Features Of Acute Liver Failure Research Articles

Pathophysiological features of acute liver failure caused by cholestasis [

Acute liver failure is a syndrome that occurs in 20-59% of patients with liver pathology and is one of the main causes of death in 40% of patients with mechanical jaundice of benign origin and in more than 70% of cases of tumor obstruction of the biliary tract and cancer of caput pancreas. In most cases, the syndrome is a consequence of acute liver damage (viral or drug-induced). Still, it can occur with longterm obstructive jaundice, be the first manifestation of Wilson’s disease, autoimmune chronic hepatitis, or superinfection of the hepatitis D virus against the background of chronic hepatitis B. The aim of the work was to study the pathophysiological features of the development of acute liver failure in patients with bile outflow disorders. The pathogenesis of acute liver failure caused by cholestasis is based on the damage and death of hepatocytes due to impaired blood circulation in the liver, as well as the toxic effect on the parenchyma of both the etiological factors themselves and their metabolites. The first week from the onset of symptoms is very important and usually accompanied by a systemic inflammatory response syndrome with significant consequences. At the same time, the main factors influencing the results of treatment of patients at different points in time are the combination of the critical functional reserve of the liver and the nature and severity of liver damage. In the case of the development of a systemic inflammatory response syndrome, there is a further increase in inflammation, which has a systemic nature and leads to the failure of other organs. Under these circumstances, understanding the pathophysiological features of the course of acute liver failure makes it possible to carry out the necessary diagnostic measures on time and offer appropriate therapy.

Prediction of severity of dengue infection in children based on hepatic involvement.

To assess the spectrum of hepatic involvement in children with dengue fever (DF) and prediction of severity of dengue infection by early detection of elevated liver enzymes. This prospective observational study was conducted at a tertiary care hospital from June 2019 to September 2019. Children admitted with DF were included. Severity of DF was graded as dengue without warning sign (DNWS), with warning sign (DWS), and severe dengue fever (SDF) according to WHO criteria. Liver injury (LI) was defined as alanine aminotransferase (ALT) more than upper limit of normal irrespective of sex. Of 190 children (male, 109) with DF, 60 had DNWS, 49 had DWS, and 81 had SDF. A total of 100 children (52.6%) had LI. The distribution of hepatic involvement spectrum involves hepatomegaly (26.3%), hepatic tenderness (25.2%), features of acute liver failure (1.5%), raised level of ALT (52.6%), raised level of aspartateaminotransferase (AST) (65.8%), prolonged prothrombin time (7.3%), and reduced level of serum albumin (44.7%) in children. Of them, 5.8% and 6.8% of children had >tenfold increase in ALT and AST values. The degree of liver function derangement significantly (P < 0.05) increased with DF severity. In our study, ALT at 422 IU/L (10 times upper limit of normal [ULN]) and AST 689 IU/L (17 times ULN) had similar sensitivity and specificity as WHO recommended cutoff of 1000 IU/L (25 times of ULN) to detect SDF. ALT ≥10 times and AST ≥17 times of ULN are as sensitive as ≥25 times (as recommended by WHO) to detect SDF.

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

The needle in the haystack: deciphering diagnostic data in a case of acute on chronic liver failure

Management of Acute Liver Failure: Update 2022.

Abbreviated pathogenesis and clinical course of the acute liver failure syndrome. The pathogenesis and clinical course of the syndrome of acute liver failure (ALF) differs depending upon the etiology of the primary liver injury. In turn, the severity of the liver injury and resulting synthetic failure is often the primary determinant of whether a patient is referred for emergency liver transplantation. Injuries by viral etiologies trigger the innate immune system via pathogen-associated molecular patterns (PAMPs), while toxin-induced (and presumably ischemia-induced) injuries do so via damage-associated molecular patterns (DAMPs). The course of the clinical syndrome further depends upon the relative intensity and composition of cytokine release, resulting in an early proinflammatory phenotype (SIRS) and later compensatory anti-inflammatory response phenotype (CARS). The outcomes of overwhelming immune activation are the systemic (extrahepatic) features of ALF (cardiovascular collapse, cerebral edema, acute kidney injury, respiratory failure, sepsis) which ultimately determine the likelihood of death.Acute liver failure (ALF) continues to carry a high risk of mortality or the need for transplantation despite recent improvements in overall outcomes over the past two decades. Optimal management begins with identifying that liver failure is indeed present and its etiology, since outcomes and the need for transplantation vary widely across the different etiologies. Most causes of ALF can be divided into hyperacute (ischemia and acetaminophen) and subacute types (other etiologies), based on time of evolution of signs and symptoms of liver failure; the former evolve in 3 to 4 days and the latter typically in 2 to 4 weeks. Both involve intense release of cytokines and hepatocellular contents into the circulation with multiorgan effects/consequences.Management involves optimizing fluid balance and cardiovascular support, including the use of continuous renal replacement therapy, vasopressors, and pulmonary ventilation. Early evaluation for liver transplantation is advised particularly for acetaminophen toxicity, which evolves so rapidly that delay is likely to lead to death.Vasopressor support, high-grade hepatic encephalopathy, and unfavorable (subacute) etiologies heighten the need for urgent listing for liver transplantation. Prognostic scores such as Kings Criteria, Model for End-Stage Liver Disease, and the Acute Liver Failure Group prognostic index take these features into account and provide reasonable but imperfect predictive accuracy. Future treatments may include liver support devices and/or agents that improve hepatocyte regeneration.

The Effect of TGF-β1 Reduced Functionality on the Expression of Selected Synaptic Proteins and Electrophysiological Parameters: Implications of Changes Observed in Acute Hepatic Encephalopathy.

Decreased platelet count represents a feature of acute liver failure (ALF) pathogenesis. Platelets are the reservoir of transforming growth factor 1 (TGF-β1), a multipotent cytokine involved in the maintenance of, i.a., central nervous system homeostasis. Here, we analyzed the effect of a decrease in TGF-β1 active form on synaptic proteins levels, and brain electrophysiology, in mice after intraperitoneal (ip) administration of TGF-β1 antibody (anti-TGF-β1; 1 mg/mL). Next, we correlated it with a thrombocytopenia-induced TGF-β1 decrease, documented in an azoxymethane-induced (AOM; 100 mM ip) model of ALF, and clarified the impact of TGF-β1 decrease on blood–brain barrier functionality. The increase of both synaptophysin and synaptotagmin in the cytosolic fraction, and its reduction in a membrane fraction, were confirmed in the AOM mice brains. Both proteins’ decrease in analyzed fractions occurred in anti-TGF-β1 mice. In turn, an increase in postsynaptic (NR1 subunit of N-methyl-D-aspartate receptor, postsynaptic density protein 95, gephyrin) proteins in the AOM brain cortex, but a selective compensatory increase of NR1 subunit in anti-TGF-β mice, was observed. The alterations of synaptic proteins levels were not translated on electrophysiological parameters in the anti-TGF-β1 model. The results suggest the impairment of synaptic vesicles docking to the postsynaptic membrane in the AOM model. Nevertheless, changes in synaptic protein level in the anti-TGF-β1 mice do not affect neurotransmission and may not contribute to neurologic deficits in AOM mice.

Impact of hepatocyte-specific deletion of staphylococcal nuclease and tudor domain containing 1 (SND1) on liver insulin resistance and acute liver failure of mice

ABSTRACT Although our previous research shows an ameliorated high-fat diet (HFD)-induced hepatic steatosis and insulin resistance in global SND1 transgenic mice, the involvement of SND1 loss-of-function in hepatic metabolism remains elusive. Herein, we aim to explore the potential impact of hepatocyte-specific SND1 deletion on insulin-resistant mice. As SND1 is reported to be linked to inflammatory response, the pathobiological feature of acute liver failure (ALF) is also investigated. Hence, we construct the conditional liver knockout (LKO) mice of SND1 for the first time. Under the condition of HFD, the absence of hepatic SND1 affects the weight of white adipose tissue, but not the gross morphology, body weight, cholesterol level, liver weight, and hepatic steatosis of mice. Furthermore, we fail to observe significant differences in either HFD-induced insulin resistance or lipopolysaccharide/D-galactosamine-induced (LPS/D-GaIN) ALF between LKO and wild type (WT) mice in terms of inflammation and tissue damage. Compared with negative controls, there is no differential SND1 expression in various species of sample with insulin resistance or ALF, based on several gene expression omnibus datasets, including GSE23343, GSE160646, GSE120243, GSE48794, GSE13271, GSE151268, GSE62026, GSE120652, and GSE38941. Enrichment result of SND1-binding partners or related genes indicates a sequence of issues related to RNA or lipid metabolism, but not glucose homeostasis or hepatic failure. Overall, hepatic SND1 is insufficient to alter the phenotypes of hepatic insulin resistance and acute liver failure in mice. The SND1 in various organs is likely to cooperate in regulating glucose homeostasis by affecting the expression of lipid metabolism-related RNA transcripts during stress.

Ammonia predicts poor outcomes in patients with hepatitis B virus-related acute-on-chronic liver failure.

BackgroundHepatic encephalopathy (HE) is a common feature of acute liver failure and has been reported to be associated with poor outcomes. Ammonia is thought to be central to the pathogenesis of HE, but its role in hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) is unclear. The present study aimed to assess the prognostic role of ammonia level for patients with HBV‐ACLF.MethodsWe retrospectively recruited 127 patients diagnosed with HBV‐ACLF for the present study.ResultsAmmonia levels at the time of admission were higher among non‐surviving participants than in survivors. Increased ammonia level was found to be associated with severe liver disease and was identified as an independent predictor for mortality in patients with HBV‐ACLF.ConclusionsOur results suggest that high ammonia level at admission is an independent factor for predicting short‐term mortality in patients with HBV‐ACLF. Therefore, ammonia levels may represent a therapeutic target for this condition.

Metastatic breast cancer presenting as acute liver injury: diagnostic dilemma in the setting of suspected hemochromatosis.

A 70-year-old female with a history of lobular carcinoma of the breast, status post-mastectomy followed by adjuvant radio-chemotherapy in remission for 4 years was admitted with the features of acute liver failure (ALF). Iron studies revealed a hemochromatosis picture and the CT and MRI scans of the abdomen suggested cirrhosis. An extensive workup failed to identify an etiology. A trans-jugular liver biopsy was obtained and revealed poorly differentiated carcinoma consistent with the metastasis of breast primary. The patient’s condition deteriorated and died within a week following the onset of acute hepatic failure. DNA testing revealed that the patient was heterozygous for H63D mutation. In cases of ALF with the suspicion of malignancy, liver biopsy should be obtained to evaluate an infiltrative hepatic disease.

Related factors of prognosis for acute liver failure in critically ill children

Objective To analyze the clinical features of acute liver failure in critically ill children, to investigate the risk factors affecting the prognosis of acute liver failure in critically ill children, and to provide evidence for clinical diagnosis and prognosis. Methods The data of 85 children with acute liver failure who conformed to the diagnostic criteria from January 2011 to January 2017 at Hunan Children′s Hospital were analyzed.According to the prognosis of children with acute liver failure, all children were divided into the survival group (49 cases) and the death group (36 cases). Univariate and multivariate Logistic regression methods were used to analyze the risk factors affecting the prognosis of children with acute liver failure. Results There were statistically significant differences of enzyme bile isolation[26.5% (13/49 cases) vs.55.6%(20/36 cases), χ2=7.361, P=0.007], hepatic encephalopathy [16.3%(8/49 cases) vs.38.9%(14/36 cases), χ2=5.507, P=0.019], total bilirubin [72.30(3.93-428.80) μmol/L vs.153.08(3.23-776.26) μmol/L, U=-2.283, P=0.027], albumin [35.02(22.89-45.30) g/L vs.28.90(18.30-40.26) g/L, U=4.640, P=0.000], alanine aminotransferase [1 626.10(23.01-9 518.41) U/L vs.533.08(7.02-5 163.83) U/L, U=2.992, P=0.004], aspartate aminotransferase [1 611.20(34.51-15 850.02) U/L vs.715.54(60.06-10 280.42) U/L, U=2.312, P=0.023], blood ammonia [71.02(16.04-148.56) μmol/L vs.81.02(33.04-274.02) μmol/L, U=-2.057, P=0.046], prothrombin time [23.10(13.61-81.23) s vs.33.91(12.62-84.57) s, U=-2.364, P=0.022], activated partial prothrombin time [52.91(4.02-181.02) s vs.67.35(31.20-180.02) s, U=-2.226, P=0.029], and end-stage liver disease model score [13.00(-9.00-52.00) score vs.27.50(-9.00-88.00) score, U=-3.082, P=0.003] in the children with acute liver failure between the survival group and the death group.Multivariate Logistic regression analysis showed that total bilirubin (OR=0.236, 95%CI: 0.059-0.946, P=0.041), albumin(OR=0.854, 95%CI: 0.746-0.976, P=0.019), enzyme bile separation (OR=1.063, 95%CI: 1.031-1.119, P=0.005) and hepatic encephalopathy (OR=1.439, 95%CI: 1.021-2.043, P=0.017) were risk factors for the prognosis of children with acute liver failure. Conclusions The level of the total bilirubin and the ratio of enzyme bile isolation and hepatic encephalopathy are positively correlated but the level of albumin is negatively correlated with the prognosis of critically ill children with acute liver failure. Key words: Critically ill; Child; Acute liver failure; Prognosis

N-ACETYLCYSTEINE, A BOON FOR YELLOW PHOSPHORUS-INDUCED ACUTE LIVER FAILURE? A CASE REPORT

Rat killer, in the form of a paste, is a commonly used rodenticide in India. It contains 3% yellow phosphorus, which is a local and a systemic toxin that damages all tissues it contacts. The lethal dose of yellow phosphorus is about 1 mg/kg of body weight. We present a case report of a 30-year-old female patient with an alleged history of intake of 30 g rat killer paste mixed with one glass juice with suicidal intent. She presented with clinical features of acute liver failure (ALF) and was treated with N-acetylcysteine (NAC) infusion with other supportive therapy and recovered completely within 13 days. Poisoning with yellow phosphorus needs to be studied in the aspect of treatment, due to the lack of any specific antidote. The patient factors that help in the recovery also need to be investigated. Although highly lethal, the recovery of ALF due to yellow phosphorus-containing rodenticide is possible. Early intravenous administration of NAC, which acts as glutathione substitute, anti-inflammatory agent, and anti-oxidant could contribute to complete resolution of ALF in yellow phosphorus poisoning.

Failed Phenotype Switching by Hepatic Macrophages Produces Persistent Inflammation in Acute Liver Failure

Acute liver failure remains a significant health problem with a high rate of mortality. Studies have revealed that acetaminophen‐induced acute liver failure patients with the poorest outcome suffer from a systemic inflammatory response‐like syndrome characterized by excessive production of immunomodulatory cytokines. Unfortunately, the cause of cytokine dysregulation in these patients remains poorly understood. In the present study, we determined whether cytokine dysregulation occurs in mice treated with a dose of acetaminophen that recapitulates many of the features of acute liver failure in patients. Further, we investigated the underlying mechanism. Treatment of mice with a dose of acetaminophen (e.g., 300 mg/kg), normally associated with full liver repair, increased expression of several proinflammatory cytokines, including tumor necrosis factor‐α (TNF‐α). Cytokine levels remained elevated at 48 hours in these mice but returned to baseline by 72 hours. In mice treated with a dose of acetaminophen (e.g., 600 mg/kg) that produces liver injury which fails to repair, cytokine levels were increased out to 48 hours and remained elevated at 72 hours. This indicated a failure to terminate the inflammatory phase of wound healing similar to what occurs in patients. Interestingly, in mice treated with 600 mg/kg acetaminophen, monocyte/macrophages failed to traffic into necrotic lesions and failed to clear dead cell debris by phagocytosis. Studies have suggested that phagocytosis of dead cells terminates cytokine production by proinflammatory monocytes/macrophages. To evaluate this in acetaminophen overdose, proinflammatory monocytes/macrophages were isolated from the livers of mice treated 24 hours earlier with acetaminophen. Exposure of these cells to necrotic hepatocytes increased expression of arginase‐1 and decreased expression of inducible nitric oxide synthase, indicating a switch from an M1‐like proinflammatory macrophage to an M2‐like prorepair macrophage. Further, treatment of these cells with necrotic hepatocytes decreased expression of several proinflammatory cytokines, including TNF‐α. Collectively, these studies suggest that persistent inflammatory cytokine production in some acute liver failure patients may result from a failure of proinflammatory monocytes/macrophages to phagocytose dead cell debris leading to a persistent M1‐like phenotype. Elucidation of the mechanism by which this occurs, could lead to therapies that restore macrophage function and liver repair in acute liver failure patients.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Stem Cell Therapy for Cirrhosis of Liver in Bangladesh: Specific Design Compatible for Developing Country.

Aims and objectivesTo assess the safety and efficacy of stem cell therapy in patients with cirrhosis of the liver (LC) in the context of developing country with limited facilities for cell-based therapy and advanced technologies.Materials and methodsA total of 34 patients received granulocyte colony-stimulating factor at a dose of 30 IU, daily for 2 to 11 days to upregulate the numbers of white blood cells and stem cells. Subsequently, stem cells were isolated from the peripheral blood of LC patients in a closed chamber using a harvesting machine. Variable amounts of autologous stem cells were injected to LC patients for once. The patients were followed for 3 months and various factors related to safety and parameters of efficacy were analyzed in this interim report.ResultsOut of 34 patients available for final analysis, 3 months after the start of stem therapy, 4 patients died within this period. There was no significant alteration in biochemical parameters due to stem cell therapy, and patients also did not develop any features of acute liver failure indicating that short-term safety parameters of stem cell therapy may be acceptable. Stem cell therapy had a dominant effect on ascites of in this cohort. Although 24 of 34 patients had ascites at the start of therapy,ascites were found in 11 patients after one month and only 4 patients had ascites after 3 months. The positive role of stem cell therapy on ascites in LC patients may be attributed, even in part, to increased serum levels of albumin after therapy compared to basal levels (p <0.001).ConclusionThis first study about stem cell therapy in Bangladesh indicates that cell therapy may be accomplished in general hospitals of developing countries if the proper design and mild to moderate types of invasive approach is utilized. The apparent safety of administered stem cells in LC patients and the observed effect on ascites of LC patients inspire optimism about the installation of new and innovative therapy in Bangladesh. Future studies with phase I/II may with stem cell and others cell may be planned at Bangladesh in patients with LC and other intractable diseases with suitable control arms.How to cite this article: Mahtab MA, Akbar SMF, Begum M, Islam MA, Rahim MA, Noor-E-Alam SM, Alam MA, Khondaker FA, Moben AL, Mohsena M, Khan SI, Huq MZ, Munshi S, Hoque A, Haque SA. Stem Cell Therapy for Cirrhosis of Liver in Bangladesh: Specific Design Compatible for Developing Country. Euroasian J Hepatogastroenterol, 2018;8(2):121-125.

Drug idiosyncrasy due to pirfenidone presenting as acute liver failure: Case report and mini-review of the literature.

Idiosyncratic drug‐induced liver injury (DILI) is ranked among the top most common etiologies of acute liver failure (ALF). It carries poor transplant‐free survival. Pirfenidone is an anti‐inflammatory and antifibrotic drug that is commonly used for the treatment of idiopathic pulmonary fibrosis (IPF). Hepatotoxicity due to pirfenidone is rare and generally manifests as a mild rise in serum aminotransferases. In this mini‐review, we report an unusual case of idiosyncratic DILI due to pirfenidone presenting as ALF, with emphasis on the definition, classification, diagnostic criteria, histopathology, molecular markers, and treatment options for DILI and related ALF. A 77‐year‐old man with known Parkinson's disease and IPF presented with jaundice for 7 days and altered mental status for 4 days. His long‐term medications included a levodopa/carbidopa combination with a recent addition of pirfenidone over the previous 1 month; there was no monitoring of liver function tests. The evaluation suggested features of acute liver failure with grade III hepatic encephalopathy, acute kidney injury, and metabolic acidosis. The diagnostic workup ruled out viral, toxic, ischemic, and other etiologies for acute liver failure. Based on a Roussel Uclaf Causality Assessment Method score of 7 and possible DILI‐ALF, pirfenidone was withdrawn. He was evaluated for liver transplantation but was declined. Despite all supportive measures in intensive care, organ failure progressed and he succumbed to the illness on day 4. Postmortem liver biopsy revealed findings consistent with DILI (final Roussel Uclaf Causality Assessment score, 10). Conclusion: DILI‐ALF carries poor prognosis, and liver transplantation should be considered early in the course. Characterization, reporting, monitoring, and labeling of pirfenidone‐related hepatotoxicity is vital given its common use in IPF. (Hepatology Communications 2018;2:142–147)

Clinical spectrum of yellow phosphorous poisoning in a tertiary care centre in South India: a case series

Rodenticides such as yellow phosphorus are highly toxic compounds which are commonly used for pest control. Reports of yellow phosphorus poisoning from tropical nations is scanty. In this retrospective study, we report the clinical features, mortality and predictors of mortality among nine patients at a tertiary care centre in south India. Yellow phosphorus consumption was common among a younger age group of patients. The mean duration of presentation after consumption was five days. The most common clinical manifestations seen were abdominal pain and vomiting followed by a depressed sensorium. Features of acute liver failure including coagulopathy were seen in all patients. Despite all patients receiving supportive therapy, a poor outcome or death resulted in the majority. Early referral to a tertiary care centre, meticulous monitoring and supportive measures are key elements of patient management as there are no specific antidotes available at present. Increase in public and physician awareness to the toxin and implementation of preventive policies is of utmost importance.

Non-metastatic Fibrolamellar Hepatocellular Carcinoma Presenting With Hyperammonemia: A Case Report

A 23 year old female presented with a 2 week history of nausea, vomiting, generalized weakness, and intermittent right upper quadrant pain. Following admission, computerized tomography of abdomen revealed a large hepatic mass measuring 13 x 9 cm (figure), without evidence of metastasis. Multiple internal enhancing vessels and altered vascular architecture were visualized. Liver function tests included AST (47 U/l), ALT (41 U/l), total bilirubin (2.2 mg/dl) and INR (1.5). Patient began to show signs of altered mentation, as ammonia levels began to peak at 437 mcg/dl. A core needle biopsy confirmed Fibrolamellar hepatocellular carcinoma (FL-HCC), while pathology report revealed a 16 cm well differentiated FL-HCC without lymphovascular invasion. After the tumor was deemed unresectable the patient was listed for transplantation. The patient was placed on immunosuppression post transplantation, which included corticosteroids, mycophenolate mofetil and tacrolimus. At 1 year follow-up, the patient continues to live without recurrent disease while on sorafenib adjuvant therapy. FL-HCC is a rare hepatocellular tumor arising in non-infected, non-cirrhotic livers, accounting for 0.3% of all HCC cases. It is more frequent in young adults with no sex preponderance. Only two cases of FL-HCC accompanied by hyperammonemia due to intrahepatic shunting have been published, none of which were successfully treated. We present a rare case of FL-HCC in a patient who was comatosed from hyperammonemia and was successfully transplanted later. This case illustrates various aspects of complex management decision that includes: treatment of a patient with features of acute liver failure, management of encephalopathy, and determination of tumor resection or transplantation (LTx). The liver transplant literature on these tumors is outdated and historically, not favorable. However, systemic therapies and immunosuppressants with anti-cancer activities are now available. This patient with advanced encephalopathy was deemed unresectable and was urgently transplanted. Outcomes reported for LTx in FL-HCC are poor as the data is outdated (from 1990's). The 5-year survival rate ranged from 29% to 55%. Only two cases have been reported of FL-HCC presenting with hyperammonemia, one from the United States of America, and another from Argentina. Young patients with unresectable FL-HCC co-existing with hyperammonemia but without evidence of metastatic disease should be considered for LTx.Figure 1Figure 2

Pharmacologic cholinesterase inhibition improves survival in acetaminophen-induced acute liver failure in the mouse.

BackgroundAcetaminophen (APAP) is one of the most widely used analgesic and antipyretic pharmaceutical substances in the world and accounts for most cases of drug induced liver injury resulting in acute liver failure. Acute liver failure initiates a sterile inflammatory response with release of cytokines and innate immune cell infiltration in the liver. This study investigates, whether pharmacologic acetylcholinesterase inhibition with neostigmine diminishes liver damage in acute liver failure via the cholinergic anti-inflammatory pathway.MethodsAcute liver failure was induced in BALB/c mice by a toxic dose of acetaminophen (APAP). Neostigmine and/or N-acetyl-cysteine (NAC) were applied therapeutically at set time points and the survival was investigated. Liver damage was assessed by serum parameters, histopathology and serum cytokine assays 12 h after initiation of acute liver failure.ResultsSerum parameters, histopathology and serum cytokine assays showed pronounced features of acute liver failure 12 h after application of acetaminophen (APAP). Neostigmine treatment led to significant reduction of serum liver enzymes (LDH (47,147 ± 12,726 IU/l vs. 15,822 ± 10,629 IU/l, p = 0.0014) and ALT (18,048 ± 4,287 IU/l vs. 7,585 ± 5,336 IU/l, p = 0.0013), APAP-alone-treated mice vs. APAP + neostigmine-treated mice), inflammatory cytokine levels (IL-1β (147 ± 19 vs. 110 ± 25, p = 0.0138) and TNF-α (184 ± 23 vs. 130 ± 33, p = 0.0086), APAP-alone-treated mice vs. APAP + neostigmine-treated mice) and histopathological signs of damage.Animals treated with NAC in combination with the peripheral cholinesterase inhibitor neostigmine showed prolonged survival and improved outcome.ConclusionsNeostigmine is an acetylcholinesterase inhibitor that ameliorates the effects of APAP-induced acute liver failure in the mouse and therefore may provide new treatment options for affected patients.

GSK-3β inhibition attenuates CLP-induced liver injury by reducing inflammation and hepatic cell apoptosis.

Liver dysfunction has been known to occur frequently in cases of sepsis. Excessive inflammation and apoptosis are pathological features of acute liver failure. Recent studies suggest that activation of glycogen synthase kinase- (GSK-) 3β is involved in inflammation and apoptosis. We aimed to investigate the protective effects of GSK-3β inhibition on polymicrobial sepsis-induced liver injury and to explore the possible mechanisms. Polymicrobial sepsis was induced by cecal ligation and puncture (CLP), and SB216763 was used to inhibit GSK-3β in C57BL/6 mice. GSK-3β was activated following CLP. Administration of SB216763 decreased mortality, ameliorated liver injury, and reduced hepatic apoptosis. The inhibition of GSK-3β also reduced leukocyte infiltration and hepatic inflammatory cytokine expression and release. Moreover, GSK-3β inhibition suppressed the transcriptional activity of nuclear factor-kappa B (NF-κB) but enhanced the transcriptional activity of cAMP response element binding protein (CREB) in the liver. In in vitro studies, GSK-3β inhibition reduced inflammatory cytokine production via modulation of NF-κB and CREB signaling pathways in lipopolysaccharide-stimulated macrophages. In conclusion, these findings suggest that GSK-3β blockade protects against CLP-induced liver via inhibition of inflammation by modulating NF-κB and CREB activity and suppression of hepatic apoptosis.

Deactivation and apoptosis of hepatic macrophages are involved in the development of concanavalin A-induced acute liver failure

Activation of hepatic macrophages and systemic immunoparesis are prominent features of acute liver failure (ALF). However, the specific mechanism linking macrophage-associated inflammation and immunoparesis remains to be elucidated. The present study investigated the functional status and fate of hepatic macrophages, as well as their association with immunoparesis in ALF. Intravenous injection of concanavalin A (con A) was administered to develop a mouse model of ALF. Flow cytometry was performed to determine toll-like receptor 4 (TLR4) expression and the apoptotic rates of isolated hepatic macrophages in mice exposed to con A. The levels of TNF-α, IL-6 and IL-12p40 in serum and cell cultures were determined with enzyme-linked immunosorbent assay. TLR4 peak expression in hepatic macrophages was observed at ~0.5 h following exposure to con A and rapidly decreased at 1-3 h. The apoptotic rates of hepatic macrophages increased significantly with the exposure time of con A. The dysfunctional hepatic macrophages associated with apoptosis were observed earlier than the biochemical and histopathological changes of ALF. In addition, the production of macrophage-related inflammatory cytokines following exposure to con A in vivo or in vitro increased significantly. These observations indicated that the deactivation and apoptosis of hepatic macrophages may be a potential link between inflammation and immunoparesis in ALF.

Elevated transaminases as a predictor of coma in a patient with anorexia nervosa: a case report and review of the literature

IntroductionLiver injury is a frequent complication associated with anorexia nervosa, and steatosis of the liver is thought to be the major underlying pathology. However, acute hepatic failure with transaminase levels over 1000 IU/mL and deep coma are very rare complications and the mechanism of pathogenesis is largely unknown.Case presentationA 37-year-old Japanese woman showed features of acute liver failure and hepatic coma which were not associated with hypoglycemia or hyper-ammonemia. Our patient's consciousness was significantly improved with the recovery of liver function and normalization of transaminase levels after administration of nutritional support.ConclusionsOur case report demonstrates that transaminase levels had an inverse relationship with the consciousness of our patient, although the pathogenesis of coma remains largely unknown. This indicates that transaminase levels can be one of the key predictors of impending coma in patients with anorexia nervosa. Therefore, frequent monitoring of transaminase levels combined with rigorous treatment of the underlying nutritional deficiency and psychiatric disorder are necessary to prevent this severe complication.

Insuffisance hépatique aiguë révélatrice d’un carcinome pulmonaire avec métastases hépatiques

Liver failure as a result of neoplasia is a rare event before the terminal stage of the illness. We report a 66-year-old man who presented with clinical features of acute liver failure as the initial manifestation of a small-cell lung carcinoma. Liver was enlarged without ascitis. Abdominal CT-scan revealed a massive hepatomegaly with multiple low-density wedge-shaped lesions. The patient developed stage 3 hepatic encephalopathy and died on day 4. The diagnosis was obtained with post-mortem study. A Medline search of acute liver failure due to small-cell carcinoma identified only 17 cases already published, with a universally poor prognosis.