemic loss of iron.

Plasma Glutamine Concentrations in Liver Failure.

BackgroundHigher than normal plasma glutamine concentration at admission to an intensive care unit is associated with an unfavorable outcome. Very high plasma glutamine levels are sometimes seen in both acute and chronic liver failure. We aimed to systematically explore the relation between different types of liver failure and plasma glutamine concentrations.MethodsFour different groups of patients were studies; chronic liver failure (n = 40), acute on chronic liver failure (n = 20), acute fulminant liver failure (n = 20), and post-hepatectomy liver failure (n = 20). Child-Pugh and Model for End-stage Liver Disease (MELD) scores were assessed as indices of liver function. All groups except the chronic liver failure group were followed longitudinally during hospitalisation. Outcomes were recorded up to 48 months after study inclusion.ResultsAll groups had individuals with very high plasma glutamine concentrations. In the total group of patients (n = 100), severity of liver failure correlated significantly with plasma glutamine concentration, but the correlation was not strong.ConclusionLiver failure, regardless of severity and course of illness, may be associated with a high plasma glutamine concentration. Further studies are needed to understand whether high glutamine levels should be regarded as a biomarker or as a contributor to symptomatology in liver failure.

Rapid and high-efficiency generation of mature functional hepatocyte-like cells from adipose-derived stem cells by a three-step protocol.

The generation of functional hepatocytes is a major challenge for regenerative medicine and drug discovery. Here we show a method that facilitates generation of induced functional hepatocytes (iHeps) from adipose-derived stem cells (ADSCs) within 9 days. iHeps express hepatocytic gene programs and display functions characteristic of mature hepatocytes, including cytochrome P450 enzyme activity. Upon transplantation into mice with carbon tetrachloride (CCl4)-induced acute fulminant liver failure, iHeps restore the liver function and prolong survival. The work could contribute to the development of alternative strategies to obtain nonhepatic cell-derived mature hepatocytes with potential for biomedical and pharmaceutical applications.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0181-3) contains supplementary material, which is available to authorized users.

Experience of hematopoietic stem cell transplantation (HSCT) in the patients infected with either hepatitis B or hepatitis C virus

BackgroundHematopoietic stem cell transplantation (HSCT) is challenging in Hbs-Ag positive or HCV-Ab positive patients due to fear of delaying engraftment and transplant-related mortality (TRM). Very few data are published internationally till date. We had done HSCT (allogenic/autologus) of 19 hepatitis B and hepatitis C positive malignant and nonmalignant patients at our institute during the years 1999–2013. Design and methodsWe performed a retrospective analysis of the patients who were either hepatitis B or hepatitis C virus seropositive at the time of HSCT (n=19). All the positive patients (Hbs-Ag positive or HCV-Ab positive) who underwent HSCT for malignant or nonmalignant causes during 1999–2013 were selected. A total of 13 patients underwent autologus HSCT and 6 patients underwent allogenic HSCT. All the included patients had performance score 1, normal liver function test, and noninfectious state of Hbe antigen before HSCT. ResultsThe median age of the seropositive patients was 25 years (range 7–54); 16 patients were Hbs-Ag positive and 3 were HCV-Ab positive. Most common indication of HSCT was lymphoma (n=12), in which 7 patients were of Hodgkin disease and 5 patients were of non-Hodgkin disease (NHL). Three patients were acute myeloid leukemia, 2 patients of thalassemia major, 1 patient was of chronic myeloid leukemia-chronic phase, and 1 of multiple myeloma. We had used high-dose chemotherapy for induction with carmustine, etoposide, cytarabine, and melphalan (BEAM) for autologus HSCT and busulfan, cyclophosphamide (BUCY), busulfan, cyclophosphamide-thymoglobulin (BUCY-THYMO), and reduced intensity HSCT (RIST) for allogenic HSCT. All the patients underwent successful engraftment except one NHL patient. The median duration of neutropenia was 14 and 11 days in the allogenic HSCT and autologus HSCT, respectively. Median duration for engraftment of neutrophils was achieved on +Day 17 with 3 consecutive absolute neutrophil counts of more than 500cumm/dL. Median duration for engraftment of platelets was achieved on +Day 19 with 3 consecutive platelet counts of more than 50,000cumm/dL without any component support. Out of 6 allogenic HSCT patients, 4 developed graft versus host disease (GVHD) (2 – liver, 1 – colon, 1 – both skin and liver). Three patients died due to liver GVHD (2 – acute, 1 – chronic). Grades of GVHD in allogeneic HSCT patients are as follows, for liver (grade 3 in 2, grade 4 in 1), colon (grade 2 in 1), and skin (grade 2 in 1). Out of the 8 patients, one patient developed grade 3 veno-occlusive disease. Median at 100 days, 1-year overall survival (OS), and 5-year OS were 89.4%, 94.1%, and 81.1%, respectively. ConclusionsHSCT is a rugged job in Hbs-Ag positive or HCV-Ab positive patients due to more complications in the form of more neutropenia, GVHD, drug toxicity of chemotherapy, acute fulminant liver failure, fear of delaying of engraftment, and TRM. Careful evaluation before embarking on HSCT and intensive assessment against complications are warranted in Hbs-Ag positive and HCV-Ab positive recipients.

A Teenager Presents With Fulminant Hepatic Failure and Acute Hemolytic Anemia

A teenager was admitted to an outside hospital ED following an episode of melena. He had been complaining of intermittent abdominal pain, nausea, malaise, and easy fatigability for 2 months, with significant worsening of symptoms 2 weeks prior to this episode. He had no significant medical, surgical, or family history. On presentation at the outside ED, he was found to be profoundly icteric and encephalopathic. Initial laboratories suggested anemia, acute kidney injury, and acute liver failure, leading to a presumptive diagnosis of acute fulminant liver failure necessitating transfer to our institution.

Disseminated Herpes Simplex Virus with Fulminant Hepatitis.

Disseminated herpes simplex virus (HSV) is a rare cause of acute fulminant liver failure. We hereby present a case series of three patients with acute disseminated HSV with necrotizing hepatitis successfully treated with a week course of acyclovir. Early empiric administration of acyclovir therapy while awaiting confirmatory tests is critical in this potentially lethal disease.

Dengue: A rare differential of acute hepatic failure

Dengue is viral illness which manifests as high grade fever, myalgia, hemorrhagic manifestation and shock. Recently, dengue has been reported with rare presentations like encephalopathy, liver failure, and renal failure. We are presenting a case of acute fulminant liver failure due to dengue in which a 19-year-old previously healthy female who presented to us in the emergency department with complaints of high grade fever for past 3 days without chills and rigors, and altered sensorium past 1 day. The patient had icterus. On laboratory evaluation, her liver function tests were deranged while neuroimaging was normal. In view of presence of coagulopathy and altered sensorium, a diagnosis of dengue related acute hepatic failure was made. The patient was provided supportive and symptomatic management to which she responded and was discharged a few days later and is on regular follow-up.

From bedside to bench and back again—molecular mechanisms in acute liver failure

From bedside to bench and back again—molecular mechanisms in acute liver failure

Successful treatment of Acute Fulminant Liver Failure due to Hepatitis B virus with Entecavir in patients with contra-indications to liver transplant

There are no randomized clinical trials on efficacy of Entecavir in Fulminant Hepatic Failure (FHF) due to Hepatitis B Virus (HBV). Definitive treatment of FHF remains Liver Transplant. However, availability of cadaveric donor organs is limited, and many of the patients with FHF may not be candidates for Liver Transplantation. There are only few case reports on beneficial effects of Entecavir in FHF due to HBV. We present 2 cases of FHF due to HBV. Both patients had severe liver cell damage among which one was immunocompromised. Transaminases were elevated up to 200 times the normal. Both were not transplant candidates, and were successfully treated with Entecavir resulting in significant clinical and transaminases improvement within 7 days of starting Entecavir. DOI: http://dx.doi.org/10.3126/jaim.v2i2.8780 Journal of Advances in Internal Medicine 2013;02(02):67-70

Cerebral microdialysis reflects the neuroprotective effect of fractionated plasma separation and adsorption in acute liver failure better and earlier than intracranial pressure: a controlled study in pigs

BackgroundCerebral edema is a well-recognized and potentially fatal complication of acute liver failure (ALF). The effectiveness of treatments that address intracranial hypertension is generally assessed by measuring intracranial pressure (ICP). The aim of this study was to determine the role of cerebral microdialysis in monitoring the efficacy of fractionated plasma separation and adsorption (FPSA) treatment for ALF. We hypothesized that in ALF cerebral microdialysis reflects the benefits of FPSA treatment on cerebral edema before ICP.MethodsA surgical resection model of ALF was used in 21 pigs. We measured plasma ammonia concentration, brain concentrations of glucose, lactate, pyruvate, glutamate and glutamine, and ICP. Animals were randomized into three groups: in one group eight animals received 6 hours of FPSA treatment 2 hours after induction of ALF; in another group 10 animals received supportive treatment for ALF only; and in the final group three underwent sham surgery.ResultsThe ICP was significantly higher in the ALF group than in the FPSA group 9 hours after surgery. The lactate/pyruvate (L/P) ratio was significantly lower in the FPSA group than the ALF group 5 hours after surgery, before any significant difference in ICP was detected. Indeed, significant changes in the L/P ratio could be observed within 1 hour of treatment. Glutamine levels were significantly lower in the FPSA group than the ALF group between 6 hours and 10 hours after surgery.ConclusionsBrain lactate/pyruvate ratio and concentration of glutamine measured by cerebral microdialysis reflected the beneficial effects of FPSA treatment on cerebral metabolism more precisely and rapidly than ICP in pigs with fulminant ALF. The role of glutamine as a marker of the efficacy of FPSA treatment for ALF appears promising, but needs further evaluation.

MARS therapy, the bridging to liver retransplantation — Three cases from the Hungarian liver transplant program

Besides orthotopic liver transplantation (OLT) there is no long-term and effective replacement therapy for severe liver failure. Artificial extracorporeal liver supply devices are able to reduce blood toxin levels, but do not replace any synthetic function of the liver. Molecular adsorbent recirculating system (MARS) is one of the methods that can be used to treat fulminant acute liver failure (ALF) or acute on chronic liver failure (AoCLF). The primary non-function (PNF) of the newly transplanted liver manifests in the clinical settings exactly like acute liver failure. MARS treatment can reduce the severity of complications by eliminating blood toxins, so that it can help hepatic encephalopathy (HE), hepatorenal syndrome (HRS), and the high rate mortality of cerebral herniation. This might serve as a bridging therapy before orthotopic liver retransplantation (reOLT). Three patients after a first liver transplantation became candidate for urgent MARS treatment as a bridging solution prior to reOLT in our center. Authors report these three cases, fo-cusing on indications, MARS sessions, clinical courses, and final outcomes.

Human Herpesvirus 6, 7 and 8 in Solid Organ Transplantation

Human Herpesvirus 6, 7 and 8 in Solid Organ Transplantation

Hepatotoxicity Induced by Cyproteron Acetate in the Prostate Carcinoma Treatment – a Case Report

Cyproterone acetate is associated with hepatotoxicity during prostate cancer treatment. The information about its toxic mechanism and risk factors is limited, based on pharmacovigilance reports and published case reports only. We describe a case of a patient treated with cyproterone acetate (200 mg/day for 9 months) for adenocarcinoma of the prostate. The 75-year-old patient was admitted for the development of jaundice and loss of appetite to the T. Bata Regional Hospital in Zlin, Czech Republic. Laboratory values ALT 994 U/l, AST 1,046 U/l, ALP 193 U/l, GGT 1,128 U/l, bilirubin 177 µmol/l, conjugated bilirubin 138 µmol/l, albumin 26 g/l, Quick time INR 1.23. The concomitant medication included atorvastatin 10 mg daily. Clinical and laboratory outcomes showed acute fulminant liver failure caused pre-dominantly by hepatocellular damage. Hepatotoxicity induced by cyproteron acetate was diagnosed after exclusion of other causes, with a gradual improvement after discontinuation of the respective drug treatment. All patients treated with cyproteron acetate for prostate cancer are in risk for the development of liver failure and therefore should be monitored and well educated. More information is needed to sufficiently identify risk factors and explain mechanism of damage.

Acute Fulminant Form of Budd–Chiari Syndrome Secondary to Inferior Vena Cava Sarcoma: a Case Report and Review of the Literature

Budd–Chiari syndrome (BCS) is a rare syndrome, which results from partial or complete obstruction of hepatic venous outflow at the level of hepatic venules, major hepatic veins, or the intrahepatic portion of the inferior vena cava (IVC) up to its junction with the right atrium [1–7]. This definition does not include sinusoidal obstruction syndrome (previously known as veno-occlusive disease, which affects central or sublobular hepatic veins), right-sided heart failure, or pericardial disease which may closely mimic BCS [1–6]. Budd–Chiari syndrome occurs more often in young and middle-aged women in their mid-30s [1, 5, 6, 8]. Abdominal pain, ascites, hepatomegaly, and jaundice are the most common symptoms [2, 4–7]. BCS may present as a chronic (42– 65 %); subacute or acute (28–41 %); or less commonly, fulminant form (7–8 %); or asymptomatic (3–6 %), depending on the extent and rapidity of hepatic venous outflow obstruction and the development of collaterals [2, 4, 5, 7]. The main etiology of this disease is the various prothrombotic disorders including primary myeloproliferative disorders, especially polycythemia vera (overt or occult); deficiencies or gene mutations in one or more coagulation factors; antiphospholipid antibody syndrome; and paroxysmal nocturnal hemoglobinuria [1, 2, 5–9]. Other etiologies include abdominal trauma, abdominal surgery, liver infections such as an abscess; inflammatory bowel disease; sarcoidosis; malignancy, especially hepatocellular and renal cell carcinomas; or vasculitis, especially Behcet’s disease [2–8]. In addition, pregnancy, peripartum period, and oral contraceptive use have been frequently identified as precipitating factors [1, 3–5, 8, 9]. Although coexistence of more than one thrombogenic risk factor is found in many patients with BCS, idiopathic BCS still accounts for 10–20 % [1–3, 5, 8–10]. Any lesions in the inferior vena cava such as membranous webs (more often in Asia and South Africa), thrombosis, stenosis, and extrinsic or intrinsic compression may cause BCS [2, 4–7]. Sarcomas in the IVC have been reported as a cause of Budd–Chiari syndrome. The reported cases of Budd–Chiari syndrome secondary to IVC sarcomas were in chronic, subacute, or acute forms; but no case of fulminant form has been recorded in the literature. We are presenting in this paper a case of an elderly man who presented with acute fulminant liver failure and died within 4 days of hospitalization and was found to have an IVC sarcoma with extensive thrombosis on autopsy. We then review the literature.

The ROS Scavenger, NAC, Regulates Hepatic Vα14iNKT Cells Signaling during Fas mAb-Dependent Fulminant Liver Failure

Uncontrolled systemic activation of the immune system is an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In this study, we demonstrate that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished Fas mAb-induced FLF through suppression of Vα14iNKT cell activation, IFN-γ signaling, apoptosis and nitrotyrosine formation in liver. In addition, enrichment of the liver with GSH due to Vα14iNKT cells deficiency, induced an anti-inflammatory response in the liver of Jα18−/− mice that inhibited apoptosis, nitrotyrosine formation, IFN-γ signaling and effector functions. In summary, we propose a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating Th1 signaling in Vα14iNKT cells to promote the development of FLF. Therefore, our study provides critical new insights into how NAC, a ROS scavenger, regulates Th1 signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.

Endogenous ROS Regulates Vα14iNKT Cells Signaling during Agonistic Fas mAb-dependent Fulminant Liver Failure (176.3)

Abstract Current theories recognize uncontrolled systemic activation of the immune system as an early initiating event that leads to development of acute fulminant liver failure (FLF) in mice after treatment with agonistic Fas mAb. In the present study, we identify a novel and previously unrecognized pro-inflammatory and pro-apoptotic role for endogenous ROS in stimulating signaling in IFN-γ-expressing Vα14iNKT cells in a pSTAT-1/T-bet dependent manner to promote the development of FLF. Specifically, we show that treatment of mice with N-acetylcysteine (NAC), an ROS scavenger and glutathione (GSH) precursor, almost completely abolished IFN-γ signaling and nitrosative stress in Vα14iNKT cells. Conversely, fortification of the antioxidant, GSH, in the liver due to Vα14iNKT cells deficiency, induces anti-inflammatory responses to prevent/limit the development of FLF and hepatic apoptosis in Jα18−/− mice through suppression of IFN-γ signaling and effector functions. This study provides critical new insights into how ROS regulates IFN-γ signaling in intrahepatic Vα14iNKT cells to impact inflammatory and pathological responses.

Next‐generation Sequencing Facilitates the Diagnosis in a Child With Twinkle Mutations Causing Cholestatic Liver Failure

Next‐generation Sequencing Facilitates the Diagnosis in a Child With Twinkle Mutations Causing Cholestatic Liver Failure

Segmental ABO‐incompatible liver graft from a donor after cardiac death in neonatal acute liver failure

Segmental liver grafts from DCD in pediatric LT have been safely used even in acute liver failure situations. Furthermore, despite the risk of antibody-mediated acute rejection, some studies have also demonstrated the safety of ABO incompatible LT in infants. The use of such grafts can be beneficial by reducing the time on the transplant waiting list but they are more susceptible to initial dysfunction and there is a lack of enthusiasm to consider their use especially for an emergency LT as a life-saving procedure. In this short article, we describe the use and successful outcome in a neonate with fulminant acute liver failure secondary to neonatal hemochromatosis who received an ABO-incompatible reduced-size DCD graft.

Tolerogenic dendritic cells and myeloid-derived suppressor cells: Potential for regulation and therapy of liver auto- and alloimmunity

Organ transplantation is now established as an accepted treatment for end-stage liver disease, acute fulminant hepatic liver failure and hepatocellular carcinoma. While early graft acceptance rates have increased markedly due to improved immunosuppressive drug regimens, rates of late graft failure remain largely unchanged. Recent findings suggest that in addition to alloimmunity, chronic rejection of liver allografts may also reflect de novo autoimmune hepatitis or recurrence of pre-existing hepatic autoimmune disease. Dendritic cell (DC)- based therapy is a promising experimental approach to promotion of transplant tolerance and the treatment of autoimmune diseases. Newly emerging evidence also demonstrates the potential efficacy of myeloid-derived suppressor cells (MDSC) in the antigen (Ag)-specific regulation of T-cell responses. Herein, we discuss current understanding of liver autoimmunity post-transplantation, along with current approaches for the development of tolerogenic DC, and the potential use of MDSC for the development of stable, Ag-specific tolerance.

Impact of Thrombocytopenia on Survival of Baboons with Genetically Modified Pig Liver Transplants: Clinical Relevance

A lack of deceased human donor livers leads to a significant mortality in patients with acute-on-chronic or acute (fulminant) liver failure or with primary nonfunction of an allograft. Genetically engineered pigs could provide livers that might bridge the patient to allotransplantation. Orthotopic liver transplantation in baboons using livers from alpha1,3-galactosyltransferase gene-knockout (GTKO) pigs (n = 2) or from GTKO pigs transgenic for CD46 (n = 8) were carried out with a clinically acceptable immunosuppressive regimen. Six of 10 baboons survived for 4-7 days. In all cases, liver function was adequate, as evidenced by tests of detoxification, protein synthesis, complement activity and coagulation parameters. The major problem that prevented more prolonged survival beyond 7 days was a profound thrombocytopenia that developed within 1 h after reperfusion, ultimately resulting in spontaneous hemorrhage at various sites. We postulate that this is associated with the expression of tissue factor on platelets after contact with pig endothelium, resulting in platelet and platelet-peripheral blood mononuclear cell(s) aggregation and deposition of aggregates in the liver graft, though we were unable to confirm this conclusively. If this problem can be resolved, we would anticipate that a pig liver could provide a period during which a patient in liver failure could be successfully bridged to allotransplantation.