Symbiotic combination of Akkermansia muciniphila and inosine alleviates alcohol-induced liver injury by modulating gut dysbiosis and immune responses.

Background: Alcoholic liver disease (ALD) is exacerbated by disruptions in intestinal microecology and immune imbalances within the gut-liver axis. The present study assesses the therapeutic potential of combining Akkermansia muciniphila (A. muciniphila) with inosine in alleviating alcohol-induced liver injury. Methods: Male C57BL/6 mice, subjected to a Lieber-DeCarli diet with 5% alcohol for 4 weeks, served as the alcoholic liver injury model. Various analyzes, including quantitative reverse transcription polymerase chain reaction (qRT-PCR), ELISA, immunochemistry, 16S rRNA gene sequencing, and flow cytometry, were employed to evaluate liver injury parameters, intestinal barrier function, microbiota composition, and immune responses. Results: Compared to the model group, the A. muciniphila and inosine groups exhibited significantly decreased alanine aminotransferase, aspartate aminotransferase, and lipopolysaccharide (LPS) levels, reduced hepatic fat deposition and neutrophil infiltration, alleviated oxidative stress and inflammation, and increased expression of intestinal tight junction proteins (Claudin-1, Occludin, and ZO-1). These effects were further pronounced in the A. muciniphila and inosine combination group compared to individual treatments. While alcohol feeding induced intestinal dysbiosis and gut barrier disruption, the combined treatment reduced the abundance of harmful bacteria (Oscillibacter, Escherichia/Shigella, and Alistipes) induced by alcohol consumption, promoting the growth of butyrate-producing bacteria (Akkermansia, Lactobacillus, and Clostridium IV). Flow cytometry revealed that alcohol consumption reduced T regulatory (Treg) populations while increasing those of T-helper (Th) 1 and Th17, which were restored by A. muciniphila combined with inosine treatment. Moreover, A. muciniphila and inosine combination increased the expression levels of intestinal CD39, CD73, and adenosine A2A receptor (A2AR) along with enhanced proportions of CD4+CD39+Treg and CD4+CD73+Treg cells in the liver and spleen. The A2AR antagonist KW6002, blocked the beneficial effects of the A. muciniphila and inosine combination on liver injury in ALD mice. Conclusion: This study reveals that the combination of A. muciniphila and inosine holds promise for ameliorating ALD by enhancing the gut ecosystem, improving intestinal barrier function, upregulating A2AR, CD73, and CD39 expression, modulating Treg cells functionality, and regulating the imbalance of Treg/Th17/Th1 cells, and these beneficial effects are partly A2AR-dependent.

Loss of GCN5L1 exacerbates damage in alcoholic liver disease through ferroptosis activation.

BACKGROUND AND AIMS: Iron overload, oxidative stress and ferroptosis are associated with liver injury in alcohol-associated liver disease (ALD), however, the crosstalk among these regulatory pathways in ALD development is unclear. METHODS: ALD mouse model and general control of amino acid synthesis 5 like 1 (GCN5L1) liver knockout mice were generated to investigate the role of GCN5L1 in ALD development. Proteomic screening tests were performed to identify the key factors mediating GCN5L1 loss-induced ALD. RESULTS: Gene Expression Omnibus data set analysis indicates that GCN5L1 expression is negatively associated with ALD progression. GCN5L1 hepatic knockout mice develop severe liver injury and lipid accumulation when fed an alcohol diet. Screening tests identified that GCN5L1 targeted the mitochondrial iron transporter CISD1 to regulate mitochondrial iron homeostasis in ethanol-induced ferroptosis. GCN5L1-modulated CISD1 acetylation and activity were crucial for iron accumulation and ferroptosis in response to alcohol exposure. CONCLUSION: Pharmaceutical modulation of CISD1 activity is critical for cellular iron homeostasis and ethanol-induced ferroptosis. The GCN5L1/CISD1 axis is crucial for oxidative stress and ethanol-induced ferroptosis in ALD and is a promising avenue for novel therapeutic strategies.

Falsely low glycosylated haemoglobin levels probably secondary to hypersplenism in a patient with diabetes mellitus.

A man in his 70s presented with a history of low glycated haemoglobin (HbA1c) values despite a diagnosis of type 2 diabetes. His blood glucose readings ranged between 8 and 15 mmol/L, but his HbA1c values were below 27 mmol/mol. Initial investigations demonstrated evidence of reduced red blood cell lifespan as a cause of misleadingly low HbA1c values. Further investigation revealed chronic liver disease and splenomegaly, with hypersplenism being the probable cause of increased red blood cell turnover. HbA1c estimation was no longer reliable, so ongoing diabetic care was guided by home capillary blood glucose monitoring. Healthcare providers and clinical laboratorians need to be aware of the possible clinical implications of very low HbA1c values in patients with type 2 diabetes.

[Mechanism of Shenling Baizhu Powder on treatment of alcoholic liver disease by regulating TLR4/NLRP3 pathway].

This study aims to investigate the regulatory effects of Shenling Baizhu Powder(SBP) on cellular autophagy in alcoholic liver disease(ALD) and its intervention effect through the TLR4/NLRP3 pathway. A rat model of chronic ALD was established by gavage of spirits. An ALD cell model was established by stimulating BRL3A cells with alcohol. High-performance liquid chromatography(HPLC) was utilized for the compositional analysis of SBP. Liver tissue from ALD rats underwent hematoxylin-eosin(HE) and oil red O staining for pathological evaluation. Enzyme-linked immunosorbent assay(ELISA) was applied to quantify lipopolysaccharides(LPS), tumor necrosis factor-alpha(TNF-α), interleukin-1 beta(IL-1ß), and interleukin-18(IL-18) levels. Quantitative reverse transcription polymerase chain reaction(qRT-PCR) was conducted to evaluate the mRNA expression of myeloid differentiation factor 88(MyD88) and Toll-like receptor 4(TLR4). The effect of different drugs on BRL3A cell proliferation activity was assessed through CCK-8 analysis. Western blot analysis was performed to examine the protein expression of NOD-like receptor pyrin domain-containing 3(NLRP3), nuclear factor-kappa B P65(NF-κB P65), phosphorylated nuclear factor-kappa B P65(p-P65), caspase-1, P62, Beclin1, and microtubule-associated protein 1 light chain 3(LC3Ⅱ). The results showed that SBP effectively ameliorated hepatic lipid accumulation, reduced liver function, mitigated hepatic tissue inflammation, and reduced levels of LPS, TNF-α, IL-1ß, and IL-18. Moreover, SBP exhibited the capacity to modulate hepatic autophagy induced by prolonged alcohol intake through the TLR4/NLRP3 signaling pathway. This modulation resulted in decreased expression of LC3Ⅱ and Beclin1, an elevation in P62 expression, and the promotion of autolysosome formation. These research findings imply that SBP can substantially enhance liver function and mitigate lipid irregularities in the context of chronic ALD. It achieves this by regulating excessive autophagic responses caused by prolonged spirit consumption, primarily through the inhibition of the TLR4/NLRP3 pathway.

Mechanism of Xing 9 ling tablet candy for alcoholic liver disease based on network pharmacology.

Xing 9 Ling tablet candy (X9LTC) effectively treats alcoholic liver disease (ALD), but its potential mechanism and molecular targets remain unstudied. We aimed to address this gap using network pharmacology. Furthermore, high-performance liquid chromatography (HPLC) and database analysis revealed a total of 35 active ingredients and 311 corresponding potential targets of X9LTC. Protein interaction analysis revealed PTGS2, JUN, and FOS as its core targets. Enrichment analysis indicated that chemical carcinogenesis-receptor activation, IL-17 and TNF signaling pathway were enriched by multiple core targets, which might be the main pathway of action. Further molecular docking validation showed that the core targets had good binding activities with the identified compounds. Animal experiments showed that X9LTC could reduce the high expression of ALT, AST and TG in the serum of ALD mice, alleviate the lesions in liver tissues, and reverse the high expression of PTGS2, JUN, and FOS proteins in the liver tissues. In this study, we established a method for the determination of X9LTC content for the first time, and predicted its active ingredient and mechanism of action in treating ALD, providing theoretical basis for further research.

Modest effect of differential dietary vitamin A intake on the pathogenesis of alcohol-associated liver disease.

BACKGROUND: Chronic alcohol consumption is a major public health issue. The primary organ damaged by alcohol abuse is the liver, leading to alcohol-associated liver disease (ALD). ALD begins with hepatic steatosis and can progress to fibrosis and cirrhosis; however, we have an incomplete understanding of ALD pathogenesis. Interestingly, the liver is also the major organ for vitamin A metabolism and storage, and ALD has previously been linked with altered hepatic vitamin A homeostasis. We hypothesize that alcohol-induced vitamin A depletion disrupts its normal function in the liver, contributing to the pathogenesis of ALD. To test this hypothesis, we postulated that adding copious vitamin A to the diet might alleviate ALD, and conversely, that a vitamin A deficient diet would worsen ALD. METHODS: We conducted two dietary intervention studies in mice comparing deficient (0 IU/g diet) and copious (25 IU/g diet) dietary vitamin A intake versus control (4 IU/g diet), using the NIAAA chronic-binge model of ALD. Hepatic steatosis was assessed using histopathological and biochemical approaches. Tissue Vitamin A levels were measured using high-performance liquid chromatography. Markers of ALD, hepatic inflammation and lipid metabolism were analyzed by the quantitative polymerase chain reaction and western blotting. RESULTS: As expected, a 0 IU/g Vitamin A diet decreased, and a 25 IU/g Vitamin A diet increased hepatic Vitamin A stores. However, alcohol induced changes in hepatic triglyceride levels, markers of hepatic lipid metabolism, inflammation and fibrosis were not significantly different in mice consuming a copious or deficient vitamin A diet compared to control. CONCLUSIONS: Altered vitamin A intake and hepatic vitamin A storage have a minor effect on the pathogenesis of ALD. Thus, given the known link between altered retinoic acid signaling and ALD, future studies that further explore this linkage are warranted.

Increased prevalence but decreased survival of nonviral hepatocellular carcinoma compared to viral hepatocellular carcinoma in recent ten years.

Due to the comprehensive hepatitis B virus vaccination program in Taiwan since 1986, the development of antiviral therapy for chronic hepatitis B and chronic hepatitis C infection and covered by National health insurance. Besides, the increased prevalence of nonalcoholic fatty liver disease (NAFLD) and currently, approved therapy for NAFLD remain developing. The etiology of liver-related diseases such as cirrhosis and hepatocellular carcinoma required reinterpretation. This study aimed to analyze the incidence and outcome of hepatocellular carcinoma (HCC) due to viral (hepatitis B and hepatitis C) infection compared to that of nonviral etiology. We retrospectively analyzed patients with HCC from January 2011 to December 2020 from the cancer registry at our institution. Viral-related hepatitis was defined as hepatitis B surface antigen positivity or anti-hepatitis C virus (HCV) antibody positivity. A total of 2748 patients with HCC were enrolled, of which 2188 had viral-related HCC and 560 had nonviral-related HCC. In viral HCC group, the median age at diagnosis was significantly lower (65 years versus 71 years, p < 0.001), and the prevalence of early-stage HCC, including stage 0 and stage A Barcelona Clinic Liver Cancer, was significantly higher (52.9% versus 33.6%, p < 0.001). In nonviral HCC group, alcohol use was more common (39.9% versus 30.1%, p < 0.001), the prevalence of type 2 diabetes mellitus (T2DM) was higher (54.5% versus 35.1%, p < 0.001), and obesity was common (25.0% versus 20.5%, p = 0.026). The prevalence of nonviral HCC increased significantly from 19.2 to 19.3% and 23.0% in the last 10 years (p = 0.046). Overall survival was better in the viral HCC group (5.95 years versus 4.00 years, p < 0.001). In the early stage of HCC, overall survival was still better in the viral HCC group (p < 0.001). The prevalence of nonviral HCC has significantly increased in the last ten years. The overall survival was significantly lower in the nonviral HCC, perhaps because the rate of early HCC detection is lower in nonviral HCC and anti-viral therapy. To detect nonviral HCC early, we should evaluate liver fibrosis in high-risk groups (including people with obesity or T2DM with NAFLD/NASH and alcoholic liver disease) and regular follow-up for those with liver fibrosis, regardless of cirrhosis.

Advances in the Pathogenesis of Metabolic Liver Disease-Related Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the sixth most common cancer globally and the primary cause of death in cancer cases, with significant public health concern worldwide. Despite the overall decline in the incidence and mortality rates of HCC in recent years in recent years, the emergence of metabolic liver disease-related HCC is causing heightened concern, especially in countries like the United States, the United Kingdom, and P.R. China. The escalation of metabolic liver disease-related HCC is attributed to a combination of factors, including genetic predisposition, lifestyle choices, and changes in the living environment. However, the pathogenesis of metabolic liver disease-associated HCC remains imperfect. In this review, we encapsulate the latest advances and essential aspects of the pathogenesis of metabolic liver disease-associated HCC, including alcoholic liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and inherited metabolic liver diseases.

Changes in the etiology of liver cirrhosis and the corresponding management strategies.

We read with interest the article by Xing Wang, which was published in the recent issue of the World Journal of Hepatology 2023; 15: 1294-1306. This article focuses particularly on the prevalence and trends in the etiology of liver cirrhosis (LC), prognosis for patients suffering from cirrhosis-related complications and hepatocellular carcinoma (HCC), and management strategies. The etiology of cirrhosis varies according to geographical, economic, and population factors. Viral hepatitis is the dominant cause in China. Vaccination and effective treatment have reduced the number of people with viral hepatitis, but the overall number is still large. Patients with viral hepatitis who progress over time to LC and HCC remain an important population to manage. The increased incidence of metabolic syndrome and alcohol consumption is likely to lead to a potential exponential increase in metabolic dysfunction-associated steatotic liver disease (MASLD)-associated LC and alcoholic liver disease in the future. Investigating the evolution of the etiology of LC is important for guiding the direction of future research and policy development. These changing trends indicate a need for greater emphasis on tackling obesity and diabetes, and implementing more effective measures to regulate alcohol consumption in order to reduce the occurrence of MASLD. In an effort to help cope with these changing trends, the authors further proposed countermeasures for healthcare authorities doctors, and patients.

Clinical efficacy of probiotics in the treatment of alcoholic liver disease: a systematic review and meta-analysis.

Objective: Alcoholic liver disease (ALD) is a liver damage disease caused by long-term heavy drinking. Currently, there is no targeted pharmaceutical intervention available for the treatment of this disease. To address this, this paper evaluates the efficacy and safety of probiotic preparation in treating ALD through conducting a meta-analysis, and provides a valuable insight for clinical decision-making. Methods: A systematic search was conducted across databases, including PubMed, Embase, Web of Science, Cochrane Library, CNKI, VIP, Wanfang, and CBM from the inception dates to October 15, 2023, to identify clinical randomized controlled trials on probiotic preparations in the treatment of ALD. After the literature underwent screening, data extraction, and quality assessment, RevMan 5.3 and Stata 14.2 were employed for data analysis and processing. Results: A total of 9 randomized controlled trials fulfilled the inclusion criteria. The results of the meta-analysis showed that probiotic preparation could significantly improve the liver function of patients with alcoholic liver disease compared with the control group. Probiotic intervention led to a significant reduction in the levels of alanine aminotransferase (MD=-13.36,95%CI:-15.80,-10.91;P<0.00001),aspartate aminotransferase (MD=-16.99,95%CI:-20.38,-13.59;P<0.00001),γ-glutamyl transpeptidase (MD=-18.79,95% CI:-28.23,-9.34; P<0.0001). Concurrently, the level of serum albumin (MD=0.19,95% CI:0.02,0.36;P=0.03) was increased. Furthermore, probiotic intervention could also modulate the composition of intestinal flora in patients with alcoholic liver disease, leading to an augmentation in Bifidobacteria and a reduction in Escherichia coli. However, in patients with alcoholic liver disease, probiotic intervention showed no significant effects on total bilirubin (MD=-0.01,95% CI:-0.17,0.15;P=0.91), tumor necrosis factor-α (MD=0.03,95% CI:-0.86,0.92;P=0.94) and interleukin-6 (MD=-5.3,95% CI:-16.04,5.45;P=0.33). Conclusion: The meta-analysis indicates that probiotics can improve liver function in alcoholic liver disease, reduce inflammatory responses, regulate intestinal flora, which have potential value in the treatment of alcoholic liver disease. Systematic review registration: https://www.crd.york.ac.uk/prospero/, identifier CRD42023472527.

ENPP2/Autotaxin: The potential drug target for alcoholic liver disease identified through Mendelian randomization analysis.

BACKGROUND AND AIMS: At present, there is still a lack of radical drug targets for intervention in alcoholic liver disease (ALD), and drug discovery through randomized controlled trials is a lengthy, risky, and expensive undertaking, so we aimed to identify effective drug targets based on human genetics. METHODS: We used Mendelian randomization (MR) and Bayesian colocalization analysis to investigate 2639 genes encoding druggable proteins and examined the causal effects on ALD (PMID 34737426: 456348 European with 451 cases and 455 897 controls). In addition, we conducted the mediation analysis to explore the potential mechanism using the genome-wide association study (GWAS) data of blood biomarkers as mediators. RESULTS: We finally identified the drug target: ENPP2/Autotaxin and genetically proxied ENPP2/Autotaxin was causally associated with the risk of ALD (OR = 2.28, 95% CI: 1.64 to 3.16, p = 7.49E-7). In addition, we found that the effect of ENPP2/Autotaxin on ALD may be partly mediated by effector memory CD8+ T cell (the proportion of mediation effect: 8.49%). CONCLUSIONS: Our integrative analysis suggested that genetically determined levels of circulating ENPP2/Autotaxin have a causal effect on ALD risk and are a promising drug target.

Infections increase the risk of decompensation and death in patients with early alcohol-related liver disease.

Background & Aims: Infections are frequent in patients with cirrhosis and worsen prognosis. We evaluated the incidence of infections and their impact on decompensation and death in patients with early alcohol-related liver disease (ALD) during long-term follow-up. Methods: We performed a prospective cohort study of patients in secondary care with a history of excess alcohol intake, no prior decompensation, and with liver biopsies along with clinical investigations conducted at baseline. During follow-up, we reviewed the patients' electronic healthcare records for cases of infections, hospitalizations, transient elastography measurements, decompensations, all-cause mortality, and alcohol intake. Results: We included 461 patients with a mean age of 56±10 years (76% males; fibrosis stage F0-1/F2/F3-4 = 259/107/93 [56%/23%/20%]). During a median follow-up of 4.5 years (IQR 2.9-6.3), 134 patients (29%) developed a total of 312 infections, most frequently pneumonia (106/312, 34%) and urinary tract infections (57/312, 18%). Excessive alcohol intake during follow-up, smoking ≥30 pack years, MELD score and elevated liver stiffness during follow-up were independent predictors of infections. Patients who developed at least one infection had a significantly increased risk of subsequent decompensation (hazard ratio 4.98, 95% CI 2.47-10.03) and death (hazard ratio 8.24, 95% CI 4.65-14.59). Infections increased the risk of decompensation and death independently of baseline fibrosis stage, age, gender, and MELD score. Conclusions: Almost one-third of patients with early ALD develop an infection, which worsens their prognosis by increasing the risk of decompensation and death. The risk of infections increases with liver disease severity and ongoing harmful use of alcohol. Impact and implications: This study reveals that infections significantly worsen the prognosis of patients with early alcohol-related liver disease (ALD), increasing the likelihood of decompensation and death by up to eight times. These findings, pertinent to healthcare providers, researchers, and policymakers, emphasize the importance of early prevention and management of infections in patients with ALD, even those in early stages who may be asymptomatic. It was observed that nearly one-third of patients with early-stage ALD developed infections over 4.5 years, with risk factors including alcohol overuse, smoking, and higher MELD scores. The research underscores the critical need to incorporate these insights into clinical practice and public health policies to improve patient outcomes and mitigate the impact of infections in patients with ALD.

Improving survival in alcohol-related hepatitis: what's new?

Alcohol-related hepatitis (AH) is the most florid presentation of alcohol-related liver disease and carries a high short-term and long-term mortality rate. Specific treatment options remain inadequate. The current management approach for AH focuses on early identification, careful screening and treatment of infection, as well as identification of those patients who may benefit from corticosteroid therapy based on validated prognostic scoring systems. In recent years, there has been growing interest in exploring novel therapies for AH, which may offer alternative treatment options beyond the traditional approaches. Additionally, early liver transplantation (LT) has emerged as a promising option in selected cases with growing evidence supporting its role. In this review, we will discuss the current evidence base for the assessment and treatment of AH, and how these advances are shaping practice to improve outcomes in the UK.

Protective effects of hepatic diseases by bioactive phytochemicals in Fusarium oxysporum - A review.

Lately, liver diseases were categorized as one of the most prevalent health problems globally as it causes a severe threat to mankind all over the world due to the wide range of occurrence. There are multiple factors causing hepatic disorders, such as alcohol, virus, poisons, adverse effects of drugs, poor diet, inherited conditions and obesity. Liver diseases have various types including alcoholic liver disease, non-alcoholic fatty liver disease, autoimmune hepatitis, liver cancer, hepatocellular carcinoma, liver fibrosis and hepatic inflammation. Therefore, it is imperative to find effective and efficacious agents in managing liver diseases. Fusarium oxysporum, an endophytic fungus and containing many bioactive compounds, could be served as a forked medication for enormous number and types of maladies. It was characterized by producing biochemical compounds which had rare pharmacological properties as it may be found in a limit number of other medicinal plants. The majority of the past researches related to Fusarium oxysporum recited the fungal negative field either on the pathogenic effects of the fungus on economical crops or on the fungal chemical components to know how to resist it. The present review will highlight on the bright side of Fusarium oxysporum and introduce the functional activities of its chemical compounds for treating its target diseases. The key point of illustrated studies in this article is displaying wide range of detected bioactive compounds isolated from Fusarium oxysporum and in other illustrated studies it was elucidated the therapeutical and pharmacological potency of these biologically active compounds (isolated from medicinal plants sources) against different types of liver diseases including non-alcoholic fatty liver disease, alcoholic liver disease, cirrhosis and others. It was demonstrated that F. oxysporum contains unique types of isoflavones, flavonoids, phenols and another active chemical compounds, and these compounds showed recently a fabulous clinical contribution in the therapy of liver injury diseases, which opens new and unprecedented way for evaluating the maintaining efficacy of Fusarium oxysporum bioactive compounds in dealing with hepatic complications and its remedy impacting on liver diseases and injured hepatocytes through recommending implement a practical study.

Sea Cucumber Polysaccharide from Stichopus japonicu and Its Photocatalytic Degradation Product Alleviate Acute Alcoholic Liver Injury in Mice.

To prevent alcoholic liver disease, the addition of bioactive substances to the alcoholic drink Baijiu has been considered a feasible option. In the present study, the hepatoprotective effects of a sea cucumber sulfated polysaccharide (SCSP) isolated from Stichopus japonicu were investigated. Moreover, in order to enhance its solubility in an alcohol solution, it was depolymerized using a photocatalytic reaction, and the photocatalytic degradation products (dSCSPs) with an average molecular weight of less than 2 kDa were studied and compared with SCSP. They were characterized by a series of chemical and spectroscopy methods and the oligosaccharide fragments in the dSCSP were further identified by HPLC-MSn analysis. Then, the in vivo experiment showed that the addition of SCSP or dSCSP to Baijiu could alleviate alcoholic liver injury in mice. Further analysis also revealed their protective effect in reducing oxidative stress damage and their regulation of the metabolism of phosphatidylcholine (PC) and phosphatidylethanolamine (PE) in the liver. Of note, dSCSP was more effective at reducing the level of malondialdehyde in the liver. These findings indicate that the addition of sea cucumber polysaccharide or its low-molecular-weight derivative in Baijiu has the potential to alleviate alcoholic liver injury.

Alcoholic Liver Disease/Nonalcoholic Fatty Liver Disease Index at Diagnosis Is Associated with All-Cause Mortality during Follow-Up in Patients with Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.

Background and Objectives: The purpose of this study was to investigate whether a new index related to chronic liver disease, the alcoholic liver disease/nonalcoholic fatty liver disease index (ANI) at diagnosis, is associated with all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: In this study, we included 270 patients with AAV. ANI was calculated using the following equation: ANI = -58.5 + 0.637 (adjusted mean corpuscular volume) + 3.91 (adjusted aspartate transaminase/alanine transaminase) - 0.406 (body mass index) + 6.35 (if male sex). All-cause mortality was defined as death from any cause during follow-up. Results: The median age of the 270 patients with AAV was 61.0 years (34.4% male and 66.6% female). The median ANI was significantly higher in deceased patients than in surviving patients. In the receiver operating characteristic curve analysis, ANI at diagnosis exhibited a statistically significant area under the curve for all-cause mortality during follow-up, and its cut-off was determined to be -0.59. Patients with ANI at diagnosis ≥ -0.59 exhibited a significantly higher risk for all-cause mortality and a significantly lower cumulative patient survival rate than those without. In the multivariable Cox analysis, ANI at diagnosis ≥ -0.59, together with age at diagnosis, was independently associated with all-cause mortality. Conclusions: This study is the first to demonstrate the predictive potential of ANI at diagnosis for all-cause mortality during follow-up in AAV patients without significant chronic liver diseases.

Hepatoprotective Effect of Allium ochotense Extracts on Chronic Alcohol-Induced Fatty Liver and Hepatic Inflammation in C57BL/6 Mice.

This study was performed to investigate the protective effects of Allium ochotense on fatty liver and hepatitis in chronic alcohol-induced hepatotoxicity. The physiological compounds of a mixture of aqueous and 60% ethanol (2:8, w/w) extracts of A. ochotense (EA) were identified as kestose, raffinose, kaempferol and quercetin glucoside, and kaempferol di-glucoside by UPLC Q-TOF MSE. The EA regulated the levels of lipid metabolism-related biomarkers such as total cholesterol, triglyceride, low-density lipoprotein (LDL), and high-density lipoprotein (HDL)-cholesterol in serum. Also, EA ameliorated the levels of liver toxicity-related biomarkers such as glutamic oxaloacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), and total bilirubin in serum. EA improved the antioxidant system by reducing malondialdehyde contents and increasing superoxide dismutase (SOD) levels and reduced glutathione content. EA improved the alcohol metabolizing enzymes such as alcohol dehydrogenase, acetaldehyde dehydrogenase, and cytochrome P450 2E1 (CYP2E1). Treatment with EA alleviated lipid accumulation-related protein expression by improving phosphorylation of AMP-activated protein kinase (p-AMPK) expression levels. Especially, EA reduced inflammatory response by regulating the toll-like receptor-4/nuclear factor kappa-light-chain-enhancer of activated B cells (TLR-4/NF-κB) signaling pathway. EA showed an anti-apoptotic effect by regulating the expression levels of B-cell lymphoma 2 (BCl-2), BCl-2-associated X protein (BAX), and caspase 3. Treatment with EA also ameliorated liver fibrosis via inhibition of transforming growth factor-beta 1/suppressor of mothers against decapentaplegic (TGF-ß1/Smad) pathway and alpha-smooth muscle actin (α-SMA). Therefore, these results suggest that EA might be a potential prophylactic agent for the treatment of alcoholic liver disease.

ERRγ-inducible FGF23 promotes alcoholic liver injury through enhancing CYP2E1 mediated hepatic oxidative stress.

Fibroblast growth factor 23 (FGF23) is a member of endocrine FGF family, along with FGF15/19 and FGF21. Recent reports showed that under pathological conditions, liver produces FGF23, although the role of hepatic FGF23 remains nebulous. Here, we investigated the role of hepatic FGF23 in alcoholic liver disease (ALD) and delineated the underlying molecular mechanism. FGF23 expression was compared in livers from alcoholic hepatitis patients and healthy controls. The role of FGF23 was examined in hepatocyte-specific knock-out (LKO) mice of cannabinoid receptor type 1 (CB1R), estrogen related receptor γ (ERRγ), or FGF23. Animals were fed with an alcohol-containing liquid diet alone or in combination with ERRγ inverse agonist. FGF23 is mainly expressed in hepatocytes in the human liver, and it is upregulated in ALD patients. In mice, chronic alcohol feeding leads to liver damage and induced FGF23 in liver, but not in other organs. FGF23 is transcriptionally regulated by ERRγ in response to alcohol-mediated activation of the CB1R. Alcohol induced upregulation of hepatic FGF23 and plasma FGF23 levels is lost in ERRγ-LKO mice, and an inverse agonist mediated inhibition of ERRγ transactivation significantly improved alcoholic liver damage. Moreover, hepatic CYP2E1 induction in response to alcohol is FGF23 dependent. In line, FGF23-LKO mice display decreased hepatic CYP2E1 expression and improved ALD through reduced hepatocyte apoptosis and oxidative stress. We recognized CBIR-ERRγ-FGF23 axis in facilitating ALD pathology through hepatic CYP2E1 induction. Thus, we propose FGF23 as a potential therapeutic target to treat ALD.

Identification of Francisella tularensis in ascites in the context of typhoidal tularaemia.

Tularaemia is a highly infectious, zoonotic disease caused by Francisella tularensis, which has become increasingly prevalent over the past decade. Depending on the route of infection, different clinical manifestations can be observed. We report a case of typhoidal tularaemia presenting as a febrile illness with gastrointestinal symptoms in a patient in her mid-80s. During the acute illness phase and in the context of alcohol-related liver cirrhosis, the patient developed progressive ascites. During paracentesis, spontaneous bacterial peritonitis was consistently reported. Blood culture revealed Gram-negative bacilli identified as F. tularensis upon microscopic examination. Immediate clinical improvement was observed after adaptation to a pathogen-specific antibiotic regime. Typhoidal tularaemia presents general, non-specific symptoms without the local manifestations seen in other forms of the disease, thus representing a diagnostic challenge. In the case of protracted fever and if the epidemiological context as well as possible exposure are compatible, tularaemia should be considered in the differential diagnosis.

Review article: Current indications and selection criteria for early liver transplantation in severe alcohol-associated hepatitis.

BACKGROUND: Alcohol-associated hepatitis (AH) is a severe inflammatory form of alcohol-associated liver disease (ALD) that carries a high mortality rate. Early liver transplantation for severe AH is increasingly available. However, specific criteria for referral and selection remain a subject of debate. AIMS: To provide a narrative review of the natural history, diagnostic criteria and indications for referral for early liver transplantation for severe AH. METHODS: We searched PubMed for articles published through August 2023. Key search terms were 'alcoholic hepatitis,' 'alcohol-associated hepatitis,' 'abstinence,' 'alcohol relapse,' and 'liver transplantation.' RESULTS: Previously, a six-month period of alcohol abstinence was required before patients with ALD were considered for liver transplantation. However, studies in recent years have demonstrated that, among carefully selected patients, patients who received early transplants have much higher survival rates than patients with similarly severe disease who did not undergo transplants (77% vs. 23%). Despite these successes, early liver transplantation remains controversial, as these patients have typically not undergone treatment for alcohol use disorder, with the ensuing risk of returning to alcohol use. CONCLUSIONS: While early liver transplantation for AH has survival benefits, many patients would not have received treatment for alcohol use disorder. An integrated approach to evaluating candidacy for early liver transplantation is needed.