Effect of lipopolysaccharide on TAK1-mediated hepatocyte PANoptosis through Toll-like receptor 4 during acute liver failure.

BACKGROUND: Intestinal endotoxemia (IETM) is an important pathogenic mechanism of acute liver failure (ALF), and TAK1-mediated PANoptosis is a novel cell death mode. This study investigated whether IETM can induce hepatocyte PANoptosis during ALF. METHOD: PANoptosis cell and mouse models were generated, and lentiviruses (LVs), adeno-associated viral vectors (AVVs), and small interfering RNAs (siRNAs) were subsequently used to overexpress or knock down TLR and TAK1. Then, the levels of hepatocyte injury, TLR4, TAK1 and PANoptosis were detected via an enzyme-labeling instrument, tissue staining, RT-PCR, western blotting, immunofluorescence, and flow cytometry. RESULTS: The BioGRID database search revealed that TAK1 might interact with TLR4. According to the in vivo experiments, compared with those in ALF mice, liver tissue damage, hepatocyte mortality and PANoptosis in mice in the AAV-TAK1 group were significantly lower, and liver function was significantly improved. According to the in vitro experiments, after promoting the expression of TLR4 in the model group, the degree of cell damage, TLR4 expression and PANoptosis further increased, while the level of TAK1 further decreased. The opposite result was obtained when TLR4 expression was inhibited. The increase in TAK1 expression in the model group reduced the degree of cell damage and PANoptosis, but the level of TLR4 was not significantly changed. In the model group of cells that exhibited TAK1 expression, further promotion of TLR4 expression inhibited the protective effect of TAK1 on cells. In the model group of cells after TAK1 expression was promoted, if the expression of TLR4 was further promoted, the protective effect of TAK1 on cells was inhibited. CONCLUSION: IETM inhibited the expression of TAK1 by binding to TLR4 molecules and promoting hepatocyte PANoptosis during ALF. Promoting TAK1 expression effectively relieved lipopolysaccharide-induced hepatocyte PANoptosis.

Human umbilical cord mesenchymal stem cells protect against ferroptosis in acute liver failure through the IGF1-hepcidin-FPN1 axis and inhibiting iron loading.

Acute liver failure (ALF) is a significant global issue with elevated morbidity and mortality rates. There is an urgent and pressing need for secure and effective treatments. Ferroptosis, a novel iron-dependent regulation of cell death, plays a significant role in multiple pathological processes associated with liver diseases, including ALF. Several studies have demonstrated that mesenchymal stem cells (MSCs) have promising therapeutic potential in the treatment of ALF. This study aims to investigate the positive effects of MSCs against ferroptosis in an ALF model and explore the underlying molecular mechanisms of their therapeutic function. Our results show that intravenously injected MSCs protect against ferroptosis in ALF mouse models. MSCs decrease iron deposition in the liver of ALF mice by downregulating hepcidin level and upregulating FPN1 level. MSCs labelled with Dil are mainly observed in the hepatic sinusoid and exhibit colocalization with the macrophage marker CD11b fluorescence. ELISA demonstrates a high level of IGF1 in the CCL 4+MSC group. Suppressing the IGF1 effect by the PPP blocks the therapeutic effect of MSCs against ferroptosis in ALF mice. Furthermore, disruption of IGF1 function results in iron deposition in the liver tissue due to impaired inhibitory effects of MSCs on hepcidin level. Our findings suggest that MSCs alleviate ferroptosis induced by disorders of iron metabolism in ALF mice by elevating IGF1 level. Moreover, MSCs are identified as a promising cell source for ferroptosis treatment in ALF mice.

Silencing of GDF11 suppresses hepatocyte apoptosis to relieve LPS/D-GalN acute liver failure.

In this paper, we generated a short hairpin RNA growth differentiation factor-11 (sh-GDF11) and evaluated the effects of sh-GDF11 on the pathogenesis of acute liver failure (ALF) in vitro and in vivo. Through bioinformatics study, the key gene related to ALF was assayed. Lipopolysaccharide (LPS) and D-galactoamine (D-GalN) were applied to establish the mouse model of LPS/D-GalN-induced liver injury, and TNF-α and D-Gal were used to construct an in vitro cell model, followed by treatment of sh-GDF11 for analysis of liver cell proliferation. Bioinformatics analysis showed that the protective effect of sh-GDF11 on ALF may be mediated by phosphatidylinositol-3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. The results of in vitro study found that sh-GDF11 could promote cell proliferation and inhibit death by blocking the PI3K/Akt/mTOR signaling pathway. In vivo animal experiments further confirmed that sh-GDF11 could suppress hepatocyte apoptosis by inhibiting the PI3K/Akt/mTOR signaling pathway. sh-GDF11 relieved LPS/D-GalN-induced ALF by blocking the PI3K/Akt/mTOR signaling pathway, emphasizing its critical role in LPS/D-GalN-induced ALF treatment.

The role and mechanisms of macrophage polarization and hepatocyte pyroptosis in acute liver failure.

Acute liver failure (ALF) is a severe liver disease caused by disruptions in the body's immune microenvironment. In the early stages of ALF, Kupffer cells (KCs) become depleted and recruit monocytes derived from the bone marrow or abdomen to replace the depleted macrophages entering the liver. These monocytes differentiate into mature macrophages, which are activated in the immune microenvironment of the liver and polarized to perform various functions. Macrophage polarization can occur in two directions: pro-inflammatory M1 macrophages and anti-inflammatory M2 macrophages. Controlling the ratio and direction of M1 and M2 in ALF can help reduce liver injury. However, the liver damage caused by pyroptosis should not be underestimated, as it is a caspase-dependent form of cell death. Inhibiting pyroptosis has been shown to effectively reduce liver damage induced by ALF. Furthermore, macrophage polarization and pyroptosis share common binding sites, signaling pathways, and outcomes. In the review, we describe the role of macrophage polarization and pyroptosis in the pathogenesis of ALF. Additionally, we preliminarily explore the relationship between macrophage polarization and pyroptosis, as well as their effects on ALF.

Garlic-derived exosome-like nanovesicles as a hepatoprotective agent alleviating acute liver failure by inhibiting CCR2/CCR5 signaling and inflammation.

Acute liver failure (ALF) is a life-threatening clinical syndrome mostly induced by viral infections or drug abuse. As a novel therapeutic adjuvant or delivery vehicle, plant-derived exosome-like nanovesicles (PELNVs) have been extensively studied in recent years. This study aimed to develop garlic-derived exosome-like nanovesicles (GaELNVs) in order to ameliorate liver injury induced by LPS/D-GalN in mice, inhibit inflammatory eruption and reduce inflammatory cells infiltration. The results showed that treatment with GaELNVs improved liver pathology and reduced the levels of soluble inflammatory mediators IL-6, IL-1ß and TNF-α in the serum of ALF mice. GaELNVs reversed the upregulation of Cleaved Caspase-9, Cleaved Caspase-3, p53 and Bax expression and decreased Bcl2 activation caused by D-GalN/LPS, and inhibited NF-κB p65 expression and translocation to the nucleus. Meanwhile, treatment with GaELNVs resulted significant reduction in NLRP3 activation and Caspase-1 maturation, as well as decrease in the release of the inflammatory mediator IL-18. Additionally, an upregulation of the expression of proteins related to energy metabolism and autophagy occurrence including Foxo3a, Sirt1, and LC3-II was detected in the liver. Oral administration of GaELNVs also led to significant alteration in the expression of F4/80 and CD11b in the liver. Furthermore, the detection of chemokines in mouse liver tissue revealed that GaELNVs exhibited minimal reduction in the expression of CCL2, CCL3, CCL5 and CCL8. The decreased expression of CCR2 and CCR5 in the liver suggests that GaELNVs have the ability to decrease the recruitment of monocytes from the circulation to the liver. A reduction in the infiltration of F4/80loCD11bhi monocyte-derived macrophages into the liver was also observed. This study provides novel evidence that GaELNVs can ameliorate inflammatory eruptions and hinder the migration of circulating monocytes to the liver, as well as decrease macrophage infiltration by inhibiting CCR2/CCR5 signaling. Consequently, GaELNVs hold promise as a novel therapeutic agent for clinical management of liver disease.

Avicularin alleviates acute liver failure by regulation of the TLR4/MyD88/NF-κB and Nrf2/HO-1/GPX4 pathways to reduce inflammation and ferroptosis.

Acute liver failure (ALF) is an inflammation-mediated hepatocyte death process associated with ferroptosis. Avicularin (AL), a Chinese herbal medicine, exerts anti-inflammatory and antioxidative effects. However, the protective effect of AL and the mechanism on ALF have not been reported. Our in vivo results suggest that AL significantly alleviated lipopolysaccharide (LPS)/D-galactosamine (D-GalN)-induced hepatic pathological injury, liver enzymes, inflammatory cytokines, reactive oxygen species and iron levels and increased the antioxidant enzyme activities (malondialdehyde and glutathione). Our further in vitro experiments demonstrated that AL suppressed inflammatory response in LPS-stimulated RAW 264.7 cells via blocking the toll-like receptor 4 (TLR4)/myeloid differentiation protein-88 (MyD88)/nuclear factor kappa B (NF-κB) pathway. Moreover, AL attenuated ferroptosis in D-GalN-induced HepG2 cells by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase 1 (HO-1)/glutathione peroxidase 4 (GPX4) pathway. Therefore, AL can alleviate inflammatory response and ferroptosis in LPS/D-GalN-induced ALF, and its protective effects are associated with blocking TLR4/MyD88/NF-κB pathway and activating Nrf2/HO-1/GPX4 pathway. Moreover, AL is a promising therapeutic option for ALF and should be clinically explored.

HIF-1α inhibition in macrophages preserves acute liver failure by reducing IL-1ß production.

The development of acute liver failure (ALF) is dependent on its local inducer. Inflammation is a high-frequency and critical factor that accelerates hepatocyte death and liver failure. In response to injury stress, the expression of the transcription factor hypoxia-inducible factor-1α (HIF-1α) in macrophages is promoted by both oxygen-dependent and oxygen-independent mechanisms, thus promoting the expression and secretion of the cytokine interleukin-1ß (IL-1ß). IL-1ß further induces hepatocyte apoptosis or necrosis by signaling through the receptor (IL-1R) on hepatocyte. HIF-1α knockout in macrophages or IL-1R knockout in hepatocytes protects against liver failure. However, whether HIF-1α inhibition in macrophages has a protective role in ALF is unclear. In this study, we revealed that the small molecule HIF-1α inhibitor PX-478 inhibits the expression and secretion of IL-1ß, but not tumor necrosis factor α (TNFα), in bone marrow-derived macrophages (BMDMs). PX-478 pretreatment alleviates liver injury in LPS/D-GalN-induced ALF mice by decreasing the hepatic inflammatory response. In addition, preventive or therapeutic administration of PX-478 combined with TNFα neutralizing antibody markedly improved LPS/D-GalN-induced ALF. Taken together, our data suggest that PX-478 administration leads to HIF-1α inhibition and decreased IL-1ß secretion in macrophages, which represents a promising therapeutic strategy for inflammation-induced ALF.

Calycosin inhibits hepatocyte apoptosis in acute liver failure by suppressing the TLR4/NF-κB pathway: An in vitro study.

BACKGROUND: Acute liver failure (ALF) is a serious liver disease that is difficult to treat owing to its unclear pathogenesis. This study aimed to investigate the roles and molecular mechanisms of calycosin (CA) in ALF. METHODS: In this study, the roles and mechanism of CA in ALF were explored using an in vitro lipopolysaccharide (LPS)-induced ALF cell model. Additionally, 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyltetrazolium bromide assay was used to assess the effect of CA on the activity of LPS-induced L02 human liver epithelial cells, and flow cytometry was used to detect apoptosis in L02 cells. Expression levels of apoptosis-related genes, Bax and Bcl-2, were measured using reverse transcription-quantitative polymerase chain reaction and Western blot analysis. Expression levels of inflammatory factors in LPS-induced L02 cells were measured using an enzyme-linked immunosorbent assay. Additionally, the effect of CA on ALF was inhibited via transfection of a toll-like receptor 4 (TLR4)-plasmid to elucidate the relationship between CA and TLR4/nuclear factor (NF)-κB signaling pathway in ALF. RESULTS: CA had no toxic effects on L02 cells, but enhanced the activity of LPS-induced L02 cells in a dose-dependent manner. Apoptosis and inflammatory factor release was increased in ALF, activating the TLR4/NF-κB signaling pathway. However, CA treatment inhibited the apoptosis and release of inflammatory factors. Further mechanistic studies revealed that the upregulation of TLR4 expression reversed the alleviating effects of CA on inflammation and apoptosis in LPS-induced L02 cells. CONCLUSION: CA alleviates inflammatory damage in LPS-induced L02 cells by inhibiting the TLR4/NF-κB pathway and may be a promising therapeutic agent for ALF treatment.

Human embryonic stem cell-derived immunity-and-matrix regulatory cells promote intrahepatic cell renewal to rescue acute liver failure.

Acute liver failure (ALF) is a clinical syndrome characterized by the accelerated development of hepatocyte necrosis and significant mortality. Given that liver transplantation is now the only curative treatment available for ALF, there is an urgent need to explore innovative therapies. Mesenchymal stem cells (MSCs) have been applied in preclinical studies for ALF. It had been demonstrated that human embryonic stem cell-derived immunity-and-matrix regulatory cells (IMRCs) met the properties of MSCs and had been employed in a wide range of conditions. In this study, we conducted a preclinical evaluation of IMRCs in the treatment of ALF and investigated the mechanism involved. ALF was induced in C57BL/6 mice via intraperitoneal administration of 50% CCl4 (6 mL/kg) mixed with corn oil, followed by intravenous injection of IMRCs (3 × 106 cells/each). IMRCs improved histopathological changes in the liver and reduced alanine transaminase (ALT) or aspartate transaminase (AST) levels in serum. IMRCs also promoted cell renewal in the liver and protected it from CCl4 damage. Furthermore, our data indicated that IMRCs protected against CCl4-induced ALF by regulating the IGFBP2-mTOR-PTEN signaling pathway, which is associated with the repopulation of intrahepatic cells. Overall, IMRCs offered protection against CCl4-induced ALF and were capable of preventing apoptosis and necrosis in hepatocytes, which provided a new perspective for treating and improving the prognosis of ALF.

Integrated Analysis of Gut Microbiome and Liver Metabolome to Evaluate the Effects of Fecal Microbiota Transplantation on Lipopolysaccharide/D-galactosamine-Induced Acute Liver Injury in Mice.

Acute liver failure (ALF) refers to the occurrence of massive hepatocyte necrosis in a short time, with multiple complications, including inflammatory response, hepatic encephalopathy, and multiple organ failure. Additionally, effective therapies for ALF are lacking. There exists a relationship between the human intestinal microbiota and liver, so intestinal microbiota modulation may be a strategy for therapy of hepatic diseases. In previous studies, fecal microbiota transplantation (FMT) from fit donors has been used to modulate intestinal microbiota widely. Here, we established a mouse model of lipopolysaccharide (LPS)/D-galactosamine (D-gal) induced ALF to explore the preventive and therapeutic effects of FMT, and its mechanism of action. We found that FMT decreased hepatic aminotransferase activity and serum total bilirubin levels, and decreased hepatic pro-inflammatory cytokines in LPS/D-gal challenged mice (p < 0.05). Moreover, FMT gavage ameliorated LPS/D-gal induced liver apoptosis and markedly reduced cleaved caspase-3 levels, and improved histopathological features of the liver. FMT gavage also restored LPS/D-gal-evoked gut microbiota dysbiosis by modifying the colonic microbial composition, improving the abundance of unclassified_o_Bacteroidales (p < 0.001), norank_f_Muribaculaceae (p < 0.001), and Prevotellaceae_UCG-001 (p < 0.001), while reducing that of Lactobacillus (p < 0.05) and unclassified_f_Lachnospiraceae (p < 0.05). Metabolomics analysis revealed that FMT significantly altered LPS/D-gal induced disordered liver metabolites. Pearson's correlation revealed strong correlations between microbiota composition and liver metabolites. Our findings suggest that FMT ameliorate ALF by modulating gut microbiota and liver metabolism, and can used as a potential preventive and therapeutic strategy for ALF.

Lipidomics Study of Sepsis-Induced Liver and Lung Injury under Anti-HMGB1 Intervention.

Sepsis usually leads to lethal multiorgan dysfunction including acute liver failure (ALF) and acute lung injury (ALI). This research sought to reveal the lipid alteration of anti-high mobility group box 1 (HMGB1) treatment in sepsis-induced ALF and ALI by lipidomics. The cecal ligation and puncture-induced mouse model was established and the anti-HMGB1 neutralizing antibody was administrated. The histopathological characteristics and inflammatory factors were determined to assess the efficacy of the antibody. Utraperformance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was used to determine lipid metabolism profiles in the liver and lung. The underlying biomarkers were identified through multivariate statistical analysis and correlation analysis with traditional physiological indicators. The pathological and biochemical results demonstrated that anti-HMGB1 neutralizing antibodies mitigated ALF and ALI in mice. Three differential metabolites in the liver and six various metabolites in the lung were significantly reversed by anti-HMGB1 treatment, mainly involved in arachidonic acid metabolism, glycerophospholipid metabolism, and sphingolipid metabolism. Additionally, we investigated several traditional signaling pathways associated with HMGB1. However, the correlation between these traditional pathways and anti-HMGB1 intervention was not significant in the current study. In conclusion, our finding provided some scientific basis for targeting HMGB1 in sepsis-induced liver and lung injury. Mass spectrometry data with identifier no. MTBLS6466 have been uploaded to MetaboLights (http://www.ebi.ac.uk/metabolights/login).

A case of acute liver failure due to aggressive natural killer-cell leukemia with a rapid course.

An 87-year-old man consulted a former doctor with a complaint of black stool and was admitted to hospital because of anemia and multiple gastric ulcers. The laboratory findings showed that his hepatobiliary enzyme levels and inflammatory response were elevated. Computed tomography showed hepatosplenomegaly and enlarged intra-abdominal lymph nodes. Two days later, he was transferred to our hospital due to deterioration of his liver function. Since he had low level of consciousness and his ammonia level was high, we diagnosed him with acute liver failure (ALF) with hepatic coma, and started on-line hemodiafiltration. As the cause of ALF, we suspected hepatic involvement of a hematologic tumor because of high lactate dehydrogenase and soluble interleukin-2 receptor levels and large abnormal lymphocyte-like cells in the peripheral blood. Because of his poor general condition, bone marrow and other histological examinations were difficult, and he died on the third day of hospitalization. Pathological autopsy showed marked hepatosplenomegaly and the proliferation of large abnormal lymphocyte-like cells in the bone marrow, liver, spleen, and lymph nodes. Immunostaining revealed aggressive natural killer-cell leukemia (ANKL).We herein report a rare case of the development of ALF with coma due to ANKL with a review of the relevant literature.

Upregulated microRNA-450b-5p represses the development of acute liver failure via modulation of liver function, inflammatory response, and hepatocyte apoptosis.

OBJECTIVE: It has been evidenced that microRNAs (miRs) exert crucial effects on acute liver failure (ALF), while the detailed function of miR-450b-5p in ALF progression remained obscure. The purpose of this research was to unravel the regulatory mechanism of miR-450b-5p in ALF via modulating Mouse Double Minute 2 protein (MDM2). METHODS: ALF was induced in mice by intraperitoneal injection of d-galactosamine ( d-GalN) and lipopolysaccharide (LPS). Adenoviruses containing overexpressed miR-450b-5p, MDM2 shRNA, and overexpressed MDM2 sequences were utilized to manipulate miR-450b-5p and MDM2 expression in the liver before the mice were treated with d-GalN/LPS-induced ALF. Subsequently, miR-450b-5p and MDM2 expression levels in liver tissues of ALF mice were examined. Serum biochemical parameters of liver function were tested, serum inflammatory factors were assessed, and the histopathological changes and hepatocyte apoptosis in liver tissues were observed. The relation between miR-450b-5p and MDM2 was verified. RESULTS: In ALF mice, miR-450b-5p was low-expressed while MDM2 was high-expressed. The upregulation of miR-450b-5p or downregulation of MDM2 could alleviate liver function, mitigate the serum inflammatory response and pathological changes in liver tissues, as well as inhibit the apoptosis of hepatocytes. MiR-450b-5p targeted MDM2. MDM2 overexpression reversed the repressive effects of elevated miR-450b-5p on ALF. CONCLUSION: The upregulated miR-450b-5p blocks the progression of ALF via targeting MDM2. This study contributes to affording novel therapeutic targets for ALF treatment.

Nrf2 and its dependent autophagy activation cooperatively counteract ferroptosis to alleviate acute liver injury.

Ferroptosis has been implicated in the pathophysiological progression of a variety of diseases. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a key regulator of cellular antioxidant response and can counteract ferroptosis by inducing autophagy and targeting genes involved in iron metabolism and glutathione (GSH) synthesis/metabolism. This study investigated how Nrf2 and autophagy interact to prevent ferroptosis in acute liver injury under sulforaphane (SFN) intervention. The results showed that SFN could activate Nrf2 signaling pathway and its downstream target genes, promote cell autophagy, and then combat ferroptosis to alleviate liver injury. After inhibiting Nrf2, the autophagy activated by SFN almost disappeared, and the anti-ferroptosis effect was greatly weakened. After inhibiting autophagy, SFN can still activate Nrf2 and its downstream target gene, but solute carrier family 7 member 11 (SLC7A11) membrane transfer and its cystine transport ability are significantly weakened, thus ultimately attenuating the anti-ferroptosis effect of SFN. Further studies showed that Nrf2-dependent autophagy activation disrupted SLC7A11 binding to S93-phosphorylated coiled-coil myosin-like BCL2-interacting protein (BECN1) and increased SLC7A11 membrane transfer to combat ferroptosis. In conclusion, Nrf2-dependent autophagy activation is essential for promoting SLC7A11 membrane localization to inhibit ferroptosis. Activation of Nrf2 not only upregulates the expression of SLC7A11, glutathione peroxidase 4 (GPX-4) and autophagy-related proteins, but also destroys the binding of SLC7A11 and BECN1 by inducing autophagy, thereby promoting SLC7A11 membrane transfer and GSH synthesis, and finally suppressing ferroptosis. However, inhibition of autophagy had no significant effect on the expression of Nrf2 and downstream genes during SFN anti-liver injury intervention.

Therapeutic potential of mesenchymal stem cells in the treatment of acute liver failure.

Acute liver failure (ALF) is a severe and life-threatening condition in which rapid deterioration of liver function develops in a patient who has no preexisting liver disease. Mesenchymal stem cells (MSCs) are immunoregulatory stem cells which are able to modulate phenotype and function of all immune cells that play pathogenic role in the development and progression of ALF. MSCs in juxtacrine and paracrine manner attenuate antigen-presenting properties of dendritic cells and macrophages, reduce production of inflammatory cytokines in T lymphocytes, suppress hepatotoxicity of natural killer T (NKT) cells and promote generation and expansion of immunosuppressive T, B and NKT regulatory cells in acutely inflamed liver. Due to their nano-sized dimension and lipid envelope, intravenously injected MSC-derived exosomes (MSC-Exos) may by-pass all biological barriers to deliver MSC-sourced immunoregulatoy factors directly into the liver-infiltrated immune cells and injured hepatocytes. Results obtained by us and others revealed that intravenous administration of MSCs and MSC-Exos efficiently attenuated detrimental immune response and acute inflammation in the liver, suggesting that MSCs and MSC-Exos could be considered as potentially new remedies in the immunotherapy of ALF. In this review, we emphasize the current knowledge about molecular and cellular mechanisms which are responsible for MSC-based modulation of liver-infiltrated immune cells and we discuss different insights regarding the therapeutic potential of MSCs in liver regeneration.

A case of drug-induced acute liver failure caused by corticosteroids.

We report a 61-year-old man treated with betamethasone for sudden-onset deafness. Several days later, he had a temperature > 38 °C. He sought care at another hospital and was admitted based on abnormal liver function tests (aspartate aminotransferase [AST], 866 IU/L [normal < 31 IU/L] and alanine aminotransferase [ALT] 1524 IU/L [normal < 31 IU/L]). Liver function improved daily and the patient was discharged from the hospital after 5 days. Two days after discharge, he had a recurrent fever and liver dysfunction. After admission to our hospital, liver function improved spontaneously. A liver biopsy was performed, but a diagnosis was not established; however, a tentative diagnosis of antinuclear antibody-negative autoimmune hepatitis was made and the patient was started on prednisolone (30 mg). Two days later, he developed a fever and persistent liver dysfunction, thus the prednisolone was discontinued. The next day, the AST and ALT increased significantly (18,000 and 12,000 U/L, respectively). Because the level of consciousness was altered, plasma exchange was started for acute liver failure. After discontinuing the prednisolone, the hospital course was uneventful. Drug-induced liver injury due to corticosteroids is rare. Herein, we report a patient with acute liver failure who survived with timely treatment.

Long COVID-19 Liver Manifestation in Children.

OBJECTIVES: Severe acute respiratory syndrome coronavirus 2, the novel coronavirus responsible for coronavirus disease (COVID-19), has been a major cause of morbidity and mortality worldwide. Gastrointestinal and hepatic manifestations during acute disease have been reported extensively in the literature. Post-COVID-19 cholangiopathy has been increasingly reported in adults. In children, data are sparse. Our aim was to describe pediatric patients who recovered from COVID-19 and later presented with liver injury. METHODS: This is a retrospective case series study of pediatric patients with post-COVID-19 liver manifestations. We collected data on demographics, medical history, clinical presentation, laboratory results, imaging, histology, treatment, and outcome. RESULTS: We report 5 pediatric patients who recovered from COVID-19 and later presented with liver injury. Two types of clinical presentation were distinguishable. Two infants aged 3 and 5 months, previously healthy, presented with acute liver failure that rapidly progressed to liver transplantation. Their liver explant showed massive necrosis with cholangiolar proliferation and lymphocytic infiltrate. Three children, 2 aged 8 years and 1 aged 13 years, presented with hepatitis with cholestasis. Two children had a liver biopsy significant for lymphocytic portal and parenchyma inflammation, along with bile duct proliferations. All 3 were started on steroid treatment; liver enzymes improved, and they were weaned successfully from treatment. For all 5 patients, extensive etiology workup for infectious and metabolic etiologies was negative. CONCLUSIONS: We report 2 distinct patterns of potentially long COVID-19 liver manifestations in children with common clinical, radiological, and histopathological characteristics after a thorough workup excluded other known etiologies.

A Dual Role of Complement Activation in the Development of Fulminant Hepatic Failure Induced by Murine-Beta-Coronavirus Infection.

With the epidemic of betacoronavirus increasing frequently, it poses a great threat to human public health. Therefore, the research on the pathogenic mechanism of betacoronavirus is becoming greatly important. Murine hepatitis virus strain-3 (MHV-3) is a strain of betacoronavirus which cause tissue damage especially fulminant hepatic failure (FHF) in mice, and is commonly used to establish models of acute liver injury. Recently, MHV-3-infected mice have also been introduced to a mouse model of COVID-19 that does not require a Biosafety Level 3 (BSL-3) facility. FHF induced by MHV-3 is a type of severe liver damage imbalanced by regenerative hepatocellular activity, which is related to numerous factors. The complement system plays an important role in host defense and inflammation and is involved in first-line immunity and/or pathogenesis of severe organ disorders. In this study, we investigated the role of aberrant complement activation in MHV-3 infection-induced FHF by strategies that use C3-deficient mice and intervene in the complement system. Our results showed that mice deficient in C3 had more severe liver damage, a higher viral load in the liver and higher serum concentrations of inflammatory cytokines than wild-type controls. Treatment of C57BL/6 mice with C3aR antagonist or anti-C5aR antibody reduced liver damage, viral load, and serum IFN-γ concentration compared with the control group. These findings indicated that complement system acts as a double-edged sword during acute MHV-3 infection. However, its dysregulated activation leads to sustained inflammatory responses and induces extensive liver damage. Collectively, by investigating the role of complement activation in MHV-3 infection, we can further understand the pathogenic mechanism of betacoronavirus, and appropriate regulation of immune responses by fine-tuning complement activation may be an intervention for the treatment of diseases induced by betacoronavirus infection.

Pediatric Acute Liver Failure: A Clinicopathological Perspective.

Pediatric acute liver failure (PALF) is a life-threatening disorder characterized by acute hepatocellular injury occurring in children without recognized underlying liver disease. The clinicopathologic evaluation of PALF requires a different approach from that in adults. The diagnostic considerations differ depending on the age, personal and family history, geographical region, and clinical presentation. Distinct entities such as gestational alloimmune liver disease, herpes simplex virus infection, and metabolic disorders should be considered in neonates with acute liver failure, while acetaminophen toxicity and autoimmune hepatitis are more frequently seen in older children and adolescents. An identified cause for PALF despite a negative complete evaluation (indeterminate) is lacking in 30 to 50% of cases. Although not routinely performed in the setting of PALF, liver biopsy may be helpful in assessing the etiology, potential mechanisms of injury, determining the appropriateness of liver transplantation, and prognostication of the patients. In this article, we review the clinicopathologic characteristics of PALF with an emphasis on general approach of pathologic evaluation and histopathologic characteristic of selected entities.

Case report: A novel cause of acute liver failure in children: A combination of human herpesvirus-6 infection and homozygous mutation in NBAS gene.

Etiologies of acute liver failure in children can be multiple factors including virus infection, drug-induced damage, and different pathogens. Next-generation sequencing (NGS) is an emerging method for pan-pathogen screening. Here we reported a case of acute liver failure in a 15-month-old male, using NGS and gene sequencing to determine the cause of acute liver failure may be caused by pathogens, drug-induction and pathogenic variant gene.