First-in-class MKK4 inhibitors enhance liver regeneration and prevent liver failure.

Diminished hepatocyte regeneration is a key feature of acute and chronic liver diseases and after extended liver resections, resulting in the inability to maintain or restore a sufficient functional liver mass. Therapies to restore hepatocyte regeneration are lacking, making liver transplantation the only curative option for end-stage liver disease. Here, we report on the structure-based development and characterization (nuclear magnetic resonance [NMR] spectroscopy) of first-in-class small molecule inhibitors of the dual-specificity kinase MKK4 (MKK4i). MKK4i increased liver regeneration upon hepatectomy in murine and porcine models, allowed for survival of pigs in a lethal 85% hepatectomy model, and showed antisteatotic and antifibrotic effects in liver disease mouse models. A first-in-human phase I trial (European Union Drug Regulating Authorities Clinical Trials [EudraCT] 2021-000193-28) with the clinical candidate HRX215 was conducted and revealed excellent safety and pharmacokinetics. Clinical trials to probe HRX215 for prevention/treatment of liver failure after extensive oncological liver resections or after transplantation of small grafts are warranted.

Variable Outcomes of Hepatitis E Infections in Patients with Hemato-Oncologic Diseases.

INTRODUCTION: The hepatitis E virus (HEV) represents an important cause of viral hepatitis and could cause chronic infections in immunocompromised patients. However, data about immunocompromised patients other than solid organ transplant recipients are limited. METHODS: We identified patients from a laboratory database and retrospectively compiled and analyzed clinical as well as laboratory data in detail. RESULTS: Overall, 22 severely immunosuppressed patients, excluding solid organ transplant recipients, were identified. Four patients did not experience viral clearance (one without and three despite ribavirin therapy). Three patients acquired the infection after allogeneic hematopoietic stem cell transplantation (alloHSCT) and recovered spontaneously, whereas another patient, infected prior to alloHSCT, developed a chronic infection. Four patients failed to clear HEV, resulting in fatal liver failure in 2 patients. The CD4+ cell counts increased in all but 1 patient attaining a sustained virological response (SVR), as compared to patients with clinical failure. Severe immunoglobulin deficiency did not appear to obviate the control of HEV. Six of ten (60%) patients with and nine of 12 (75%) patients without ribavirin therapy achieved an SVR. CONCLUSIONS: Upfront ribavirin therapy does not appear mandatory in patients without CD4+ lymphopenia, but a prolonged HEV replication carries the risk of liver failure. Our data suggest that chronic HEV infections could cause T-cell exhaustion, which might be overruled with ribavirin therapy.

[Intrahepatic and extrahepatic clinical manifestations and treatment progress for hepatitis type E].

Hepatitis type E virus (HEV) is one of the main causes of acute hepatitis globally and has thus gained attention as a public health issue. The diverse clinical manifestations of hepatitis type E are typically acute and self-limiting with mild symptoms, but populations with underlying liver disease or immunocompromised patients can have severe and chronic symptoms. Severity and chronicity can arise and manifest as fulminant hepatitis, chronic hepatitis, or even hepatic failure. HEV infection-induced hepatic failure (acute-on-chronic liver failure), based on the different backgrounds of chronic liver disease, is a clinical phenotype of severe HEV infection that requires attention. In addition, HEV infection can exhibit extrahepatic clinical manifestations of multi-system and organ involvement like neurological diseases (Guillain-Barré syndrome), renal diseases (membranous/membranous proliferative glomerulonephritis, cryoglobulinemia), and blood diseases (thrombocytopenia). At home or abroad, there are no antiviral drugs approved, particularly for HE treatment. Since most acute HE can resolve spontaneously, no special treatment is required clinically. However, in patients with severe or chronic HE, ribavirin (RBV) monotherapy and/or pegylated interferon-combination therapy have achieved certain antiviral effects. Combined small-molecule drugs and RBV have been attempted to treat HEV, but high-level evidence-based treatment is still lacking. Thus, new, highly effective anti-HEV drugs are clinical priorities to address these concerns. Severe and chronic HEV infections' clinical phenotype, early detection, mechanism, intervention, and outcome need additional study.

Regional Citrate Anticoagulation or Heparin Anticoagulation for Renal Replacement Therapy in Patients With Liver Failure: A Systematic Review and Meta-Analysis.

In patients with liver failure complicated by acute kidney injury, renal replacement therapy (RRT) is often required to improve the internal environment. The use of anticoagulants for RRT in patients with liver failure remains controversial. We searched the PubMed, Embase, Cochrane Library, and Web of Science databases for studies. The methodological quality of the included studies was assessed using the Methodological Index for Nonrandomized Studies. A meta-analysis was performed using R software (version 3.5.1) and Review Manager (version 5.3.5). During RRT, 348 patients from 9 studies received regional citrate anticoagulation (RCA), and 127 patients from 5 studies received heparin anticoagulation (including heparin and LMWH). Among patients who received RCA, the incidence of citrate accumulation, metabolic acidosis, and metabolic alkalosis were 5.3% (95% confidence interval [CI]: 0%-25.3%), 26.4% (95% CI: 0-76.9), and 1.8% (95% CI: 0-6.8), respectively. The potassium, phosphorus, total bilirubin (TBIL), and creatinine levels were lower, whereas the serum pH, bicarbonate, base excess levels, and total calcium/ionized calcium ratio were higher after treatment than before treatment. Among patients who received heparin anticoagulation, the TBIL levels were lower, whereas the activated partial thromboplastin clotting time and D-dimer levels were higher after treatment than before treatment. The mortality rates in the RCA and heparin anticoagulation groups were 58.9% (95% CI: 39.2-77.3) and 47.4% (95% CI: 31.1-63.7), respectively. No statistical difference in mortality was observed between the 2 groups. For patients with liver failure, the administration of RCA or heparin for anticoagulation during RRT under strict monitoring may be safe and effective.

Genotypic and phenotypic spectrum of infantile liver failure due to pathogenic TRMU variants.

PURPOSE: This study aimed to define the genotypic and phenotypic spectrum of reversible acute liver failure (ALF) of infancy resulting from biallelic pathogenic TRMU variants and determine the role of cysteine supplementation in its treatment. METHODS: Individuals with biallelic (likely) pathogenic variants in TRMU were studied within an international retrospective collection of de-identified patient data. RESULTS: In 62 individuals, including 30 previously unreported cases, we described 47 (likely) pathogenic TRMU variants, of which 17 were novel, and 1 intragenic deletion. Of these 62 individuals, 42 were alive at a median age of 6.8 (0.6-22) years after a median follow-up of 3.6 (0.1-22) years. The most frequent finding, occurring in all but 2 individuals, was liver involvement. ALF occurred only in the first year of life and was reported in 43 of 62 individuals; 11 of whom received liver transplantation. Loss-of-function TRMU variants were associated with poor survival. Supplementation with at least 1 cysteine source, typically N-acetylcysteine, improved survival significantly. Neurodevelopmental delay was observed in 11 individuals and persisted in 4 of the survivors, but we were unable to determine whether this was a primary or a secondary consequence of TRMU deficiency. CONCLUSION: In most patients, TRMU-associated ALF was a transient, reversible disease and cysteine supplementation improved survival.

Voriconazole-induced severe skin allergy and neurological adverse event in a liver failure patient: A case report.

WHAT IS KNOWN AND OBJECTIVE: Triazole antifungal-associated severe skin allergy has received little attention. Here we report a case of an acute-on-chronic liver failure (ACLF) patient with diffused skin allergy pervading from the chest, abdomen, back, knees to perineum, with red colour and partially desquamation as well as a neurological adverse (insomnia) event after voriconazole treatment. CASE SUMMARY: A 40-year-old man with liver failure in our hospital had received voriconazole for invasive fungal infection therapy, and while waiting for liver transplantation exhibited a severe diffuse rash and a neurological adverse event. WHAT IS NEW AND CONCLUSION: To the best of our knowledge, this is the first report of a liver failure patient who suffered a severe allergy accompanied with a neurological adverse event after voriconazole administration.

[Clinical study of heparin anticoagulation scheme during plasma adsorption therapy for liver failure].

Objective: To investigate the reasonable dosage of heparin anticoagulation scheme during plasma adsorption (PA) therapy for liver failure. Methods: Patients with liver failure treated with PA therapy were retrospectively collected and divided according to the anticoagulation scheme into the first-dose heparin anticoagulation group and the first-dose plus maintenance heparin anticoagulation group. Clinical data and laboratory test results were compared before and after treatment between the two groups. Paired t-tests were used for comparison within the normally distributed groups. An independent two-sample t-test was used for inter group comparison. Wilcoxon rank-sum test was used for measurement data that did not conform to a normal distribution. Fisher's exact test was used to compare the count data between groups. Results: There were 138 cases with liver failure treated with PA therapy from October 2017 to September 2020. Among them, 83 and 55 cases were in the first-dose heparin anticoagulation and first-dose plus maintenance heparin anticoagulation group, respectively. Age, gender, and laboratory data before treatment were comparable between the two groups. PA treatment was successfully completed in both groups of patient, and there was no statistically significant difference in the determination of coagulation level with plasma separators (Z=-0.15, P=0.216). There were different degrees of bleeding complications in both groups. In the first-dose heparin anticoagulation group, there were two cases (2.4%) of central venous catheter bleeding and one case (1.2%) of epistaxis. In the first-dose plus maintenance heparin anticoagulation group, there were five cases (9.1%) of central venous catheter bleeding, two cases (3.6%) of skin bleeding, one case (1.8%) of epistaxis, and one case (1.8%) of upper gastrointestinal bleeding. The incidence of bleeding complications was lower in the first-dose of heparin anticoagulation than first-dose plus maintenance heparin anticoagulation group, and the difference was statistically significant (P<0.001). The activated partial thromboplastin time of the two groups was prolonged after therapy withdrawal than with therapy, and the difference was statistically significant (first-dose heparin anticoagulation group: t=3.850, P=0.022; first-dose plus maintenance heparin anticoagulation group: t=6.733, P=0.007). The activated partial thromboplastin time was prolonged in patients with first-dose plus maintenance heparin anticoagulation than first-dose heparin anticoagulation group, and the difference was statistically significant (P=0.025). The total bilirubin of the two groups before and after PA was significantly changed (the first-dose heparin anticoagulation group: Z=-2.455, P=0.017; the first-dose plus maintenance heparin anticoagulation group: Z=-2.307, P=0.024), and there was no statistically significant difference between the two groups (P=0.412). There was no statistically significant difference in platelet changes before and after PA therapy between the two groups (the first dose of heparin anticoagulation group: Z=-0.529, P=0.480; the first-dose plus maintenance heparin anticoagulation group: Z=-0.276, P=0.362). Conclusion: Anticoagulation scheme without maintenance medication is feasible with prothrombin activity before ≤20-40%, activated partial thromboplastin time of ≤87 s (2 times the upper normal value), platelet count before treatment (excluding contraindications to heparin) ≥50×109/L, and the first dose of heparin administration of 0.2 mg/kg during PA therapy in patients with liver failure.

Glucocorticoid Treatment Strategies in Liver Failure.

Liver failure is characterized by serious liver decompensation and high mortality. The activation of systemic immune responses and systemic inflammation are widely accepted as the core pathogenesis of liver failure. Glucocorticoids (GCs) are most regularly utilized to suppress excessive inflammatory reactions and immunological responses. GCs have been used in the clinical treatment of liver failure for nearly 60 years. While there has been no unanimity on the feasibility and application of GC treatment in liver failure until recently. The most recent trials have produced conflicting results when it comes to the dose and time for GC therapy of different etiology of liver failure. Our review outlines the issues and options in managing GC treatment in liver failure based on an investigation of the molecular mechanism that GC may give in the treatment.

Liver failure caused by intravenous amiodarone and effective intervention measures: A case report.

WHAT IS KNOWN AND OBJECTIVE: We present a case of intravenous amiodarone-induced liver injury, pharmacy monitoring and its therapy. CASE SUMMARY: A 76-year-old male patient developed acute liver injury 24 h after starting intravenous amiodarone. His liver enzymes improved after discontinuing amiodarone and anti-inflammatory liver therapy, which used reduced glutathione, magnesium isoglycyrrhizinate and ademetionine1,4-butanedisulfonate for injection. WHAT IS NEW AND CONCLUSION: Amiodarone is a highly effective antiarrhythmic agent for the treatment and prevention of atrial and ventricular arrhythmias. Acute liver damage after intravenous amiodarone is rare but potentially harmful. Amiodarone loading should be adapted to the necessity of an immediate effect of the drug, and liver function should be monitored closely in critically ill patients. Timely stopped suspected drug and anti-inflammatory liver therapy may reduce the occurrence of drug-induced diseases.

Effect of conditioned medium from adipose derived mesenchymal stem cells on endoplasmic reticulum stress and lipid metabolism after hepatic ischemia reperfusion injury and hepatectomy in swine.

AIMS: Hepatic ischemia reperfusion injury (HIRI) is associated with liver failure after liver transplantation and hepatectomy. Thus, this study aims to explore the effect of conditioned medium from adipose derived stem cells (ADSC-CM) on endoplasmic reticulum stress (ERS) and lipid metabolism after HIRI combined with hepatectomy in miniature pigs. MAIN METHODS: A model of HIRI combined with hepatectomy in miniature pigs was established. The expression of ERS-related proteins and lipid metabolism related genes, as well as triglyceride (TG), total cholesterol (TC), high density lipoprotein (HDL), very low density lipoprotein (VLDL) and acetyl-CoA carboxylase 1 (ACC1) level were measured in liver tissues. KEY FINDINGS: Both ADSCs and ADSC-CM could improve the damage in the ultrastructure of hepatocytes. ADSC-CM significantly decreased the protein expression of GRP78, ATF6, XBP1, p-eIF2α, ATF4, p-JNK and CHOP. Oil red O staining revealed that the degree of hepatocyte steatosis was also significantly reduced after treatment with ADSC-CM. In addition, ADSC-CM remarkably decreased TG, TC, HDL and ACC1 level in liver tissues, while enhanced VLDL content. Finally, SREBP1, SCAP, FASN, ACC1, HMGCR and HMGCS1 mRNA expression was also markedly downregulated in liver tissues. SIGNIFICANCE: Injection of ADSC-CM into the hepatic parenchymal could represent a novel cell-free therapeutic approach to improve HIRI combined with hepatectomy injury. The inhibition of ERS and the improvement of lipid metabolism in the hepatocytes might be a potential mechanism used by ADSC-CM to prevent liver injury from HIRI combined with hepatectomy.

The synergy of dietary supplements Lactobacillus salivarius LI01 and Bifidobacterium longum TC01 in alleviating liver failure in rats treated with D-galactosamine.

Lactobacillus salivarius (L. salivarius) has been widely used in dietary supplements and clinical treatments. Previous studies demonstrated the protective effect of L. salivarius LI01 on liver injury induced by D-galactosamine (D-GaIN) in rats. Accumulating evidence indicates that Lactobacillus and Bifidobacterium are highly coordinated; so in this study, we focus on the synergistic effect of L. salivarius LI01 and B. longum TC01 on the alleviation of liver injury caused by D-GaIN in rats and aim to find out the underlying interaction between the two strains. We observed reduced hepatic damage in the D-GaIN-treated rats with probiotic pre-administration, characterized by lower levels of AST and ALT (p < 0.05) and decreased HAI (Histological Activity Index) scores. Moreover, cotreatment with LI01 and TC01 more effectively decreases proinflammatory cytokines TNF-α, MCP-1 and M-CSF (p < 0.05) so as to inhibit systemic inflammation. Gut barrier dysfunction was ameliorated with compound probiotic pretreatment, as evidenced by the ultrastructure integrity, decreased histological score and elevated TJP-1 expression. What's more, supplementation with LI01 and TC01 markedly alleviates gut dysbiosis in the G-DaIN-treated rats, with enrichment of short chain fatty acid (SCFA) producers Faecalibaculum and Eubacterium_xylanophilum_group, a decreased Firmicutes/Bacteroidetes (F/B) ratio and depletion of proinflammatory microbes, such as Peptococcaeae and Ruminococcaceae_UCG-005. This study highlights the synergistic effect of dietary supplements LI01 and TC01 on the protection against liver failure, which is probably via altering gut microbiota.

HDAC6 inhibitor ACY1215 inhibits the activation of NLRP3 inflammasome in acute liver failure by regulating the ATM/F-actin signalling pathway.

Acute liver failure (ALF) is a rare and critical medical condition. This study was designed to investigate the protective effects and underlying mechanism of ACY1215 in ALF mice. Our findings suggested that ACY1215 treatment ameliorates the pathological hepatic damage of ALF and decreases the serum levels of ALT and AST. Furthermore, ACY1215 pretreatment increased the level of ATM, γ-H2AX, Chk2, p53, p21, F-actin and vinculin in ALF. Moreover, ACY1215 inhibited the level of NLRP3, ASC, caspase-1, IL-1ß and IL-18 in ALF. The ATM inhibitor KU55933 could decrease the level of ATM, γ-H2AX, Chk2, p53, p21, F-actin and vinculin in ALF with ACY1215 pretreatment. The F-actin inhibitor cytochalasin B decreased the level of F-actin and vinculin in ALF with ACY1215 pretreatment. However, cytochalasin B had no effect on protein levels of ATM, Chk2, p53 and p21 in ALF with ACY1215 pretreatment. Cytochalasin B could dramatically increase the level of NLRP3, ASC, caspase-1, IL-1ß and IL-18 in ALF with ACY1215 pretreatment. These results indicated that ACY1215 exhibited hepatoprotective properties, which was associated with the inhibition of NLRP3 inflammasome, and this effect of ACY1215 was connected with upregulation of the ATM/F-actin mediated signalling pathways.

Preliminary study on the possible impact of Thalassodendron ciliatum (Forss.) den Hartog acidic polysaccharide fractions against TAA induced liver failure.

The water-soluble acidic polysaccharide from Thalassodendron ciliatum (Forss.) den Hartog was successfully extracted, fractionated and purified. The phytochemical profile of the two water-soluble fractions (F1 and F2), were detected using different analytic techniques. GC-MS analysis revealed the presence of 22 saccharide. Acidic polysaccharide, galacturonic and glucuronic acid were the most abundant. Moreover, paper chromatography and electrophoresis also performed as a preliminary chemical characterization of the polymer. The hepatoprotective activity of the fractions against thioacetamide (TAA) induced liver failure; antioxidant potential and preliminary immunomodulatory activity were assigned in-vivo. The results revealed a potent competence to improve the liver function profile (ALT, AST, total bilirubin, total glyceride, etc.) and a remarkable improvement in liver architecture in comparison to the challenged intoxicated groups. Moreover, they showed high anti-oxidative properties and a promising immunomodulatory influence via Il6. These findings provide new insight into the possible role of polysaccharide purified two fractions in the treatment of acute liver injury.

Emerging roles of ferroptosis in liver pathophysiology.

Ferroptosis is a widely recognized process of regulated cell death linking redox state, metabolism, and human health. It is considered a defense mechanism against extensive lipid peroxidation, a complex process that may disrupt the membrane integrity, eventually leading to toxic cellular injury. Ferroptosis is controlled by iron, reactive oxygen species, and polyunsaturated fatty acids. Accumulating evidence has addressed that ferroptosis plays an unneglectable role in regulating the development and progression of multiple pathologies of the liver, including hepatocellular carcinoma, liver fibrosis, nonalcoholic steatosis, hepatic ischemia-reperfusion injury, and liver failure. This review may increase our understating of the cellular and molecular mechanisms of liver disease progression and establish the foundation of strategies for pharmacological intervention.

[Liver failure and glucocorticoid resistance].

The main pathogenesis of liver failure is immune damage and uncontrolled inflammatory response. Glucocorticoids have strong immunosuppressive and anti-inflammatory effects, and are considered to be useful for the treatment of liver failure. However, the results of many clinical studies have shown that the application of glucocorticoids in patients with liver failure cannot effectively improve the prognosis, but instead increases the chance of infection and endangers life. Provided that, it seems reasonable to assume that glucocorticoid resistance exists in patients with liver failure. This article analyzes the mechanism by which P-glycoprotein reverses glucocorticoid transport, intracellular glucocorticoid signaling pathway dysfunction and related gene mutations when the inflammatory response is uncontrolled. In addition, we also evaluated the sensitivity of glucocorticoids in patients with liver failure, so as to provide theoretical basis for efficacy and medication timing.

Living-donor liver transplantation providing an adequate chemotherapy for a pediatric patient with anaplastic large cell lymphoma complicated with liver failure due to the aggravation of biliary hepatopathy by secondary hemophagocytic lymphohistiocytosis.

Anaplastic large cell lymphoma (ALCL) accounts for 10-15% of childhood non-Hodgkin lymphoma cases; it is generally chemo-sensitive and is one of the most curable pediatric cancers. We report here a case of pediatric ALCL complicated with acute liver failure due to the aggravation of pre-existing biliary hepatopathy by lymphoma-associated hemophagocytic lymphohistiocytosis (HLH). Although the initial treatment response against ALCL was very good, poor and irreversible liver function due to biliary cirrhosis worsening by lymphoma-associated HLH prevented the patient from receiving further consolidation chemotherapies. To make matters worse, his condition was accompanied with intrahepatic fungal pseudoaneurysm and invasive fungal infection. Thus, we decided to perform an urgent living-donor liver transplantation from his father to correct the patient's liver function and make it possible to proceed with further ALCL therapy. After the living-donor liver transplantation, the patient successfully received consolidation therapy with brentuximab vedotin. To our knowledge, this may be an early reported case of a pediatric patient undergoing liver transplantation during treatment for ALCL. In most patients with HLH-associated ALCL, liver function improves when ALCL is controlled. However, acute liver failure is occasionally observed in HLH cases with pre-existing liver dysfunction. In such cases, liver transplantation should be considered to correct liver dysfunctions if the disease control of HLH is satisfactory.

Detection of immunoglobulin indexes by immunoturbidimetry: patients with chronic hepatitis B.

BACKGROUND: The objective of this study was to explore the clinical effect of immunoglobulin test in patients with chronic hepatitis B. METHODS: Fifty patients with chronic hepatitis B, 50 patients with liver failure and 50 patients with cirrhosis were selected from the Third People's Hospital of Baoji as experimental groups, and 50 healthy people as the control group. The immunoglobulin M (IgM), IgG and IgA levels in serum of the patients were tested by immunoturbidimetry before and after targeted treatment. RESULTS: Before treatment, the level of Ig in patients with hepatitis B, liver failure and cirrhosis were significantly higher than those in normal people; the level of Ig in patients with hepatitis B were significantly lower than those in patients with liver failure and cirrhosis, and the level of Ig in patients in different groups increased significantly as the disease developed. After treatment, the level of Ig in patients in different groups decreased significantly; patients in the experimental group who had good treatment result had significant decrease of Ig level, while patients in the experimental group who had aggravated disease condition had significant increase of Ig level. CONCLUSIONS: Detection of serum Ig level in patients with chronic hepatitis B can effectively help determine the condition of patients before and after treatment, so as to formulate appropriate treatment plan.

Network Pharmacology-Based Approaches of Rheum undulatum Linne and Glycyrriza uralensis Fischer Imply their Regulation of Liver Failure with Hepatic Encephalopathy in Mice.

Rheum undulatum and Glycyrrhiza uralensis have been used as supplementary ingredients in various herbal medicines. They have been reported to have anti-inflammatory and antioxidant effects and, therefore, have potential in the treatment and prevention of various liver diseases. Considering that hepatic encephalopathy (HE) is often associated with chronic liver failure, we investigated whether an R. undulatum and G. uralensis extract mixture (RG) could reduce HE. We applied systems-based pharmacological tools to identify the active ingredients in RG and the pharmacological targets of RG by examining mechanism-of-action profiles. A CCl4-induced HE mouse model was used to investigate the therapeutic mechanisms of RG on HE. We successfully identified seven bioactive ingredients in RG with 40 potential targets. Based on an integrated target-disease network, RG was predicted to be effective in treating neurological diseases. In animal models, RG consistently relieved HE symptoms by protecting blood-brain barrier permeability via downregulation of matrix metalloproteinase-9 (MMP-9) and upregulation of claudin-5. In addition, RG inhibited mRNA expression levels of both interleukin (IL)-1ß and transforming growth factor (TGF)-ß1. Based on our results, RG is expected to function various biochemical processes involving neuroinflammation, suggesting that RG may be considered a therapeutic agent for treating not only chronic liver disease but also HE.